SLC22A5

UniProt ID: O76082
Organism: Homo sapiens
Review Status: INITIALIZED
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Gene Description

SLC22A5 (OCTN2) is a plasma-membrane, sodium-dependent, high-affinity L-carnitine transporter of the SLC22 organic cation/carnitine transporter family (major facilitator superfamily). It couples the inward movement of one sodium ion to the uptake of one molecule of (R)-carnitine (Km in the low micromolar range), mediating cellular import of carnitine from blood and diet. This uptake is the essential first step that makes carnitine available for the mitochondrial carnitine shuttle (CPT1/CACT/CPT2) and hence for long-chain fatty-acid beta-oxidation, and OCTN2 also drives renal tubular reabsorption of filtered carnitine. Beyond carnitine it is polyspecific, transporting acyl-carnitines, glycine betaine, and diverse organic cations and cationic drugs (e.g. tetraethylammonium), the latter in a lower-affinity, sodium-independent manner. It is an integral multipass membrane protein expressed at the plasma membrane, apical/brush-border in absorptive and reabsorptive epithelia (kidney proximal tubule, intestine, placenta) and at the basal membrane of Sertoli cells. Loss-of-function variants cause systemic primary carnitine deficiency, an autosomal-recessive fatty-acid oxidation disorder presenting with hypoketotic hypoglycemia, cardiomyopathy and skeletal myopathy that is treatable with oral L-carnitine.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005886 plasma membrane
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetically-inferred plasma-membrane localization. OCTN2 is a well-established integral plasma-membrane transporter, directly demonstrated in multiple systems, so this IBA is correct and represents the site of action.
Reason: OCTN2 is an integral plasma-membrane, multipass transporter; extensive experimental evidence (below) confirms plasma-membrane localization and function.
Supporting Evidence:
PMID:33334877
The carnitine/organic cation transporter novel 2 (OCTN2) is responsible for the cellular uptake of carnitine in most tissues.
GO:0015697 quaternary ammonium group transport
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: Phylogenetic inference that OCTN2 is involved in quaternary ammonium group transport. Carnitine and many OCTN2 organic-cation substrates are quaternary ammonium compounds, so this is a correct family-level process term, though broader than the specific carnitine transport that is the core function.
Reason: Correct but general; OCTN2 does transport quaternary ammonium compounds (carnitine, TEA), but the informative core process is carnitine transmembrane transport. Retained as a valid broader process.
Supporting Evidence:
PMID:10454528
OCTN2 transports organic cations without involving Na(+), but it transports carnitine only in the presence of Na(+).
GO:0015651 quaternary ammonium group transmembrane transporter activity
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: Phylogenetically-inferred quaternary ammonium group transmembrane transporter activity. OCTN2 transports quaternary ammonium substrates (carnitine, TEA), so the activity is real, but it is broader than the specific carnitine transporter activity that defines the gene.
Reason: A valid but general molecular-function term for the family; the specific core MF is carnitine transmembrane transporter activity (GO:0015226).
Supporting Evidence:
PMID:10454528
novel organic cation transporter (OCTN) 2 is a transporter for organic cations as well as carnitine.
GO:0005524 ATP binding
IEA
GO_REF:0000002 		REMOVE
Summary: Electronic InterPro2GO mapping (IPR045915) assigning ATP binding. OCTN2 is a secondary active transporter that couples carnitine uptake to the sodium electrochemical gradient (Na+ symport); it is not an ATP-driven pump and there is no evidence it binds or hydrolyses ATP. This is a spurious domain-based inference.
Reason: OCTN2 is an MFS-family Na+-coupled symporter, not an ATP-binding/ATP-driven transporter. The InterPro-to-GO ATP-binding mapping is biologically incorrect for this protein; no experimental support exists.
Supporting Evidence:
PMID:10966938
hOCTN2 mediates electrogenic Na(+)-dependent stereoselective high-affinity transport of L-carnitine and Na(+).
GO:0005783 endoplasmic reticulum
IEA
GO_REF:0000044 		KEEP AS NON CORE
Summary: Electronic subcellular-location mapping to endoplasmic reticulum. ER localization applies only to the non-functional splice variant OCTN2VT (isoform 3), which is retained in the ER; the functional transporter is at the plasma membrane.
Reason: ER localization is real but pertains to the ER-retained, transport-dead isoform 3 (OCTN2VT); it is not the location of the functional carnitine transporter. Retained as a non-core, isoform-restricted annotation.
Supporting Evidence:
PMID:17509700
OCTN2VT was retained in the endoplasmic reticulum (ER) with poor N-glycosylation. In addition, the retention in the ER caused no carnitine uptake into the cells.
GO:0005886 plasma membrane
IEA
GO_REF:0000044 		ACCEPT
Summary: Electronic subcellular-location mapping to plasma membrane, consistent with the well-established localization of the functional transporter.
Reason: Correctly captures the plasma-membrane localization of OCTN2, confirmed experimentally.
Supporting Evidence:
PMID:33334877
OCTN2 must interact with the surrounding lipid microenvironment to function.
GO:0009925 basal plasma membrane
IEA
GO_REF:0000120 		KEEP AS NON CORE
Summary: Electronic annotation of basal plasma membrane localization. OCTN2 is predominantly apical/brush-border in most epithelia but is localized to the basal membrane of Sertoli cells, so a basal-membrane annotation is supportable in specific cell types.
Reason: Cell-type-specific basal localization (Sertoli cells) is documented; not the predominant (apical) localization, so kept as non-core.
Supporting Evidence:
PMID:35307651
OCTN2, multidrug resistance protein (MRP) 3, MRP6, and MRP7 localized to SC basal membranes and peritubular myoid cells (PMCs)
GO:0015199 amino-acid betaine transmembrane transporter activity
IEA
GO_REF:0000117 		KEEP AS NON CORE
Summary: Electronic (ARBA) annotation of amino-acid betaine transmembrane transporter activity. OCTN2 does transport glycine betaine, so this is correct; it is a secondary substrate rather than the core carnitine activity.
Reason: OCTN2-mediated betaine transport is experimentally documented; a genuine but non-core polyspecific activity.
Supporting Evidence:
PMID:10966938
hOCTN2 mediated transport of betaine.
GO:0015837 amine transport
IEA
GO_REF:0000117 		KEEP AS NON CORE
Summary: Electronic (ARBA) annotation to the broad process amine transport. OCTN2 transports amine-containing organic cations and carnitine, so this is correct but very general.
Reason: A correct but broad parent process; the specific process is carnitine transmembrane transport.
Supporting Evidence:
PMID:10454528
OCTN2 transports organic cations without involving Na(+)
GO:0015879 carnitine transport
IEA
GO_REF:0000002 		ACCEPT
Summary: Electronic InterPro2GO annotation to carnitine transport, matching the defining physiological role of OCTN2.
Reason: Carnitine transport is the core biological process of OCTN2, extensively documented experimentally.
Supporting Evidence:
PMID:9685390
OCTN2 is a physiologically important, high affinity sodium-carnitine cotransporter in humans.
GO:0016020 membrane
IEA
GO_REF:0000002 		KEEP AS NON CORE
Summary: Electronic InterPro annotation to the generic term membrane. Correct (OCTN2 is a multipass membrane protein) but uninformative relative to the specific plasma-membrane annotations.
Reason: Trivially correct generic location; superseded by the more specific plasma-membrane annotations.
Supporting Evidence:
PMID:17509700
OCTN2 was expressed on the plasma membrane with robust N-glycosylation
GO:0016324 apical plasma membrane
IEA
GO_REF:0000120 		ACCEPT
Summary: Electronic annotation of apical plasma membrane localization, consistent with the polarized apical/brush-border localization of OCTN2 in epithelia.
Reason: Apical localization is directly documented in kidney, intestine, placenta and ocular epithelia; correct.
Supporting Evidence:
PMID:17274673
an apical membrane expression pattern of OCTN2 in Caki-1 cells was discovered.
GO:0022857 transmembrane transporter activity
IEA
GO_REF:0000002 		KEEP AS NON CORE
Summary: Electronic InterPro annotation to the root transmembrane transporter activity term. Correct but maximally general.
Reason: Trivially correct high-level MF; the informative MF is carnitine transmembrane transporter activity.
Supporting Evidence:
PMID:9685390
OCTN2 is a physiologically important, high affinity sodium-carnitine cotransporter in humans.
GO:0030165 PDZ domain binding
IEA
GO_REF:0000117 		KEEP AS NON CORE
Summary: Electronic (ARBA) annotation of PDZ domain binding. OCTN2 has a C-terminal PDZ-binding motif that binds the PDZ protein PDZK1, which regulates its transport activity; this is experimentally confirmed (see PMID:15523054 IPI annotation below).
Reason: PDZ-domain binding (via the C-terminal motif, to PDZK1) is real and functionally relevant to OCTN2 regulation, but is an accessory regulatory interaction rather than the transporter's core function.
Supporting Evidence:
PMID:15523054
a requirement of the last four amino acids in OCTN1 and OCTN2 for the interaction
GO:0055085 transmembrane transport
IEA
GO_REF:0000002 		KEEP AS NON CORE
Summary: Electronic InterPro annotation to the broad process transmembrane transport. Correct but general.
Reason: Correct high-level process; superseded by carnitine transmembrane transport.
Supporting Evidence:
PMID:9685390
uptake of L-[3H]carnitine was strongly enhanced in a sodium-dependent manner
GO:0005515 protein binding
IPI
PMID:28514442
Architecture of the human interactome defines protein commun... 		MARK AS OVER ANNOTATED
Summary: High-throughput interactome (HuRI/CCSB) interaction, here with HMGCS1. Bare protein binding is uninformative about molecular function and this HT-derived binary interaction has no independent functional validation for OCTN2.
Reason: Generic protein binding from a proteome-scale interactome screen; provides no functional insight and the specific interaction (HMGCS1) is not biologically characterized for OCTN2. Per curation guidelines, bare protein binding is not retained as informative.
Supporting Evidence:
PMID:28514442
Architecture of the human interactome defines protein communities and disease networks
GO:0005515 protein binding
IPI
PMID:32296183
A reference map of the human binary protein interactome. 		MARK AS OVER ANNOTATED
Summary: High-throughput binary interactome (HuRI) interactions (with keratins KRT34, KRTAP6-3, MTUS2, NOTCH2NLC and others). Bare protein binding from a large-scale Y2H map, uninformative about OCTN2 molecular function.
Reason: Generic protein binding from a proteome-scale interactome map; keratin/keratin- associated-protein partners are common Y2H artifacts and are not biologically validated for OCTN2. Not informative of function.
Supporting Evidence:
PMID:32296183
A reference map of the human binary protein interactome
GO:0005515 protein binding
IPI
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling... 		MARK AS OVER ANNOTATED
Summary: High-throughput proteome-scale interactome (BioPlex) interaction, here with HMGCS1. Bare protein binding, uninformative about molecular function.
Reason: Generic protein binding from a proteome-scale affinity-purification map; no functional characterization for OCTN2. Not retained as informative.
Supporting Evidence:
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome
GO:0015837 amine transport
TAS
Reactome:R-HSA-549127 		KEEP AS NON CORE
Summary: Reactome-asserted involvement in the broad process amine transport (SLC-mediated transport of organic cations). Correct but general; the specific OCTN2 process is carnitine transmembrane transport.
Reason: Reactome pathway assertion for a general amine/organic-cation transport process; correct but broader than the specific carnitine function.
Supporting Evidence:
PMID:10454528
OCTN2 transports organic cations without involving Na(+)
GO:1902603 carnitine transmembrane transport
TAS
Reactome:R-HSA-165026 		ACCEPT
Summary: Reactome-asserted involvement in carnitine transmembrane transport (OCTN2 transports carnitine from extracellular space to cytosol). This is the core biological process of OCTN2.
Reason: Directly captures the defining process; supported by Reactome and by extensive experimental evidence.
Supporting Evidence:
PMID:9685390
uptake of L-[3H]carnitine was strongly enhanced in a sodium-dependent manner
GO:0015226 carnitine transmembrane transporter activity
IDA
PMID:15238359
L-Carnitine transport in human placental brush-border membra... 		ACCEPT
Summary: Direct assay of OCTN2-mediated Na+-dependent, high-affinity L-carnitine transport in human placental brush-border membranes. This is the core molecular function of OCTN2.
Reason: Experimentally demonstrated carnitine transmembrane transporter activity; core molecular function.
Supporting Evidence:
PMID:15238359
OCTN2, a high-affinity, Na(+)-dependent carnitine transporter, was present in placental BBM
GO:1902603 carnitine transmembrane transport
IDA
PMID:15238359
L-Carnitine transport in human placental brush-border membra... 		ACCEPT
Summary: Direct evidence that OCTN2 mediates L-carnitine transport across the placental brush-border membrane. Core biological process.
Reason: Experimentally demonstrated carnitine transmembrane transport; core process.
Supporting Evidence:
PMID:15238359
l-carnitine uptake was sodium and temperature dependent, showed high affinity for carnitine
GO:0015226 carnitine transmembrane transporter activity
IDA
PMID:15523054
PDZK1 directly regulates the function of organic cation/carn... 		ACCEPT
Summary: OCTN2-mediated carnitine uptake measured directly (and shown to be stimulated ~6-fold by PDZK1 co-expression). Confirms carnitine transporter activity.
Reason: Direct assay of OCTN2 carnitine transport activity; core molecular function.
Supporting Evidence:
PMID:15523054
double transfection of OCTN2 with PDZK1 stimulated the uptake by OCTN2 of its endogenous substrate carnitine
GO:1902603 carnitine transmembrane transport
IDA
PMID:15523054
PDZK1 directly regulates the function of organic cation/carn... 		ACCEPT
Summary: Direct evidence of OCTN2-mediated carnitine transport (endogenous substrate carnitine), core biological process.
Reason: Experimentally demonstrated carnitine transmembrane transport; core process.
Supporting Evidence:
PMID:15523054
the uptake by OCTN2 of its endogenous substrate carnitine
GO:0005783 endoplasmic reticulum
EXP
PMID:17509700
OCTN2VT, a splice variant of OCTN2, does not transport carni... 		KEEP AS NON CORE
Summary: Experimental demonstration of ER localization for the OCTN2VT splice variant (isoform 3), which is ER-retained and unable to transport carnitine. This is an isoform-specific, non-functional location.
Reason: ER localization is genuine but restricted to the transport-dead isoform 3 (OCTN2VT); it does not describe the functional transporter's location. Kept as isoform-specific non-core.
Supporting Evidence:
PMID:17509700
OCTN2VT was retained in the endoplasmic reticulum (ER) with poor N-glycosylation.
GO:0005886 plasma membrane
EXP
PMID:33334877
Cholesterol stimulates the cellular uptake of L-carnitine by... 		ACCEPT
Summary: Experimental plasma-membrane localization of functional OCTN2 (HEK293 cells overexpressing OCTN2; cholesterol modulation studies). Core localization.
Reason: Directly documented plasma-membrane localization of the active transporter.
Supporting Evidence:
PMID:33334877
how plasma membrane cholesterol modulates OCTN2 transport of L-carnitine
GO:0016324 apical plasma membrane
EXP
PMID:10966938
Functional and pharmacological characterization of human Na(... 		ACCEPT
Summary: Functional/pharmacological characterization of hOCTN2 as an electrogenic Na+-carnitine cotransporter; UniProt records apical cell-membrane localization from this work. Apical localization is well-supported across epithelia.
Reason: Apical plasma-membrane localization of OCTN2 is documented here and in multiple epithelial systems; correct.
Supporting Evidence:
PMID:10966938
hOCTN2 mediates electrogenic Na(+)-dependent stereoselective high-affinity transport of L-carnitine and Na(+).
GO:0015199 amino-acid betaine transmembrane transporter activity
IDA
PMID:33124720
Deorphaning a solute carrier 22 family member, SLC22A15, thr... 		KEEP AS NON CORE
Summary: OCTN2 is used here as a reference zwitterion transporter and its betaine/dimethylglycine transport is noted; UniProt records betaine and N,N-dimethylglycine as OCTN2 substrates. Betaine transport by OCTN2 was demonstrated experimentally in PMID:10966938.
Reason: OCTN2-mediated betaine (and dimethylglycine) transport is a genuine but secondary polyspecific activity; not the core carnitine function.
Supporting Evidence:
PMID:33124720
Dimethylglycine, known to interact with SLC22A5
PMID:10966938
hOCTN2 mediated transport of betaine.
GO:0034341 response to type II interferon
IDA
PMID:20722056
Cytokine regulation of OCTN2 expression and activity in smal... 		KEEP AS NON CORE
Summary: Intestinal OCTN2 expression and Na+-dependent carnitine uptake activity are increased by IFN-gamma. This is a regulatory response (OCTN2 is induced by the cytokine), not a core transporter function.
Reason: OCTN2 responds to (is induced by) IFN-gamma in intestine; a genuine but peripheral/regulatory biological process rather than the transporter's core function.
Supporting Evidence:
PMID:20722056
IFN-γ increased both total and apical membrane expression of Caco2BBE OCTN2
GO:0034612 response to tumor necrosis factor
IDA
PMID:20722056
Cytokine regulation of OCTN2 expression and activity in smal... 		KEEP AS NON CORE
Summary: Intestinal OCTN2 apical membrane expression and carnitine uptake are increased by TNF-alpha. A regulatory/response process, not core transport function.
Reason: OCTN2 responds to (is regulated by) TNF; peripheral regulatory process.
Supporting Evidence:
PMID:20722056
TNF-α stimulated apical expression
GO:1900749 (R)-carnitine transport
IDA
PMID:20722056
Cytokine regulation of OCTN2 expression and activity in smal... 		ACCEPT
Summary: Na+-dependent 3H-carnitine uptake by OCTN2 measured directly in intestinal epithelial cells (siRNA-confirmed as OCTN2-dependent). Core carnitine transport process.
Reason: Directly demonstrated OCTN2-mediated (R)-carnitine transport; core process.
Supporting Evidence:
PMID:20722056
more than 80% of Na+-dependent carnitine uptake is due to OCTN2 in Caco2BBE cells
GO:1901235 (R)-carnitine transmembrane transporter activity
IDA
PMID:20722056
Cytokine regulation of OCTN2 expression and activity in smal... 		ACCEPT
Summary: OCTN2-mediated Na+-dependent (R)-carnitine transporter activity demonstrated directly (siRNA knockdown abolishes >80% of Na+-dependent uptake). Core molecular function at the specific substrate level.
Reason: Direct evidence of (R)-carnitine transmembrane transporter activity; core molecular function.
Supporting Evidence:
PMID:20722056
The Na+-dependent 3H-carnitine uptake in cells treated with OCTN2 siRNA was reduced from 0.88 ± 0.10 to 0.16 ± 0.06
GO:0009925 basal plasma membrane
IDA
PMID:35307651
Localization of Xenobiotic Transporters Expressed at the Hum... 		KEEP AS NON CORE
Summary: Immunohistological localization of OCTN2 to Sertoli-cell basal membranes and peritubular myoid cells at the human blood-testis barrier. Cell-type-specific basal localization.
Reason: Documented basal-membrane localization in specific testicular cell types; not the predominant apical localization, so non-core.
Supporting Evidence:
PMID:35307651
OCTN2, multidrug resistance protein (MRP) 3, MRP6, and MRP7 localized to SC basal membranes and peritubular myoid cells (PMCs)
GO:0005886 plasma membrane
IDA
PMID:17509700
OCTN2VT, a splice variant of OCTN2, does not transport carni... 		ACCEPT
Summary: Functional OCTN2 shown at the plasma membrane (with robust N-glycosylation), contrasted with the ER-retained OCTN2VT variant. Core localization.
Reason: Direct plasma-membrane localization of the functional transporter.
Supporting Evidence:
PMID:17509700
OCTN2 was expressed on the plasma membrane with robust N-glycosylation
GO:0016324 apical plasma membrane
IDA
PMID:18005709
The Bacillus subtilis quorum-sensing molecule CSF contribute... 		ACCEPT
Summary: OCTN2 identified as an apical membrane organic cation transporter in intestinal epithelial cells, mediating uptake of the bacterial CSF pentapeptide. Apical localization is the site of action in absorptive epithelia.
Reason: Apical plasma-membrane site of action directly demonstrated in intestinal epithelia.
Supporting Evidence:
PMID:18005709
These effects of CSF depend on its uptake by an apical membrane organic cation transporter-2 (OCTN2).
GO:0016324 apical plasma membrane
IDA
PMID:20722056
Cytokine regulation of OCTN2 expression and activity in smal... 		ACCEPT
Summary: OCTN2 localized to the apical (brush-border) membrane of intestinal epithelial cells by immunohistochemistry and surface biotinylation. Core polarized localization.
Reason: Directly documented apical plasma-membrane localization in intestine.
Supporting Evidence:
PMID:20722056
OCTN2 was highly expressed in the brush border (apical membrane) and subapical region of epithelial cells
GO:0022857 transmembrane transporter activity
IDA
PMID:18005709
The Bacillus subtilis quorum-sensing molecule CSF contribute... 		KEEP AS NON CORE
Summary: OCTN2 demonstrated to transport the bacterial CSF pentapeptide across the apical membrane. This supports transmembrane transporter activity, though the annotation uses the maximally general MF term.
Reason: Correct but general MF; the specific informative MF is carnitine transmembrane transporter activity. Retained as a valid broader term.
Supporting Evidence:
PMID:18005709
OCTN2-mediated CSF transport serves as an example of a host-bacterial interaction
GO:0070715 sodium-dependent organic cation transport
IDA
PMID:18005709
The Bacillus subtilis quorum-sensing molecule CSF contribute... 		KEEP AS NON CORE
Summary: OCTN2-mediated apical uptake of the cationic bacterial pentapeptide CSF; UniProt records this as a Na+-coupled transport reaction. Supports Na+-dependent organic cation (peptide) transport.
Reason: A genuine polyspecific Na+-dependent organic-cation transport activity (CSF peptide), distinct from the core carnitine function; retained as non-core.
Supporting Evidence:
PMID:18005709
These effects of CSF depend on its uptake by an apical membrane organic cation transporter-2 (OCTN2).
GO:1900749 (R)-carnitine transport
IDA
PMID:17509700
OCTN2VT, a splice variant of OCTN2, does not transport carni... 		ACCEPT
Summary: OCTN2 shown to be indispensable for carnitine transport across the plasma membrane (the functional variant transports carnitine, the ER-retained variant does not). Core carnitine transport process.
Reason: Direct evidence for OCTN2-mediated (R)-carnitine transport; core process.
Supporting Evidence:
PMID:17509700
A novel organic cation transporter OCTN2 is indispensable for carnitine transport across plasma membrane
GO:1900749 (R)-carnitine transport
IDA
PMID:33334877
Cholesterol stimulates the cellular uptake of L-carnitine by... 		ACCEPT
Summary: OCTN2 responsible for cellular uptake of carnitine; carnitine transport measured directly in OCTN2-overexpressing cells (and shown to be cholesterol- dependent). Core carnitine transport process.
Reason: Direct evidence for OCTN2-mediated carnitine uptake; core process.
Supporting Evidence:
PMID:33334877
The carnitine/organic cation transporter novel 2 (OCTN2) is responsible for the cellular uptake of carnitine in most tissues.
GO:1901235 (R)-carnitine transmembrane transporter activity
IDA
PMID:17509700
OCTN2VT, a splice variant of OCTN2, does not transport carni... 		ACCEPT
Summary: OCTN2 (functional isoform) transports carnitine across the plasma membrane; the ER-retained OCTN2VT does not, confirming that plasma-membrane OCTN2 is the carnitine transporter. Core molecular function.
Reason: Direct evidence for (R)-carnitine transmembrane transporter activity; core molecular function.
Supporting Evidence:
PMID:17509700
the retention in the ER caused no carnitine uptake into the cells
GO:1901235 (R)-carnitine transmembrane transporter activity
IDA
PMID:33334877
Cholesterol stimulates the cellular uptake of L-carnitine by... 		ACCEPT
Summary: Direct carnitine transport assays in OCTN2-overexpressing HEK293 cells establish OCTN2 (R)-carnitine transporter activity (modulated by membrane cholesterol). Core molecular function.
Reason: Direct evidence for (R)-carnitine transmembrane transporter activity; core molecular function.
Supporting Evidence:
PMID:33334877
how plasma membrane cholesterol modulates OCTN2 transport of L-carnitine
GO:0015226 carnitine transmembrane transporter activity
IDA
PMID:10454528
Functional characteristics and tissue distribution pattern o... 		ACCEPT
Summary: Functional characterization establishing OCTN2 as a Na+-dependent carnitine transporter (and Na+-independent organic cation transporter). Core molecular function.
Reason: Direct experimental demonstration of carnitine transmembrane transporter activity; core molecular function.
Supporting Evidence:
PMID:10454528
it transports carnitine only in the presence of Na(+)
GO:0015226 carnitine transmembrane transporter activity
IDA
PMID:10966938
Functional and pharmacological characterization of human Na(... 		ACCEPT
Summary: Electrophysiological and flux characterization of hOCTN2 as an electrogenic Na+-carnitine cotransporter (Km ~4.8 uM). Core molecular function.
Reason: Direct evidence for high-affinity carnitine transmembrane transporter activity; core molecular function.
Supporting Evidence:
PMID:10966938
hOCTN2 mediates electrogenic Na(+)-dependent stereoselective high-affinity transport of L-carnitine and Na(+).
GO:0015226 carnitine transmembrane transporter activity
IDA
PMID:17855766
Transport of butyryl-L-carnitine, a potential prodrug, via t... 		ACCEPT
Summary: OCTN2 transports L-carnitine and its butyryl ester (butyryl-L-carnitine) as a high-affinity transporter. Confirms carnitine transporter activity.
Reason: Direct evidence of OCTN2 carnitine (and acyl-carnitine) transport activity; core molecular function.
Supporting Evidence:
PMID:17855766
OCTN2 is a high-affinity/low-capacity transporter
GO:0015651 quaternary ammonium group transmembrane transporter activity
IMP
PMID:10454528
Functional characteristics and tissue distribution pattern o... 		KEEP AS NON CORE
Summary: OCTN2 transports quaternary ammonium substrates (carnitine, organic cations); loss-of-function mutants (M352R, P478L) abolish transport. Correct family-level MF, broader than the specific carnitine activity.
Reason: A correct but general quaternary ammonium transporter activity; the specific core MF is carnitine transmembrane transporter activity.
Supporting Evidence:
PMID:10454528
Two mutations, M352R and P478L, in human OCTN2 are associated with loss of transport function
GO:0015651 quaternary ammonium group transmembrane transporter activity
IMP
PMID:10966938
Functional and pharmacological characterization of human Na(... 		KEEP AS NON CORE
Summary: hOCTN2 transports carnitine and betaine (quaternary ammonium compounds); shows only small currents with classic OCT substrates. Correct but general MF.
Reason: Correct family-level quaternary-ammonium MF; superseded by the specific carnitine transporter activity as the core function.
Supporting Evidence:
PMID:10966938
hOCTN2 mediated transport of betaine.
GO:0015697 quaternary ammonium group transport
IMP
PMID:10454528
Functional characteristics and tissue distribution pattern o... 		KEEP AS NON CORE
Summary: OCTN2 mediates transport of quaternary ammonium compounds (carnitine and organic cations); mutation studies confirm transport function. Correct but broad process.
Reason: Correct but general process; the specific process is carnitine transmembrane transport.
Supporting Evidence:
PMID:10454528
OCTN2 transports organic cations without involving Na(+)
GO:0015697 quaternary ammonium group transport
IMP
PMID:10966938
Functional and pharmacological characterization of human Na(... 		KEEP AS NON CORE
Summary: hOCTN2 transports the quaternary ammonium compounds carnitine and betaine. Correct but broad process term.
Reason: Correct general process; superseded by carnitine transmembrane transport.
Supporting Evidence:
PMID:10966938
hOCTN2 mediated transport of betaine.
GO:1902270 (R)-carnitine transmembrane transport
IDA
PMID:10454528
Functional characteristics and tissue distribution pattern o... 		ACCEPT
Summary: Direct demonstration that OCTN2 transports carnitine (Na+-dependently) across the membrane. Core carnitine transport process at the specific substrate level.
Reason: Direct evidence for (R)-carnitine transmembrane transport; core process.
Supporting Evidence:
PMID:10454528
it transports carnitine only in the presence of Na(+)
GO:1902270 (R)-carnitine transmembrane transport
IDA
PMID:10966938
Functional and pharmacological characterization of human Na(... 		ACCEPT
Summary: Electrogenic Na+-dependent L-carnitine transport by hOCTN2 characterized by voltage clamp/flux. Core carnitine transport process.
Reason: Direct evidence for (R)-carnitine transmembrane transport; core process.
Supporting Evidence:
PMID:10966938
L-carnitine transport was electrogenic.
GO:1902270 (R)-carnitine transmembrane transport
IDA
PMID:17855766
Transport of butyryl-L-carnitine, a potential prodrug, via t... 		ACCEPT
Summary: OCTN2 transports L-carnitine (and butyryl-L-carnitine) in an electrogenic, Na+-dependent manner. Core carnitine transport process.
Reason: Direct evidence for (R)-carnitine transmembrane transport; core process.
Supporting Evidence:
PMID:17855766
Transport of BC via OCTN2 is electrogenic
GO:1901235 (R)-carnitine transmembrane transporter activity
IMP
PMID:23877104
Functional expression of organic cation/carnitine transporte... 		ACCEPT
Summary: OCTN2 gene silencing dramatically suppresses Na+-dependent L-carnitine uptake in human brain capillary endothelial cells, demonstrating OCTN2 (R)-carnitine transporter activity. Core molecular function.
Reason: siRNA knockdown directly implicates OCTN2 in (R)-carnitine transporter activity; core molecular function.
Supporting Evidence:
PMID:23877104
[(3)H]L-Carnitine uptake was dramatically suppressed by silencing of the OCTN2 gene.
GO:0005737 cytoplasm
ISS
GO_REF:0000024 		REMOVE
Summary: Sequence-similarity transfer (from mouse Octn2, O70594) of a cytoplasm annotation. OCTN2 is an integral multipass plasma-membrane transporter; a bulk cytoplasm localization does not describe its functional location and is a likely mislocalization/over-annotation.
Reason: OCTN2 is an integral membrane protein resident in the plasma membrane (and ER for the non-functional isoform); a generic cytoplasm location is not supported and is misleading. This ISS is an over-annotation.
Supporting Evidence:
PMID:17509700
OCTN2 was expressed on the plasma membrane with robust N-glycosylation
GO:1901235 (R)-carnitine transmembrane transporter activity
ISS
GO_REF:0000024 		ACCEPT
Summary: Sequence-similarity transfer (from mouse Octn2) of (R)-carnitine transporter activity. Consistent with the directly demonstrated human OCTN2 function.
Reason: ISS from mouse ortholog matches the extensive direct human evidence for (R)-carnitine transmembrane transporter activity; core molecular function.
Supporting Evidence:
PMID:10966938
high-affinity transport of L-carnitine and Na(+).
GO:1902270 (R)-carnitine transmembrane transport
ISS
GO_REF:0000024 		ACCEPT
Summary: Sequence-similarity transfer (from mouse Octn2) of (R)-carnitine transmembrane transport. Consistent with the directly demonstrated human process.
Reason: ISS matches abundant direct human evidence for (R)-carnitine transmembrane transport; core process.
Supporting Evidence:
PMID:10454528
it transports carnitine only in the presence of Na(+)
GO:0015226 carnitine transmembrane transporter activity
EXP
PMID:9685390
Molecular and functional identification of sodium ion-depend... 		ACCEPT
Summary: Original molecular/functional identification of OCTN2 as a high-affinity, Na+-dependent carnitine transporter (Km 4.34 uM). Foundational evidence for the core molecular function.
Reason: Direct experimental identification of OCTN2 carnitine transporter activity; core molecular function.
Supporting Evidence:
PMID:9685390
uptake of L-[3H]carnitine was strongly enhanced in a sodium-dependent manner with Km value of 4.34 microM
GO:0015226 carnitine transmembrane transporter activity
TAS
Reactome:R-HSA-549297 		ACCEPT
Summary: Reactome assertion that SLC22A5 (with SLC22A4/15/16) cotransports carnitine and Na+ from extracellular region to cytosol. Core molecular function.
Reason: Reactome pathway assertion matching the well-established core carnitine transporter activity.
Supporting Evidence:
PMID:9685390
OCTN2 is a physiologically important, high affinity sodium-carnitine cotransporter in humans.
GO:0015226 carnitine transmembrane transporter activity
TAS
Reactome:R-HSA-5625674 		ACCEPT
Summary: Reactome assertion (defective SLC22A5 does not cotransport carnitine/Na+) referencing the normal carnitine transporter activity of OCTN2. Core molecular function.
Reason: Reactome pathway assertion consistent with the established core carnitine transporter activity (and its loss in disease).
Supporting Evidence:
PMID:9916797
loss of OCTN2 function causes SCD
GO:0005829 cytosol
ISS
GO_REF:0000024 		REMOVE
Summary: Sequence-similarity transfer (from mouse Octn2) of a cytosol annotation. As with the cytoplasm annotation, OCTN2 is an integral plasma-membrane protein; a cytosol localization is not supported.
Reason: OCTN2 is an integral membrane transporter, not a cytosolic/soluble protein; the ISS cytosol annotation is a mislocalization/over-annotation.
Supporting Evidence:
PMID:17509700
OCTN2 was expressed on the plasma membrane with robust N-glycosylation
GO:0005886 plasma membrane
ISS
GO_REF:0000024 		ACCEPT
Summary: Sequence-similarity transfer (from mouse Octn2) of plasma-membrane localization, consistent with the direct human evidence. Core localization.
Reason: ISS matches abundant direct evidence for plasma-membrane localization of OCTN2.
Supporting Evidence:
PMID:33334877
OCTN2 must interact with the surrounding lipid microenvironment to function.
GO:0150104 transport across blood-brain barrier
ISS
GO_REF:0000024 		KEEP AS NON CORE
Summary: Sequence-similarity transfer (from rat Octn2, Q9Z0E8) of a role in transport across the blood-brain barrier. OCTN2 is functionally expressed at the human BBB and mediates L-carnitine uptake there (confirmed by siRNA in PMID:23877104).
Reason: OCTN2 contributes to carnitine transport at the blood-brain barrier, a tissue-specific manifestation of its core carnitine transport function rather than a distinct core process.
Supporting Evidence:
PMID:23877104
OCTN2 is involved in L-carnitine transport at the human BBB.
GO:1902270 (R)-carnitine transmembrane transport
IMP
PMID:23877104
Functional expression of organic cation/carnitine transporte... 		ACCEPT
Summary: OCTN2 gene silencing suppresses Na+-dependent L-carnitine uptake in human brain endothelial cells, implicating OCTN2 in (R)-carnitine transmembrane transport. Core carnitine transport process.
Reason: siRNA knockdown directly implicates OCTN2 in (R)-carnitine transmembrane transport; core process.
Supporting Evidence:
PMID:23877104
[(3)H]L-Carnitine uptake was dramatically suppressed by silencing of the OCTN2 gene.
GO:0015651 quaternary ammonium group transmembrane transporter activity
IDA
PMID:23567998
Transport of gabapentin by LAT1 (SLC7A5). 		UNDECIDED
Summary: This paper concerns gabapentin transport by LAT1 (SLC7A5) at the blood-brain barrier; its abstract characterizes LAT1 and reports that gabapentin was negative for OCT-like transport. The cached abstract does not document an OCTN2/quaternary-ammonium transport assay, and the full text is unavailable, so the basis of the ARUK-UCL IDA annotation to OCTN2 cannot be verified from the cache.
Reason: Cannot verify the OCTN2-specific supporting evidence from the abstract-only cache (the paper foregrounds LAT1); per curation policy, an experimental annotation whose full text I cannot read is left UNDECIDED rather than removed.
Supporting Evidence:
PMID:23567998
Gabapentin was negative for OCT like transport and LAT2 activity
GO:0015697 quaternary ammonium group transport
IDA
PMID:23567998
Transport of gabapentin by LAT1 (SLC7A5). 		UNDECIDED
Summary: As above (PMID:23567998, gabapentin/LAT1). The cached abstract does not document an OCTN2 quaternary-ammonium transport assay; full text unavailable.
Reason: The OCTN2-specific evidence cannot be verified from the abstract-only cache; left UNDECIDED rather than removed per policy on experimental annotations.
Supporting Evidence:
PMID:23567998
Gabapentin was negative for OCT like transport and LAT2 activity
GO:0150104 transport across blood-brain barrier
NAS
PMID:30280653
Blood-Brain Barrier: From Physiology to Disease and Back. 		KEEP AS NON CORE
Summary: Non-traceable author-statement annotation citing a general blood-brain- barrier review. The specific functional evidence for OCTN2 at the BBB comes from the experimental PMID:23877104; this NAS from a review is weak support.
Reason: A weak (NAS, from a review) restatement of OCTN2's tissue-specific BBB carnitine-transport role; kept as non-core, with the experimental evidence provided by PMID:23877104.
Supporting Evidence:
PMID:23877104
OCTN2 is involved in L-carnitine transport at the human BBB.
GO:0150104 transport across blood-brain barrier
NAS
PMID:26590417
Establishment and Dysfunction of the Blood-Brain Barrier. 		KEEP AS NON CORE
Summary: Non-traceable author-statement annotation citing a general blood-brain- barrier review. Weak support; the functional OCTN2 BBB evidence is experimental (PMID:23877104).
Reason: Weak (NAS, review-based) restatement of the tissue-specific BBB carnitine- transport role; non-core.
Supporting Evidence:
PMID:23877104
OCTN2 is involved in L-carnitine transport at the human BBB.
GO:0009609 response to symbiotic bacterium
IMP
PMID:18005709
The Bacillus subtilis quorum-sensing molecule CSF contribute... 		KEEP AS NON CORE
Summary: OCTN2-dependent uptake of the Bacillus subtilis quorum-sensing peptide CSF in intestinal epithelia links the transporter to host responses to commensal bacteria. A downstream, tissue-specific biology of OCTN2's cationic- peptide transport, not a core transporter function.
Reason: Genuine but peripheral role (mediating uptake of a bacterial signaling peptide) downstream of OCTN2's transport activity; non-core.
Supporting Evidence:
PMID:18005709
OCTN2-mediated CSF transport serves as an example of a host-bacterial interaction that allows the host to monitor and respond to changes in the behavior or composition of colonic flora.
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-5625674 		ACCEPT
Summary: Reactome-asserted plasma-membrane localization of SLC22A5. Consistent with the established core localization.
Reason: Reactome pathway assertion matching well-established plasma-membrane localization.
Supporting Evidence:
PMID:17509700
OCTN2 was expressed on the plasma membrane with robust N-glycosylation
GO:0070062 extracellular exosome
HDA
PMID:19056867
Large-scale proteomics and phosphoproteomics of urinary exos... 		MARK AS OVER ANNOTATED
Summary: High-throughput proteomic detection of OCTN2 among proteins in human urinary exosomes. Incidental proteomic co-purification (renal epithelial membrane proteins are commonly recovered in urinary exosomes); not a functional subcellular location.
Reason: Exosome detection is a mass-spectrometry co-occurrence consistent with shedding of apical renal membrane proteins; it does not indicate a functional exosomal role and over-annotates the localization.
Supporting Evidence:
PMID:19056867
Normal human urine contains large numbers of exosomes
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-165026 		ACCEPT
Summary: Reactome-asserted plasma-membrane localization of SLC22A5 (in the carnitine transport reaction). Consistent with core localization.
Reason: Reactome assertion matching established plasma-membrane localization.
Supporting Evidence:
PMID:33334877
OCTN2 must interact with the surrounding lipid microenvironment to function.
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-549297 		ACCEPT
Summary: Reactome-asserted plasma-membrane localization of SLC22A5 (in the carnitine/Na+ cotransport reaction). Consistent with core localization.
Reason: Reactome assertion matching established plasma-membrane localization.
Supporting Evidence:
PMID:17509700
OCTN2 was expressed on the plasma membrane with robust N-glycosylation
GO:0060731 positive regulation of intestinal epithelial structure maintenance
IMP
PMID:18005709
The Bacillus subtilis quorum-sensing molecule CSF contribute... 		KEEP AS NON CORE
Summary: OCTN2-mediated uptake of the bacterial CSF peptide induces cytoprotective heat shock proteins that prevent oxidant-induced intestinal epithelial injury and loss of barrier function, linking OCTN2 to intestinal homeostasis. A downstream, tissue-specific process rather than a core transporter function.
Reason: Genuine but peripheral physiological consequence of OCTN2 cationic-peptide transport in the intestine; non-core.
Supporting Evidence:
PMID:18005709
CSF also induces cytoprotective heat shock proteins (Hsps), which prevent oxidant-induced intestinal epithelial cell injury and loss of barrier function.
GO:0070715 sodium-dependent organic cation transport
IDA
PMID:15238359
L-Carnitine transport in human placental brush-border membra... 		ACCEPT
Summary: OCTN2-mediated Na+-dependent, high-affinity L-carnitine uptake in placental brush-border membranes. Carnitine is a zwitterionic organic cation; this Na+-dependent organic-cation transport is essentially the core carnitine uptake function.
Reason: Directly demonstrated Na+-dependent organic-cation (carnitine) transport by OCTN2; reflects the core function.
Supporting Evidence:
PMID:15238359
l-carnitine uptake was sodium and temperature dependent
GO:0070715 sodium-dependent organic cation transport
IDA
PMID:9685390
Molecular and functional identification of sodium ion-depend... 		ACCEPT
Summary: OCTN2 characterized as a sodium-dependent high-affinity carnitine (zwitterionic organic cation) transporter. Reflects the core Na+-coupled transport mechanism.
Reason: Directly demonstrated Na+-dependent organic-cation (carnitine) transport; reflects the core function/mechanism.
Supporting Evidence:
PMID:9685390
OCTN2 is a physiologically important, high affinity sodium-carnitine cotransporter in humans.
GO:0005515 protein binding
IPI
PMID:15523054
PDZK1 directly regulates the function of organic cation/carn... 		MARK AS OVER ANNOTATED
Summary: OCTN2 binds the PDZ scaffolding protein PDZK1 (interaction data). While recorded as generic protein binding, this specific interaction is functionally important (PDZK1 stimulates OCTN2 carnitine transport). The informative capture is the PDZ-domain-binding annotation (GO:0030165) from the same study.
Reason: Bare protein binding is uninformative per curation guidelines; the biologically meaningful content (binding PDZK1 via a PDZ motif) is better captured by the PDZ domain binding annotation from the same reference.
Supporting Evidence:
PMID:15523054
The present findings are the first to identify PDZK1 as a functional regulator of OCTN2 through direct interaction with the C terminus.
GO:0005886 plasma membrane
IC
PMID:9618255
cDNA sequence, transport function, and genomic organization ... 		ACCEPT
Summary: Plasma-membrane localization inferred by the curator from the demonstrated transport function (OCTN2 mediates TEA transport when expressed in HeLa cells). Consistent with the established core localization.
Reason: Plasma-membrane localization inferred from surface transport function and confirmed by later direct evidence; correct.
Supporting Evidence:
PMID:9618255
OCTN2 mediates the transport of tetraethylammonium, a prototypical organic cation, in a pH-dependent manner.
GO:0015226 carnitine transmembrane transporter activity
IDA
PMID:9685390
Molecular and functional identification of sodium ion-depend... 		ACCEPT
Summary: Original identification of OCTN2 as a high-affinity Na+-dependent carnitine transporter. Core molecular function.
Reason: Direct experimental demonstration of carnitine transporter activity; core molecular function.
Supporting Evidence:
PMID:9685390
uptake of L-[3H]carnitine was strongly enhanced in a sodium-dependent manner with Km value of 4.34 microM
GO:0015226 carnitine transmembrane transporter activity
IMP
PMID:9916797
Primary systemic carnitine deficiency is caused by mutations... 		ACCEPT
Summary: Mutational evidence that loss of OCTN2 function causes systemic carnitine deficiency (jvs mouse mutation abrogates carnitine transport; human SLC22A5 mutations in SCD pedigrees). Confirms OCTN2 carnitine transporter activity via loss-of-function. Core molecular function.
Reason: Loss-of-function (disease/mutation) evidence directly supports carnitine transporter activity; core molecular function.
Supporting Evidence:
PMID:9916797
this mutation abrogates carnitine transport.
GO:0015651 quaternary ammonium group transmembrane transporter activity
IDA
PMID:9618255
cDNA sequence, transport function, and genomic organization ... 		KEEP AS NON CORE
Summary: OCTN2 mediates transport of the quaternary ammonium compound tetraethylammonium (TEA) in a pH-dependent manner when expressed in HeLa cells. Correct family-level MF, broader than the specific carnitine activity.
Reason: Genuine quaternary-ammonium (organic cation) transporter activity, but the informative core MF is carnitine transmembrane transporter activity.
Supporting Evidence:
PMID:9618255
OCTN2 mediates the transport of tetraethylammonium, a prototypical organic cation, in a pH-dependent manner.
GO:0015697 quaternary ammonium group transport
IDA
PMID:9618255
cDNA sequence, transport function, and genomic organization ... 		KEEP AS NON CORE
Summary: OCTN2 transports the quaternary ammonium organic cation TEA (and competing organic cations MPP+, MPTP, methamphetamine). Correct but broad process.
Reason: Correct but general organic-cation transport process; the specific process is carnitine transmembrane transport.
Supporting Evidence:
PMID:9618255
Several organic cations, including the neurotoxins 1-methyl-4-phenylpyridinium
GO:0015879 carnitine transport
IDA
PMID:9685390
Molecular and functional identification of sodium ion-depend... 		ACCEPT
Summary: OCTN2 identified as the physiologically important high-affinity Na+-carnitine cotransporter. Core carnitine transport process.
Reason: Direct evidence of OCTN2-mediated carnitine transport; core process.
Supporting Evidence:
PMID:9685390
OCTN2 is a physiologically important, high affinity sodium-carnitine cotransporter in humans.
GO:0015879 carnitine transport
IMP
PMID:9916797
Primary systemic carnitine deficiency is caused by mutations... 		ACCEPT
Summary: Loss-of-function OCTN2 mutations abrogate carnitine transport and cause systemic carnitine deficiency, confirming OCTN2's role in carnitine transport. Core process.
Reason: Mutation/disease evidence directly supports OCTN2 involvement in carnitine transport; core process.
Supporting Evidence:
PMID:9916797
this mutation abrogates carnitine transport.
GO:0016324 apical plasma membrane
IDA
PMID:17274673
OCTN2-mediated carnitine uptake in a newly discovered human ... 		ACCEPT
Summary: OCTN2 localized to the apical membrane of the human proximal tubule cell line Caki-1, where it mediates carnitine reabsorption. Core polarized localization in kidney.
Reason: Directly documented apical plasma-membrane localization in proximal tubule cells; correct.
Supporting Evidence:
PMID:17274673
an apical membrane expression pattern of OCTN2 in Caki-1 cells was discovered.
GO:0016324 apical plasma membrane
IDA
PMID:18641280
Expression and localization of carnitine/organic cation tran... 		ACCEPT
Summary: OCTN2 predominantly localized to the apical membranes of human corneal and conjunctival epithelial cells, with apical L-carnitine uptake. Apical localization consistent across epithelia.
Reason: Directly documented apical plasma-membrane localization in ocular epithelia; correct.
Supporting Evidence:
PMID:18641280
OCTN1 and OCTN2 were predominately localized in the apical membranes of the cells.
GO:0030165 PDZ domain binding
IPI
PMID:15523054
PDZK1 directly regulates the function of organic cation/carn... 		KEEP AS NON CORE
Summary: The OCTN2 C-terminal PDZ-binding motif (last four residues) binds the PDZ protein PDZK1 (and NHERF2), and PDZK1 co-expression stimulates OCTN2 carnitine transport capacity ~6-fold. An informative, functionally relevant molecular function (accessory regulatory interaction).
Reason: A specific, biologically meaningful protein-domain interaction that regulates OCTN2 transport; retained as an informative non-core molecular function (the core MF remains carnitine transport).
Supporting Evidence:
PMID:15523054
a specific interaction of apical transporters OCTN1 and OCTN2, but not basolateral transporters OCT1 and OCT2, with PDZK1
GO:0031526 brush border membrane
IDA
PMID:15238359
L-Carnitine transport in human placental brush-border membra... 		ACCEPT
Summary: OCTN2 detected by Western blot in placental brush-border (but not basal) membrane vesicles. Brush-border (apical) localization consistent with the transporter's polarized reabsorptive/absorptive role.
Reason: Directly documented brush-border membrane localization; correct and informative (specific apical sub-localization).
Supporting Evidence:
PMID:15238359
OCTN2, a high-affinity, Na(+)-dependent carnitine transporter, was present in placental BBM but not in isolated basal plasma membrane vesicles.
GO:0031526 brush border membrane
ISS
PMID:15523054
PDZK1 directly regulates the function of organic cation/carn... 		ACCEPT
Summary: Brush-border membrane localization supported by sequence-similarity transfer (rat Octn2, Q9Z0E8) alongside the demonstrated colocalization of OCTN2 and PDZK1 in kidney brush-border membranes. Consistent with the direct human evidence.
Reason: Brush-border localization is corroborated directly (placenta, OCTN2/PDZK1 colocalization in kidney BBM) and by ISS from the rat ortholog; correct.
Supporting Evidence:
PMID:15523054
both PDZK1 and OCTN2 are colocalized in brush-border membranes of the kidney.
GO:0005886 plasma membrane
TAS
PMID:9916797
Primary systemic carnitine deficiency is caused by mutations... 		ACCEPT
Summary: Author-asserted plasma-membrane localization of the carnitine transporter (membrane-physiological studies indicated a plasma-membrane carnitine transport defect in SCD). Consistent with the established core localization.
Reason: Traceable author statement of plasma-membrane carnitine transporter localization, corroborated by extensive direct evidence.
Supporting Evidence:
PMID:9916797
a defect of the carnitine transport system in the plasma membrane in SCD patients

Core Functions

Sodium-coupled, high-affinity import of L-carnitine across the plasma membrane. OCTN2 symports one Na+ with one (R)-carnitine molecule, enabling cellular uptake and renal reabsorption of carnitine that supplies the mitochondrial carnitine shuttle for long-chain fatty-acid beta-oxidation.

Molecular Function:
carnitine transmembrane transporter activity
Directly Involved In:
carnitine transmembrane transport
Cellular Locations:
plasma membrane apical plasma membrane
Supporting Evidence:
  • PMID:9685390
    OCTN2 is a physiologically important, high affinity sodium-carnitine cotransporter in humans.
  • PMID:10966938
    hOCTN2 mediates electrogenic Na(+)-dependent stereoselective high-affinity transport of L-carnitine and Na(+).

Stereospecific (R)-carnitine transmembrane transporter activity, demonstrated directly in heterologous systems and native epithelia and lost in disease-causing SLC22A5 mutants; this is the specific-substrate resolution of the core carnitine transport function.

Molecular Function:
(R)-carnitine transmembrane transporter activity
Directly Involved In:
(R)-carnitine transmembrane transport
Cellular Locations:
plasma membrane
Supporting Evidence:
  • PMID:9916797
    this mutation abrogates carnitine transport.
  • PMID:17509700
    A novel organic cation transporter OCTN2 is indispensable for carnitine transport across plasma membrane

Sodium-dependent transport of carnitine and other zwitterionic/cationic organic solutes; the Na+-coupled symport mechanism underlies OCTN2's high-affinity carnitine uptake, while OCTN2 also transports organic cations more weakly in a Na+-independent manner (polyspecific secondary activity).

Molecular Function:
carnitine transmembrane transporter activity
Directly Involved In:
sodium-dependent organic cation transport
Cellular Locations:
apical plasma membrane
Supporting Evidence:

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000024
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
GO_REF:0000117
Electronic Gene Ontology annotations created by ARBA machine learning models
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:10454528
Functional characteristics and tissue distribution pattern of organic cation transporter 2 (OCTN2), an organic cation/carnitine transporter.
  • OCTN2 transports organic cations independently of Na+ but transports carnitine only in the presence of Na+; short-chain acylcarnitines are also substrates; disease mutations M352R and P478L abolish transport.
    "OCTN2 transports organic cations without involving Na(+), but it transports carnitine only in the presence of Na(+)."
PMID:10966938
Functional and pharmacological characterization of human Na(+)-carnitine cotransporter hOCTN2.
  • hOCTN2 is an electrogenic Na+-dependent, stereoselective, high-affinity L-carnitine cotransporter (Km ~4.8 uM) that also transports betaine and is inhibited by emetine, quinidine and verapamil.
    "hOCTN2 mediates electrogenic Na(+)-dependent stereoselective high-affinity transport of L-carnitine and Na(+)."
PMID:15238359
L-Carnitine transport in human placental brush-border membranes is mediated by the sodium-dependent organic cation transporter OCTN2.
  • OCTN2 protein is present in placental brush-border (but not basal) membranes and mediates Na+-dependent, high-affinity L-carnitine uptake for maternofetal transport.
    "OCTN2, a high-affinity, Na(+)-dependent carnitine transporter, was present in placental BBM but not in isolated basal plasma membrane vesicles."
PMID:15523054
PDZK1 directly regulates the function of organic cation/carnitine transporter OCTN2.
  • The OCTN2 C-terminal PDZ-binding motif (last four residues) binds PDZK1; PDZK1 co-expression stimulates OCTN2 carnitine transport capacity ~6-fold, and the two colocalize in kidney brush-border membranes.
    "The present findings are the first to identify PDZK1 as a functional regulator of OCTN2 through direct interaction with the C terminus."
PMID:17274673
OCTN2-mediated carnitine uptake in a newly discovered human proximal tubule cell line (Caki-1).
  • OCTN2 shows an apical membrane expression pattern in human proximal tubule Caki-1 cells and mediates Na+-dependent high-affinity carnitine uptake, consistent with renal tubular carnitine reabsorption.
    "an apical membrane expression pattern of OCTN2 in Caki-1 cells was discovered."
PMID:17509700
OCTN2VT, a splice variant of OCTN2, does not transport carnitine because of the retention in the endoplasmic reticulum caused by insertion of 24 amino acids in the first extracellular loop of OCTN2.
  • The functional OCTN2 is a plasma-membrane, N-glycosylated carnitine transporter; the OCTN2VT splice variant (isoform 3) is retained in the ER, poorly glycosylated, and cannot take up carnitine.
    "OCTN2VT was retained in the endoplasmic reticulum (ER) with poor N-glycosylation. In addition, the retention in the ER caused no carnitine uptake into the cells."
PMID:17855766
Transport of butyryl-L-carnitine, a potential prodrug, via the carnitine transporter OCTN2 and the amino acid transporter ATB(0,+).
  • OCTN2 is a high-affinity, low-capacity transporter for butyryl-L-carnitine (electrogenic, Na+-dependent), in addition to L-carnitine.
    "OCTN2 is a high-affinity/low-capacity transporter"
PMID:18005709
The Bacillus subtilis quorum-sensing molecule CSF contributes to intestinal homeostasis via OCTN2, a host cell membrane transporter.
  • OCTN2 is an apical intestinal organic cation transporter that takes up the B. subtilis quorum-sensing pentapeptide CSF, inducing cytoprotective heat shock proteins and contributing to intestinal homeostasis.
    "These effects of CSF depend on its uptake by an apical membrane organic cation transporter-2 (OCTN2)."
PMID:18641280
Expression and localization of carnitine/organic cation transporter OCTN1 and OCTN2 in ocular epithelium.
  • OCTN2 is expressed and predominantly apically localized in human corneal and conjunctival epithelial cells, mediating apical L-carnitine uptake.
    "OCTN1 and OCTN2 were predominately localized in the apical membranes of the cells."
PMID:19056867
Large-scale proteomics and phosphoproteomics of urinary exosomes.
  • Large-scale proteomic profiling of human urinary exosomes; OCTN2 is among detected renal-epithelial membrane proteins (incidental co-purification).
    "Normal human urine contains large numbers of exosomes"
PMID:20722056
Cytokine regulation of OCTN2 expression and activity in small and large intestine.
  • Intestinal OCTN2 apical expression and Na+-dependent carnitine uptake are increased by IFN-gamma and TNF-alpha; siRNA knockdown confirms >80% of Na+-dependent carnitine uptake is OCTN2-dependent.
    "more than 80% of Na+-dependent carnitine uptake is due to OCTN2 in Caco2BBE cells"
PMID:23567998
Transport of gabapentin by LAT1 (SLC7A5).
  • Gabapentin is transported by LAT1 (SLC7A5) at the blood-brain barrier and was negative for OCT-like transport; the abstract does not document an OCTN2 quaternary-ammonium transport assay.
    "Gabapentin was negative for OCT like transport and LAT2 activity"
PMID:23877104
Functional expression of organic cation/carnitine transporter 2 (OCTN2/SLC22A5) in human brain capillary endothelial cell line hCMEC/D3, a human blood-brain barrier model.
  • OCTN2 siRNA knockdown dramatically suppresses Na+-dependent L-carnitine uptake in human brain endothelial cells, showing OCTN2 mediates carnitine transport at the human blood-brain barrier.
    "OCTN2 is involved in L-carnitine transport at the human BBB."
PMID:26590417
Establishment and Dysfunction of the Blood-Brain Barrier.
  • General review of blood-brain barrier physiology and dysfunction; cited (NAS) for OCTN2's role in transport across the BBB.
    "Establishment and Dysfunction of the Blood-Brain Barrier."
PMID:28514442
Architecture of the human interactome defines protein communities and disease networks.
  • Proteome-scale binary interactome mapping; source of a high-throughput OCTN2 protein-binding annotation (HMGCS1) without independent functional validation.
    "Architecture of the human interactome defines protein communities and disease networks"
PMID:30280653
Blood-Brain Barrier: From Physiology to Disease and Back.
  • General blood-brain barrier review; cited (NAS) for OCTN2's role in transport across the BBB.
    "Blood-Brain Barrier: From Physiology to Disease and Back."
PMID:32296183
A reference map of the human binary protein interactome.
  • Proteome-scale binary (Y2H) interactome map; source of high-throughput OCTN2 protein-binding annotations (keratins, KRTAP6-3, MTUS2, NOTCH2NLC) without functional validation.
    "A reference map of the human binary protein interactome"
PMID:33124720
Deorphaning a solute carrier 22 family member, SLC22A15, through functional genomic studies.
  • In deorphaning SLC22A15, OCTN2 (SLC22A5) is used as a reference zwitterion transporter; dimethylglycine is noted to interact with SLC22A5 and betaine is a known SLC22A5 substrate.
    "Dimethylglycine, known to interact with SLC22A5"
PMID:33334877
Cholesterol stimulates the cellular uptake of L-carnitine by the carnitine/organic cation transporter novel 2 (OCTN2).
  • OCTN2 is responsible for cellular carnitine uptake in most tissues and resides in the plasma membrane; membrane cholesterol modulates its L-carnitine transport.
    "The carnitine/organic cation transporter novel 2 (OCTN2) is responsible for the cellular uptake of carnitine in most tissues."
PMID:33961781
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  • Proteome-scale affinity-purification interactome (BioPlex); source of a high-throughput OCTN2 protein-binding annotation without functional validation.
    "Dual proteome-scale networks reveal cell-specific remodeling of the human interactome"
PMID:35307651
Localization of Xenobiotic Transporters Expressed at the Human Blood-Testis Barrier.
  • At the human blood-testis barrier, OCTN2 localizes to Sertoli-cell basal membranes and peritubular myoid cells, consistent with a role in transport across the barrier.
    "OCTN2, multidrug resistance protein (MRP) 3, MRP6, and MRP7 localized to SC basal membranes and peritubular myoid cells (PMCs)"
PMID:9618255
cDNA sequence, transport function, and genomic organization of human OCTN2, a new member of the organic cation transporter family.
  • OCTN2 is a 557-aa, 12-transmembrane organic cation transporter (chr 5q31) that mediates pH-dependent transport of tetraethylammonium and other organic cations (including neurotoxins MPP+/MPTP).
    "OCTN2 mediates the transport of tetraethylammonium, a prototypical organic cation, in a pH-dependent manner."
PMID:9685390
Molecular and functional identification of sodium ion-dependent, high affinity human carnitine transporter OCTN2.
  • OCTN2 is a high-affinity (Km 4.34 uM), Na+-dependent human carnitine cotransporter, strongly expressed in kidney, skeletal muscle, heart and placenta.
    "OCTN2 is a physiologically important, high affinity sodium-carnitine cotransporter in humans."
PMID:9916797
Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter.
  • Loss-of-function mutations in SLC22A5/OCTN2 (in jvs mice and human SCD pedigrees) abrogate carnitine transport and cause systemic primary carnitine deficiency.
    "this mutation abrogates carnitine transport."
Reactome:R-HSA-165026
OCTN2 / SLC22A5 transports CAR from extracellular space to cytosol
Reactome:R-HSA-549127
SLC-mediated transport of organic cations
Reactome:R-HSA-549297
SLC22A4, 5,15,16 cotransport CAR, Na+ from extracellular region to cytosol
Reactome:R-HSA-5625674
Defective SLC22A5 does not cotransport CAR, Na+ from extracellular region to cytosol

📚 Additional Documentation

Notes

(SLC22A5-notes.md)

SLC22A5 (OCTN2, O76082) — review notes

Summary of gene function

SLC22A5 / OCTN2 is a plasma-membrane, sodium-dependent, high-affinity L-carnitine
transporter of the SLC22 (MFS, TC 2.A.1.19) family. It couples Na+ symport to carnitine
uptake (1 Na+ : 1 carnitine), Km ~4–20 µM for (R)-carnitine [file UniProt CATALYTIC
ACTIVITY RHEA:72091; PMID:9685390 "Km value of 4.34 microM"; PMID:10966938 "K(m)) of
4.8 +/- 0.3 microM for L-carnitine"]. It also transports organic cations (e.g. TEA)
in a Na+-independent, lower-affinity manner PMID:10454528. Carnitine uptake feeds the mitochondrial carnitine shuttle (CPT1/CACT/CPT2)
for long-chain fatty-acid beta-oxidation, and OCTN2 drives renal tubular carnitine
reabsorption (>95% of filtered carnitine) PMID:17274673.

Core function

  • MF: carnitine transmembrane transporter activity (GO:0015226); also
    (R)-carnitine transmembrane transporter activity (GO:1901235); Na+-coupled symport.
  • BP: carnitine transmembrane transport (GO:1902603) / (R)-carnitine transmembrane
    transport; renal reabsorption; carnitine import feeding fatty-acid oxidation.
  • CC: plasma membrane (GO:0005886), apical/brush-border in epithelia (GO:0016324,
    GO:0031526); basal membrane in Sertoli cells (GO:0009925).

Disease

Loss-of-function biallelic variants cause Systemic Primary Carnitine Deficiency
(CDSP / CUD, MIM 212140, MONDO:0008919): hypoketotic hypoglycemia + acute metabolic
decompensation in infancy, and cardiomyopathy / skeletal myopathy; treatable with
oral L-carnitine [PMID:9916797 "loss of OCTN2 function causes SCD"; dismech
Primary_Carnitine_Deficiency.yaml].

Substrate breadth (polyspecific / secondary activities — genuine but non-core)

  • Betaine (glycine betaine) PMID:10966938;
    dimethylglycine [file UniProt RHEA:76591; PMID:33124720 "Dimethylglycine, known to
    interact with SLC22A5"].
  • Acyl-carnitines: acetyl-, propionyl-, butyryl- [PMID:17855766 butyryl-L-carnitine
    via OCTN2, high-affinity].
  • Organic cations / drugs (TEA, quinidine, verapamil, cimetidine, many DrugBank
    substrates) — Na+-independent, lower affinity.
  • Bacterial quorum-sensing pentapeptide CSF (competence & sporulation factor) uptake
    in intestinal epithelia PMID:18005709.

Localization

  • Plasma membrane (multipass) [file UniProt SUBCELLULAR LOCATION Cell membrane].
  • Apical / brush-border in kidney proximal tubule, intestine, placenta, cornea/conjunctiva
    [PMID:15238359 placental BBM; PMID:17274673 Caki-1 apical; PMID:18641280 ocular apical].
  • Basal membrane of Sertoli cells at blood-testis barrier PMID:35307651.
  • Isoform 3 (OCTN2VT) retained in ER, non-functional PMID:17509700.
  • Extracellular exosome (urinary) — HDA proteomics, incidental PMID:19056867.
  • Cytosol/cytoplasm ISS annotations (from mouse O70594) — not a functional location;
    the transporter is an integral membrane protein.

Regulation / partners

  • PDZK1 binds OCTN2 C-terminus (last 4 aa) and stimulates carnitine transport capacity
    ~6-fold PMID:15523054. This is the informative interaction; bare protein-binding IPIs
    (HMGCS1, keratins, KRTAP6-3, MTUS2, NOTCH2NLC from HT interactome screens) are
    uninformative.
  • Intestinal expression induced by IFN-γ and TNF-α PMID:20722056.
  • Carnitine transport stimulated by membrane cholesterol PMID:33334877.

Annotations to treat cautiously

  • GO:0005524 ATP binding (IEA, InterPro IPR045915) & KW Nucleotide-binding: OCTN2 is a
    secondary active (Na+-symport) MFS transporter, NOT an ATP-driven pump. This IEA is a
    spurious InterPro→GO mapping; MARK_AS_OVER_ANNOTATED / effectively wrong.
  • GO:0005737 cytoplasm, GO:0005829 cytosol (ISS from O70594): mislocalization; integral
    membrane protein. Over-annotation.
  • GO:0150104 transport across blood-brain barrier: OCTN2 is at the BBB and takes up
    carnitine there [PMID:23877104 IMP], but the NAS refs (26590417, 30280653) are generic
    BBB reviews — keep MF/IMP, the review NAS are weak.
  • GO:0034341 / GO:0034612 (response to IFN-γ / TNF): these are gene-expression/regulation
    responses (OCTN2 is induced), non-core.
  • GO:0009609 response to symbiotic bacterium & GO:0060731 positive regulation of
    intestinal epithelial structure maintenance (PMID:18005709 IMP): downstream biology of
    CSF uptake, non-core.
  • PMID:23567998 (gabapentin/LAT1) IDA for GO:0015651/GO:0015697: abstract is about LAT1;
    cannot verify OCTN2 quaternary-ammonium assay from cache → UNDECIDED (defer to curator).

Deep research

just deep-research-falcon failed (script TypeError: dict | None under the runtime
python); no falcon DR file generated. Grounded review in UniProt record, GOA, cached
publications/PMID_.md, and dismech Primary_Carnitine_Deficiency.yaml. Did NOT fabricate
a -deep-research-.md.

📄 View Raw YAML

 
id: O76082
gene_symbol: SLC22A5
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: SLC22A5 (OCTN2) is a plasma-membrane, sodium-dependent, high-affinity
  L-carnitine transporter of the SLC22 organic cation/carnitine transporter family
  (major facilitator superfamily). It couples the inward movement of one sodium ion
  to the uptake of one molecule of (R)-carnitine (Km in the low micromolar range),
  mediating cellular import of carnitine from blood and diet. This uptake is the
  essential first step that makes carnitine available for the mitochondrial carnitine
  shuttle (CPT1/CACT/CPT2) and hence for long-chain fatty-acid beta-oxidation, and
  OCTN2 also drives renal tubular reabsorption of filtered carnitine. Beyond carnitine
  it is polyspecific, transporting acyl-carnitines, glycine betaine, and diverse
  organic cations and cationic drugs (e.g. tetraethylammonium), the latter in a
  lower-affinity, sodium-independent manner. It is an integral multipass membrane
  protein expressed at the plasma membrane, apical/brush-border in absorptive and
  reabsorptive epithelia (kidney proximal tubule, intestine, placenta) and at the
  basal membrane of Sertoli cells. Loss-of-function variants cause systemic primary
  carnitine deficiency, an autosomal-recessive fatty-acid oxidation disorder presenting
  with hypoketotic hypoglycemia, cardiomyopathy and skeletal myopathy that is treatable
  with oral L-carnitine.
alternative_products:
- name: '1'
  id: O76082-1
- name: '2'
  id: O76082-2
  sequence_note: VSP_011120, VSP_011121
- name: 3 (OCTN2VT {ECO:0000303|PubMed:17509700})
  id: O76082-3
  sequence_note: VSP_043904
existing_annotations:
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetically-inferred plasma-membrane localization. OCTN2 is a
      well-established integral plasma-membrane transporter, directly demonstrated
      in multiple systems, so this IBA is correct and represents the site of action.
    action: ACCEPT
    reason: OCTN2 is an integral plasma-membrane, multipass transporter; extensive
      experimental evidence (below) confirms plasma-membrane localization and function.
    supported_by:
    - reference_id: PMID:33334877
      supporting_text: The carnitine/organic cation transporter novel 2 (OCTN2) is
        responsible for the cellular uptake of carnitine in most tissues.
- term:
    id: GO:0015697
    label: quaternary ammonium group transport
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic inference that OCTN2 is involved in quaternary ammonium
      group transport. Carnitine and many OCTN2 organic-cation substrates are
      quaternary ammonium compounds, so this is a correct family-level process term,
      though broader than the specific carnitine transport that is the core function.
    action: KEEP_AS_NON_CORE
    reason: Correct but general; OCTN2 does transport quaternary ammonium compounds
      (carnitine, TEA), but the informative core process is carnitine transmembrane
      transport. Retained as a valid broader process.
    supported_by:
    - reference_id: PMID:10454528
      supporting_text: OCTN2 transports organic cations without involving Na(+), but
        it transports carnitine only in the presence of Na(+).
- term:
    id: GO:0015651
    label: quaternary ammonium group transmembrane transporter activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetically-inferred quaternary ammonium group transmembrane
      transporter activity. OCTN2 transports quaternary ammonium substrates
      (carnitine, TEA), so the activity is real, but it is broader than the specific
      carnitine transporter activity that defines the gene.
    action: KEEP_AS_NON_CORE
    reason: A valid but general molecular-function term for the family; the specific
      core MF is carnitine transmembrane transporter activity (GO:0015226).
    supported_by:
    - reference_id: PMID:10454528
      supporting_text: novel organic cation transporter (OCTN) 2 is a transporter
        for organic cations as well as carnitine.
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: Electronic InterPro2GO mapping (IPR045915) assigning ATP binding. OCTN2
      is a secondary active transporter that couples carnitine uptake to the sodium
      electrochemical gradient (Na+ symport); it is not an ATP-driven pump and there
      is no evidence it binds or hydrolyses ATP. This is a spurious domain-based
      inference.
    action: REMOVE
    reason: OCTN2 is an MFS-family Na+-coupled symporter, not an ATP-binding/ATP-driven
      transporter. The InterPro-to-GO ATP-binding mapping is biologically incorrect
      for this protein; no experimental support exists.
    supported_by:
    - reference_id: PMID:10966938
      supporting_text: hOCTN2 mediates electrogenic Na(+)-dependent stereoselective
        high-affinity transport of L-carnitine and Na(+).
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic subcellular-location mapping to endoplasmic reticulum. ER
      localization applies only to the non-functional splice variant OCTN2VT
      (isoform 3), which is retained in the ER; the functional transporter is at the
      plasma membrane.
    action: KEEP_AS_NON_CORE
    reason: ER localization is real but pertains to the ER-retained, transport-dead
      isoform 3 (OCTN2VT); it is not the location of the functional carnitine
      transporter. Retained as a non-core, isoform-restricted annotation.
    supported_by:
    - reference_id: PMID:17509700
      supporting_text: OCTN2VT was retained in the endoplasmic reticulum (ER) with
        poor N-glycosylation. In addition, the retention in the ER caused no carnitine
        uptake into the cells.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic subcellular-location mapping to plasma membrane, consistent
      with the well-established localization of the functional transporter.
    action: ACCEPT
    reason: Correctly captures the plasma-membrane localization of OCTN2, confirmed
      experimentally.
    supported_by:
    - reference_id: PMID:33334877
      supporting_text: OCTN2 must interact with the surrounding lipid microenvironment
        to function.
- term:
    id: GO:0009925
    label: basal plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic annotation of basal plasma membrane localization. OCTN2 is
      predominantly apical/brush-border in most epithelia but is localized to the
      basal membrane of Sertoli cells, so a basal-membrane annotation is supportable
      in specific cell types.
    action: KEEP_AS_NON_CORE
    reason: Cell-type-specific basal localization (Sertoli cells) is documented; not
      the predominant (apical) localization, so kept as non-core.
    supported_by:
    - reference_id: PMID:35307651
      supporting_text: OCTN2, multidrug resistance protein (MRP) 3, MRP6, and MRP7
        localized to SC basal membranes and peritubular myoid cells (PMCs)
- term:
    id: GO:0015199
    label: amino-acid betaine transmembrane transporter activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    summary: Electronic (ARBA) annotation of amino-acid betaine transmembrane
      transporter activity. OCTN2 does transport glycine betaine, so this is correct;
      it is a secondary substrate rather than the core carnitine activity.
    action: KEEP_AS_NON_CORE
    reason: OCTN2-mediated betaine transport is experimentally documented; a genuine
      but non-core polyspecific activity.
    supported_by:
    - reference_id: PMID:10966938
      supporting_text: hOCTN2 mediated transport of betaine.
- term:
    id: GO:0015837
    label: amine transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: Electronic (ARBA) annotation to the broad process amine transport.
      OCTN2 transports amine-containing organic cations and carnitine, so this is
      correct but very general.
    action: KEEP_AS_NON_CORE
    reason: A correct but broad parent process; the specific process is carnitine
      transmembrane transport.
    supported_by:
    - reference_id: PMID:10454528
      supporting_text: OCTN2 transports organic cations without involving Na(+)
- term:
    id: GO:0015879
    label: carnitine transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: Electronic InterPro2GO annotation to carnitine transport, matching the
      defining physiological role of OCTN2.
    action: ACCEPT
    reason: Carnitine transport is the core biological process of OCTN2, extensively
      documented experimentally.
    supported_by:
    - reference_id: PMID:9685390
      supporting_text: OCTN2 is a physiologically important, high affinity
        sodium-carnitine cotransporter in humans.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  review:
    summary: Electronic InterPro annotation to the generic term membrane. Correct
      (OCTN2 is a multipass membrane protein) but uninformative relative to the
      specific plasma-membrane annotations.
    action: KEEP_AS_NON_CORE
    reason: Trivially correct generic location; superseded by the more specific
      plasma-membrane annotations.
    supported_by:
    - reference_id: PMID:17509700
      supporting_text: OCTN2 was expressed on the plasma membrane with robust
        N-glycosylation
- term:
    id: GO:0016324
    label: apical plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic annotation of apical plasma membrane localization, consistent
      with the polarized apical/brush-border localization of OCTN2 in epithelia.
    action: ACCEPT
    reason: Apical localization is directly documented in kidney, intestine, placenta
      and ocular epithelia; correct.
    supported_by:
    - reference_id: PMID:17274673
      supporting_text: an apical membrane expression pattern of OCTN2 in Caki-1 cells
        was discovered.
- term:
    id: GO:0022857
    label: transmembrane transporter activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: Electronic InterPro annotation to the root transmembrane transporter
      activity term. Correct but maximally general.
    action: KEEP_AS_NON_CORE
    reason: Trivially correct high-level MF; the informative MF is carnitine
      transmembrane transporter activity.
    supported_by:
    - reference_id: PMID:9685390
      supporting_text: OCTN2 is a physiologically important, high affinity
        sodium-carnitine cotransporter in humans.
- term:
    id: GO:0030165
    label: PDZ domain binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    summary: Electronic (ARBA) annotation of PDZ domain binding. OCTN2 has a
      C-terminal PDZ-binding motif that binds the PDZ protein PDZK1, which regulates
      its transport activity; this is experimentally confirmed (see PMID:15523054
      IPI annotation below).
    action: KEEP_AS_NON_CORE
    reason: PDZ-domain binding (via the C-terminal motif, to PDZK1) is real and
      functionally relevant to OCTN2 regulation, but is an accessory regulatory
      interaction rather than the transporter's core function.
    supported_by:
    - reference_id: PMID:15523054
      supporting_text: a requirement of the last four amino acids in OCTN1 and OCTN2
        for the interaction
- term:
    id: GO:0055085
    label: transmembrane transport
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: Electronic InterPro annotation to the broad process transmembrane
      transport. Correct but general.
    action: KEEP_AS_NON_CORE
    reason: Correct high-level process; superseded by carnitine transmembrane
      transport.
    supported_by:
    - reference_id: PMID:9685390
      supporting_text: uptake of L-[3H]carnitine was strongly enhanced in a
        sodium-dependent manner
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: High-throughput interactome (HuRI/CCSB) interaction, here with HMGCS1.
      Bare protein binding is uninformative about molecular function and this
      HT-derived binary interaction has no independent functional validation for
      OCTN2.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding from a proteome-scale interactome screen; provides
      no functional insight and the specific interaction (HMGCS1) is not biologically
      characterized for OCTN2. Per curation guidelines, bare protein binding is not
      retained as informative.
    supported_by:
    - reference_id: PMID:28514442
      supporting_text: Architecture of the human interactome defines protein
        communities and disease networks
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: High-throughput binary interactome (HuRI) interactions (with keratins
      KRT34, KRTAP6-3, MTUS2, NOTCH2NLC and others). Bare protein binding from a
      large-scale Y2H map, uninformative about OCTN2 molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding from a proteome-scale interactome map; keratin/keratin-
      associated-protein partners are common Y2H artifacts and are not biologically
      validated for OCTN2. Not informative of function.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: A reference map of the human binary protein interactome
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: High-throughput proteome-scale interactome (BioPlex) interaction, here
      with HMGCS1. Bare protein binding, uninformative about molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic protein binding from a proteome-scale affinity-purification map;
      no functional characterization for OCTN2. Not retained as informative.
    supported_by:
    - reference_id: PMID:33961781
      supporting_text: Dual proteome-scale networks reveal cell-specific remodeling
        of the human interactome
- term:
    id: GO:0015837
    label: amine transport
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-549127
  qualifier: involved_in
  review:
    summary: Reactome-asserted involvement in the broad process amine transport
      (SLC-mediated transport of organic cations). Correct but general; the specific
      OCTN2 process is carnitine transmembrane transport.
    action: KEEP_AS_NON_CORE
    reason: Reactome pathway assertion for a general amine/organic-cation transport
      process; correct but broader than the specific carnitine function.
    supported_by:
    - reference_id: PMID:10454528
      supporting_text: OCTN2 transports organic cations without involving Na(+)
- term:
    id: GO:1902603
    label: carnitine transmembrane transport
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-165026
  qualifier: involved_in
  review:
    summary: Reactome-asserted involvement in carnitine transmembrane transport
      (OCTN2 transports carnitine from extracellular space to cytosol). This is the
      core biological process of OCTN2.
    action: ACCEPT
    reason: Directly captures the defining process; supported by Reactome and by
      extensive experimental evidence.
    supported_by:
    - reference_id: PMID:9685390
      supporting_text: uptake of L-[3H]carnitine was strongly enhanced in a
        sodium-dependent manner
- term:
    id: GO:0015226
    label: carnitine transmembrane transporter activity
  evidence_type: IDA
  original_reference_id: PMID:15238359
  qualifier: enables
  review:
    summary: Direct assay of OCTN2-mediated Na+-dependent, high-affinity L-carnitine
      transport in human placental brush-border membranes. This is the core molecular
      function of OCTN2.
    action: ACCEPT
    reason: Experimentally demonstrated carnitine transmembrane transporter activity;
      core molecular function.
    supported_by:
    - reference_id: PMID:15238359
      supporting_text: OCTN2, a high-affinity, Na(+)-dependent carnitine transporter,
        was present in placental BBM
- term:
    id: GO:1902603
    label: carnitine transmembrane transport
  evidence_type: IDA
  original_reference_id: PMID:15238359
  qualifier: involved_in
  review:
    summary: Direct evidence that OCTN2 mediates L-carnitine transport across the
      placental brush-border membrane. Core biological process.
    action: ACCEPT
    reason: Experimentally demonstrated carnitine transmembrane transport; core
      process.
    supported_by:
    - reference_id: PMID:15238359
      supporting_text: l-carnitine uptake was sodium and temperature dependent,
        showed high affinity for carnitine
- term:
    id: GO:0015226
    label: carnitine transmembrane transporter activity
  evidence_type: IDA
  original_reference_id: PMID:15523054
  qualifier: enables
  review:
    summary: OCTN2-mediated carnitine uptake measured directly (and shown to be
      stimulated ~6-fold by PDZK1 co-expression). Confirms carnitine transporter
      activity.
    action: ACCEPT
    reason: Direct assay of OCTN2 carnitine transport activity; core molecular
      function.
    supported_by:
    - reference_id: PMID:15523054
      supporting_text: double transfection of OCTN2 with PDZK1 stimulated the uptake
        by OCTN2 of its endogenous substrate carnitine
- term:
    id: GO:1902603
    label: carnitine transmembrane transport
  evidence_type: IDA
  original_reference_id: PMID:15523054
  qualifier: involved_in
  review:
    summary: Direct evidence of OCTN2-mediated carnitine transport (endogenous
      substrate carnitine), core biological process.
    action: ACCEPT
    reason: Experimentally demonstrated carnitine transmembrane transport; core
      process.
    supported_by:
    - reference_id: PMID:15523054
      supporting_text: the uptake by OCTN2 of its endogenous substrate carnitine
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: EXP
  original_reference_id: PMID:17509700
  qualifier: located_in
  review:
    summary: Experimental demonstration of ER localization for the OCTN2VT splice
      variant (isoform 3), which is ER-retained and unable to transport carnitine.
      This is an isoform-specific, non-functional location.
    action: KEEP_AS_NON_CORE
    reason: ER localization is genuine but restricted to the transport-dead isoform 3
      (OCTN2VT); it does not describe the functional transporter's location. Kept as
      isoform-specific non-core.
    supported_by:
    - reference_id: PMID:17509700
      supporting_text: OCTN2VT was retained in the endoplasmic reticulum (ER) with
        poor N-glycosylation.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: EXP
  original_reference_id: PMID:33334877
  qualifier: located_in
  review:
    summary: Experimental plasma-membrane localization of functional OCTN2 (HEK293
      cells overexpressing OCTN2; cholesterol modulation studies). Core localization.
    action: ACCEPT
    reason: Directly documented plasma-membrane localization of the active transporter.
    supported_by:
    - reference_id: PMID:33334877
      supporting_text: how plasma membrane cholesterol modulates OCTN2 transport of
        L-carnitine
- term:
    id: GO:0016324
    label: apical plasma membrane
  evidence_type: EXP
  original_reference_id: PMID:10966938
  qualifier: located_in
  review:
    summary: Functional/pharmacological characterization of hOCTN2 as an electrogenic
      Na+-carnitine cotransporter; UniProt records apical cell-membrane localization
      from this work. Apical localization is well-supported across epithelia.
    action: ACCEPT
    reason: Apical plasma-membrane localization of OCTN2 is documented here and in
      multiple epithelial systems; correct.
    supported_by:
    - reference_id: PMID:10966938
      supporting_text: hOCTN2 mediates electrogenic Na(+)-dependent stereoselective
        high-affinity transport of L-carnitine and Na(+).
- term:
    id: GO:0015199
    label: amino-acid betaine transmembrane transporter activity
  evidence_type: IDA
  original_reference_id: PMID:33124720
  qualifier: enables
  review:
    summary: OCTN2 is used here as a reference zwitterion transporter and its
      betaine/dimethylglycine transport is noted; UniProt records betaine and
      N,N-dimethylglycine as OCTN2 substrates. Betaine transport by OCTN2 was
      demonstrated experimentally in PMID:10966938.
    action: KEEP_AS_NON_CORE
    reason: OCTN2-mediated betaine (and dimethylglycine) transport is a genuine but
      secondary polyspecific activity; not the core carnitine function.
    additional_reference_ids:
    - PMID:10966938
    supported_by:
    - reference_id: PMID:33124720
      supporting_text: Dimethylglycine, known to interact with SLC22A5
    - reference_id: PMID:10966938
      supporting_text: hOCTN2 mediated transport of betaine.
- term:
    id: GO:0034341
    label: response to type II interferon
  evidence_type: IDA
  original_reference_id: PMID:20722056
  qualifier: involved_in
  review:
    summary: Intestinal OCTN2 expression and Na+-dependent carnitine uptake activity
      are increased by IFN-gamma. This is a regulatory response (OCTN2 is induced by
      the cytokine), not a core transporter function.
    action: KEEP_AS_NON_CORE
    reason: OCTN2 responds to (is induced by) IFN-gamma in intestine; a genuine but
      peripheral/regulatory biological process rather than the transporter's core
      function.
    supported_by:
    - reference_id: PMID:20722056
      supporting_text: IFN-γ increased both total and apical membrane expression of
        Caco2BBE OCTN2
- term:
    id: GO:0034612
    label: response to tumor necrosis factor
  evidence_type: IDA
  original_reference_id: PMID:20722056
  qualifier: involved_in
  review:
    summary: Intestinal OCTN2 apical membrane expression and carnitine uptake are
      increased by TNF-alpha. A regulatory/response process, not core transport
      function.
    action: KEEP_AS_NON_CORE
    reason: OCTN2 responds to (is regulated by) TNF; peripheral regulatory process.
    supported_by:
    - reference_id: PMID:20722056
      supporting_text: TNF-α stimulated apical expression
- term:
    id: GO:1900749
    label: (R)-carnitine transport
  evidence_type: IDA
  original_reference_id: PMID:20722056
  qualifier: involved_in
  review:
    summary: Na+-dependent 3H-carnitine uptake by OCTN2 measured directly in
      intestinal epithelial cells (siRNA-confirmed as OCTN2-dependent). Core
      carnitine transport process.
    action: ACCEPT
    reason: Directly demonstrated OCTN2-mediated (R)-carnitine transport; core
      process.
    supported_by:
    - reference_id: PMID:20722056
      supporting_text: more than 80% of Na+-dependent carnitine uptake is due to
        OCTN2 in Caco2BBE cells
- term:
    id: GO:1901235
    label: (R)-carnitine transmembrane transporter activity
  evidence_type: IDA
  original_reference_id: PMID:20722056
  qualifier: enables
  review:
    summary: OCTN2-mediated Na+-dependent (R)-carnitine transporter activity
      demonstrated directly (siRNA knockdown abolishes >80% of Na+-dependent uptake).
      Core molecular function at the specific substrate level.
    action: ACCEPT
    reason: Direct evidence of (R)-carnitine transmembrane transporter activity;
      core molecular function.
    supported_by:
    - reference_id: PMID:20722056
      supporting_text: The Na+-dependent 3H-carnitine uptake in cells treated with
        OCTN2 siRNA was reduced from 0.88 ± 0.10 to 0.16 ± 0.06
- term:
    id: GO:0009925
    label: basal plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:35307651
  qualifier: located_in
  review:
    summary: Immunohistological localization of OCTN2 to Sertoli-cell basal membranes
      and peritubular myoid cells at the human blood-testis barrier. Cell-type-specific
      basal localization.
    action: KEEP_AS_NON_CORE
    reason: Documented basal-membrane localization in specific testicular cell types;
      not the predominant apical localization, so non-core.
    supported_by:
    - reference_id: PMID:35307651
      supporting_text: OCTN2, multidrug resistance protein (MRP) 3, MRP6, and MRP7
        localized to SC basal membranes and peritubular myoid cells (PMCs)
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:17509700
  qualifier: located_in
  review:
    summary: Functional OCTN2 shown at the plasma membrane (with robust
      N-glycosylation), contrasted with the ER-retained OCTN2VT variant. Core
      localization.
    action: ACCEPT
    reason: Direct plasma-membrane localization of the functional transporter.
    supported_by:
    - reference_id: PMID:17509700
      supporting_text: OCTN2 was expressed on the plasma membrane with robust
        N-glycosylation
- term:
    id: GO:0016324
    label: apical plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:18005709
  qualifier: is_active_in
  review:
    summary: OCTN2 identified as an apical membrane organic cation transporter in
      intestinal epithelial cells, mediating uptake of the bacterial CSF pentapeptide.
      Apical localization is the site of action in absorptive epithelia.
    action: ACCEPT
    reason: Apical plasma-membrane site of action directly demonstrated in intestinal
      epithelia.
    supported_by:
    - reference_id: PMID:18005709
      supporting_text: These effects of CSF depend on its uptake by an apical membrane
        organic cation transporter-2 (OCTN2).
- term:
    id: GO:0016324
    label: apical plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:20722056
  qualifier: located_in
  review:
    summary: OCTN2 localized to the apical (brush-border) membrane of intestinal
      epithelial cells by immunohistochemistry and surface biotinylation. Core
      polarized localization.
    action: ACCEPT
    reason: Directly documented apical plasma-membrane localization in intestine.
    supported_by:
    - reference_id: PMID:20722056
      supporting_text: OCTN2 was highly expressed in the brush border (apical
        membrane) and subapical region of epithelial cells
- term:
    id: GO:0022857
    label: transmembrane transporter activity
  evidence_type: IDA
  original_reference_id: PMID:18005709
  qualifier: enables
  review:
    summary: OCTN2 demonstrated to transport the bacterial CSF pentapeptide across
      the apical membrane. This supports transmembrane transporter activity, though
      the annotation uses the maximally general MF term.
    action: KEEP_AS_NON_CORE
    reason: Correct but general MF; the specific informative MF is carnitine
      transmembrane transporter activity. Retained as a valid broader term.
    supported_by:
    - reference_id: PMID:18005709
      supporting_text: OCTN2-mediated CSF transport serves as an example of a
        host-bacterial interaction
- term:
    id: GO:0070715
    label: sodium-dependent organic cation transport
  evidence_type: IDA
  original_reference_id: PMID:18005709
  qualifier: involved_in
  review:
    summary: OCTN2-mediated apical uptake of the cationic bacterial pentapeptide CSF;
      UniProt records this as a Na+-coupled transport reaction. Supports Na+-dependent
      organic cation (peptide) transport.
    action: KEEP_AS_NON_CORE
    reason: A genuine polyspecific Na+-dependent organic-cation transport activity
      (CSF peptide), distinct from the core carnitine function; retained as non-core.
    supported_by:
    - reference_id: PMID:18005709
      supporting_text: These effects of CSF depend on its uptake by an apical membrane
        organic cation transporter-2 (OCTN2).
- term:
    id: GO:1900749
    label: (R)-carnitine transport
  evidence_type: IDA
  original_reference_id: PMID:17509700
  qualifier: involved_in
  review:
    summary: OCTN2 shown to be indispensable for carnitine transport across the plasma
      membrane (the functional variant transports carnitine, the ER-retained variant
      does not). Core carnitine transport process.
    action: ACCEPT
    reason: Direct evidence for OCTN2-mediated (R)-carnitine transport; core process.
    supported_by:
    - reference_id: PMID:17509700
      supporting_text: A novel organic cation transporter OCTN2 is indispensable for
        carnitine transport across plasma membrane
- term:
    id: GO:1900749
    label: (R)-carnitine transport
  evidence_type: IDA
  original_reference_id: PMID:33334877
  qualifier: involved_in
  review:
    summary: OCTN2 responsible for cellular uptake of carnitine; carnitine transport
      measured directly in OCTN2-overexpressing cells (and shown to be cholesterol-
      dependent). Core carnitine transport process.
    action: ACCEPT
    reason: Direct evidence for OCTN2-mediated carnitine uptake; core process.
    supported_by:
    - reference_id: PMID:33334877
      supporting_text: The carnitine/organic cation transporter novel 2 (OCTN2) is
        responsible for the cellular uptake of carnitine in most tissues.
- term:
    id: GO:1901235
    label: (R)-carnitine transmembrane transporter activity
  evidence_type: IDA
  original_reference_id: PMID:17509700
  qualifier: enables
  review:
    summary: OCTN2 (functional isoform) transports carnitine across the plasma
      membrane; the ER-retained OCTN2VT does not, confirming that plasma-membrane
      OCTN2 is the carnitine transporter. Core molecular function.
    action: ACCEPT
    reason: Direct evidence for (R)-carnitine transmembrane transporter activity;
      core molecular function.
    supported_by:
    - reference_id: PMID:17509700
      supporting_text: the retention in the ER caused no carnitine uptake into the
        cells
- term:
    id: GO:1901235
    label: (R)-carnitine transmembrane transporter activity
  evidence_type: IDA
  original_reference_id: PMID:33334877
  qualifier: enables
  review:
    summary: Direct carnitine transport assays in OCTN2-overexpressing HEK293 cells
      establish OCTN2 (R)-carnitine transporter activity (modulated by membrane
      cholesterol). Core molecular function.
    action: ACCEPT
    reason: Direct evidence for (R)-carnitine transmembrane transporter activity;
      core molecular function.
    supported_by:
    - reference_id: PMID:33334877
      supporting_text: how plasma membrane cholesterol modulates OCTN2 transport of
        L-carnitine
- term:
    id: GO:0015226
    label: carnitine transmembrane transporter activity
  evidence_type: IDA
  original_reference_id: PMID:10454528
  qualifier: enables
  review:
    summary: Functional characterization establishing OCTN2 as a Na+-dependent
      carnitine transporter (and Na+-independent organic cation transporter). Core
      molecular function.
    action: ACCEPT
    reason: Direct experimental demonstration of carnitine transmembrane transporter
      activity; core molecular function.
    supported_by:
    - reference_id: PMID:10454528
      supporting_text: it transports carnitine only in the presence of Na(+)
- term:
    id: GO:0015226
    label: carnitine transmembrane transporter activity
  evidence_type: IDA
  original_reference_id: PMID:10966938
  qualifier: enables
  review:
    summary: Electrophysiological and flux characterization of hOCTN2 as an
      electrogenic Na+-carnitine cotransporter (Km ~4.8 uM). Core molecular function.
    action: ACCEPT
    reason: Direct evidence for high-affinity carnitine transmembrane transporter
      activity; core molecular function.
    supported_by:
    - reference_id: PMID:10966938
      supporting_text: hOCTN2 mediates electrogenic Na(+)-dependent stereoselective
        high-affinity transport of L-carnitine and Na(+).
- term:
    id: GO:0015226
    label: carnitine transmembrane transporter activity
  evidence_type: IDA
  original_reference_id: PMID:17855766
  qualifier: enables
  review:
    summary: OCTN2 transports L-carnitine and its butyryl ester (butyryl-L-carnitine)
      as a high-affinity transporter. Confirms carnitine transporter activity.
    action: ACCEPT
    reason: Direct evidence of OCTN2 carnitine (and acyl-carnitine) transport activity;
      core molecular function.
    supported_by:
    - reference_id: PMID:17855766
      supporting_text: OCTN2 is a high-affinity/low-capacity transporter
- term:
    id: GO:0015651
    label: quaternary ammonium group transmembrane transporter activity
  evidence_type: IMP
  original_reference_id: PMID:10454528
  qualifier: enables
  review:
    summary: OCTN2 transports quaternary ammonium substrates (carnitine, organic
      cations); loss-of-function mutants (M352R, P478L) abolish transport. Correct
      family-level MF, broader than the specific carnitine activity.
    action: KEEP_AS_NON_CORE
    reason: A correct but general quaternary ammonium transporter activity; the
      specific core MF is carnitine transmembrane transporter activity.
    supported_by:
    - reference_id: PMID:10454528
      supporting_text: Two mutations, M352R and P478L, in human OCTN2 are associated
        with loss of transport function
- term:
    id: GO:0015651
    label: quaternary ammonium group transmembrane transporter activity
  evidence_type: IMP
  original_reference_id: PMID:10966938
  qualifier: enables
  review:
    summary: hOCTN2 transports carnitine and betaine (quaternary ammonium compounds);
      shows only small currents with classic OCT substrates. Correct but general MF.
    action: KEEP_AS_NON_CORE
    reason: Correct family-level quaternary-ammonium MF; superseded by the specific
      carnitine transporter activity as the core function.
    supported_by:
    - reference_id: PMID:10966938
      supporting_text: hOCTN2 mediated transport of betaine.
- term:
    id: GO:0015697
    label: quaternary ammonium group transport
  evidence_type: IMP
  original_reference_id: PMID:10454528
  qualifier: involved_in
  review:
    summary: OCTN2 mediates transport of quaternary ammonium compounds (carnitine and
      organic cations); mutation studies confirm transport function. Correct but broad
      process.
    action: KEEP_AS_NON_CORE
    reason: Correct but general process; the specific process is carnitine
      transmembrane transport.
    supported_by:
    - reference_id: PMID:10454528
      supporting_text: OCTN2 transports organic cations without involving Na(+)
- term:
    id: GO:0015697
    label: quaternary ammonium group transport
  evidence_type: IMP
  original_reference_id: PMID:10966938
  qualifier: involved_in
  review:
    summary: hOCTN2 transports the quaternary ammonium compounds carnitine and betaine.
      Correct but broad process term.
    action: KEEP_AS_NON_CORE
    reason: Correct general process; superseded by carnitine transmembrane transport.
    supported_by:
    - reference_id: PMID:10966938
      supporting_text: hOCTN2 mediated transport of betaine.
- term:
    id: GO:1902270
    label: (R)-carnitine transmembrane transport
  evidence_type: IDA
  original_reference_id: PMID:10454528
  qualifier: involved_in
  review:
    summary: Direct demonstration that OCTN2 transports carnitine (Na+-dependently)
      across the membrane. Core carnitine transport process at the specific
      substrate level.
    action: ACCEPT
    reason: Direct evidence for (R)-carnitine transmembrane transport; core process.
    supported_by:
    - reference_id: PMID:10454528
      supporting_text: it transports carnitine only in the presence of Na(+)
- term:
    id: GO:1902270
    label: (R)-carnitine transmembrane transport
  evidence_type: IDA
  original_reference_id: PMID:10966938
  qualifier: involved_in
  review:
    summary: Electrogenic Na+-dependent L-carnitine transport by hOCTN2 characterized
      by voltage clamp/flux. Core carnitine transport process.
    action: ACCEPT
    reason: Direct evidence for (R)-carnitine transmembrane transport; core process.
    supported_by:
    - reference_id: PMID:10966938
      supporting_text: L-carnitine transport was electrogenic.
- term:
    id: GO:1902270
    label: (R)-carnitine transmembrane transport
  evidence_type: IDA
  original_reference_id: PMID:17855766
  qualifier: involved_in
  review:
    summary: OCTN2 transports L-carnitine (and butyryl-L-carnitine) in an
      electrogenic, Na+-dependent manner. Core carnitine transport process.
    action: ACCEPT
    reason: Direct evidence for (R)-carnitine transmembrane transport; core process.
    supported_by:
    - reference_id: PMID:17855766
      supporting_text: Transport of BC via OCTN2 is electrogenic
- term:
    id: GO:1901235
    label: (R)-carnitine transmembrane transporter activity
  evidence_type: IMP
  original_reference_id: PMID:23877104
  qualifier: enables
  review:
    summary: OCTN2 gene silencing dramatically suppresses Na+-dependent L-carnitine
      uptake in human brain capillary endothelial cells, demonstrating OCTN2
      (R)-carnitine transporter activity. Core molecular function.
    action: ACCEPT
    reason: siRNA knockdown directly implicates OCTN2 in (R)-carnitine transporter
      activity; core molecular function.
    supported_by:
    - reference_id: PMID:23877104
      supporting_text: '[(3)H]L-Carnitine uptake was dramatically suppressed by
        silencing of the OCTN2 gene.'
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Sequence-similarity transfer (from mouse Octn2, O70594) of a cytoplasm
      annotation. OCTN2 is an integral multipass plasma-membrane transporter; a bulk
      cytoplasm localization does not describe its functional location and is a likely
      mislocalization/over-annotation.
    action: REMOVE
    reason: OCTN2 is an integral membrane protein resident in the plasma membrane
      (and ER for the non-functional isoform); a generic cytoplasm location is not
      supported and is misleading. This ISS is an over-annotation.
    supported_by:
    - reference_id: PMID:17509700
      supporting_text: OCTN2 was expressed on the plasma membrane with robust
        N-glycosylation
- term:
    id: GO:1901235
    label: (R)-carnitine transmembrane transporter activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: Sequence-similarity transfer (from mouse Octn2) of (R)-carnitine
      transporter activity. Consistent with the directly demonstrated human OCTN2
      function.
    action: ACCEPT
    reason: ISS from mouse ortholog matches the extensive direct human evidence for
      (R)-carnitine transmembrane transporter activity; core molecular function.
    supported_by:
    - reference_id: PMID:10966938
      supporting_text: high-affinity transport of L-carnitine and Na(+).
- term:
    id: GO:1902270
    label: (R)-carnitine transmembrane transport
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Sequence-similarity transfer (from mouse Octn2) of (R)-carnitine
      transmembrane transport. Consistent with the directly demonstrated human
      process.
    action: ACCEPT
    reason: ISS matches abundant direct human evidence for (R)-carnitine transmembrane
      transport; core process.
    supported_by:
    - reference_id: PMID:10454528
      supporting_text: it transports carnitine only in the presence of Na(+)
- term:
    id: GO:0015226
    label: carnitine transmembrane transporter activity
  evidence_type: EXP
  original_reference_id: PMID:9685390
  qualifier: enables
  review:
    summary: Original molecular/functional identification of OCTN2 as a high-affinity,
      Na+-dependent carnitine transporter (Km 4.34 uM). Foundational evidence for the
      core molecular function.
    action: ACCEPT
    reason: Direct experimental identification of OCTN2 carnitine transporter activity;
      core molecular function.
    supported_by:
    - reference_id: PMID:9685390
      supporting_text: uptake of L-[3H]carnitine was strongly enhanced in a
        sodium-dependent manner with Km value of 4.34 microM
- term:
    id: GO:0015226
    label: carnitine transmembrane transporter activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-549297
  qualifier: enables
  review:
    summary: Reactome assertion that SLC22A5 (with SLC22A4/15/16) cotransports
      carnitine and Na+ from extracellular region to cytosol. Core molecular function.
    action: ACCEPT
    reason: Reactome pathway assertion matching the well-established core carnitine
      transporter activity.
    supported_by:
    - reference_id: PMID:9685390
      supporting_text: OCTN2 is a physiologically important, high affinity
        sodium-carnitine cotransporter in humans.
- term:
    id: GO:0015226
    label: carnitine transmembrane transporter activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5625674
  qualifier: enables
  review:
    summary: Reactome assertion (defective SLC22A5 does not cotransport carnitine/Na+)
      referencing the normal carnitine transporter activity of OCTN2. Core molecular
      function.
    action: ACCEPT
    reason: Reactome pathway assertion consistent with the established core carnitine
      transporter activity (and its loss in disease).
    supported_by:
    - reference_id: PMID:9916797
      supporting_text: loss of OCTN2 function causes SCD
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Sequence-similarity transfer (from mouse Octn2) of a cytosol annotation.
      As with the cytoplasm annotation, OCTN2 is an integral plasma-membrane protein;
      a cytosol localization is not supported.
    action: REMOVE
    reason: OCTN2 is an integral membrane transporter, not a cytosolic/soluble protein;
      the ISS cytosol annotation is a mislocalization/over-annotation.
    supported_by:
    - reference_id: PMID:17509700
      supporting_text: OCTN2 was expressed on the plasma membrane with robust
        N-glycosylation
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Sequence-similarity transfer (from mouse Octn2) of plasma-membrane
      localization, consistent with the direct human evidence. Core localization.
    action: ACCEPT
    reason: ISS matches abundant direct evidence for plasma-membrane localization of
      OCTN2.
    supported_by:
    - reference_id: PMID:33334877
      supporting_text: OCTN2 must interact with the surrounding lipid microenvironment
        to function.
- term:
    id: GO:0150104
    label: transport across blood-brain barrier
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Sequence-similarity transfer (from rat Octn2, Q9Z0E8) of a role in
      transport across the blood-brain barrier. OCTN2 is functionally expressed at
      the human BBB and mediates L-carnitine uptake there (confirmed by siRNA in
      PMID:23877104).
    action: KEEP_AS_NON_CORE
    reason: OCTN2 contributes to carnitine transport at the blood-brain barrier, a
      tissue-specific manifestation of its core carnitine transport function rather
      than a distinct core process.
    additional_reference_ids:
    - PMID:23877104
    supported_by:
    - reference_id: PMID:23877104
      supporting_text: OCTN2 is involved in L-carnitine transport at the human BBB.
- term:
    id: GO:1902270
    label: (R)-carnitine transmembrane transport
  evidence_type: IMP
  original_reference_id: PMID:23877104
  qualifier: involved_in
  review:
    summary: OCTN2 gene silencing suppresses Na+-dependent L-carnitine uptake in
      human brain endothelial cells, implicating OCTN2 in (R)-carnitine transmembrane
      transport. Core carnitine transport process.
    action: ACCEPT
    reason: siRNA knockdown directly implicates OCTN2 in (R)-carnitine transmembrane
      transport; core process.
    supported_by:
    - reference_id: PMID:23877104
      supporting_text: '[(3)H]L-Carnitine uptake was dramatically suppressed by
        silencing of the OCTN2 gene.'
- term:
    id: GO:0015651
    label: quaternary ammonium group transmembrane transporter activity
  evidence_type: IDA
  original_reference_id: PMID:23567998
  qualifier: enables
  review:
    summary: This paper concerns gabapentin transport by LAT1 (SLC7A5) at the
      blood-brain barrier; its abstract characterizes LAT1 and reports that gabapentin
      was negative for OCT-like transport. The cached abstract does not document an
      OCTN2/quaternary-ammonium transport assay, and the full text is unavailable, so
      the basis of the ARUK-UCL IDA annotation to OCTN2 cannot be verified from the
      cache.
    action: UNDECIDED
    reason: Cannot verify the OCTN2-specific supporting evidence from the abstract-only
      cache (the paper foregrounds LAT1); per curation policy, an experimental
      annotation whose full text I cannot read is left UNDECIDED rather than removed.
    supported_by:
    - reference_id: PMID:23567998
      supporting_text: Gabapentin was negative for OCT like transport and LAT2
        activity
- term:
    id: GO:0015697
    label: quaternary ammonium group transport
  evidence_type: IDA
  original_reference_id: PMID:23567998
  qualifier: involved_in
  review:
    summary: As above (PMID:23567998, gabapentin/LAT1). The cached abstract does not
      document an OCTN2 quaternary-ammonium transport assay; full text unavailable.
    action: UNDECIDED
    reason: The OCTN2-specific evidence cannot be verified from the abstract-only
      cache; left UNDECIDED rather than removed per policy on experimental annotations.
    supported_by:
    - reference_id: PMID:23567998
      supporting_text: Gabapentin was negative for OCT like transport and LAT2
        activity
- term:
    id: GO:0150104
    label: transport across blood-brain barrier
  evidence_type: NAS
  original_reference_id: PMID:30280653
  qualifier: involved_in
  review:
    summary: Non-traceable author-statement annotation citing a general blood-brain-
      barrier review. The specific functional evidence for OCTN2 at the BBB comes from
      the experimental PMID:23877104; this NAS from a review is weak support.
    action: KEEP_AS_NON_CORE
    reason: A weak (NAS, from a review) restatement of OCTN2's tissue-specific BBB
      carnitine-transport role; kept as non-core, with the experimental evidence
      provided by PMID:23877104.
    supported_by:
    - reference_id: PMID:23877104
      supporting_text: OCTN2 is involved in L-carnitine transport at the human BBB.
- term:
    id: GO:0150104
    label: transport across blood-brain barrier
  evidence_type: NAS
  original_reference_id: PMID:26590417
  qualifier: involved_in
  review:
    summary: Non-traceable author-statement annotation citing a general blood-brain-
      barrier review. Weak support; the functional OCTN2 BBB evidence is experimental
      (PMID:23877104).
    action: KEEP_AS_NON_CORE
    reason: Weak (NAS, review-based) restatement of the tissue-specific BBB carnitine-
      transport role; non-core.
    supported_by:
    - reference_id: PMID:23877104
      supporting_text: OCTN2 is involved in L-carnitine transport at the human BBB.
- term:
    id: GO:0009609
    label: response to symbiotic bacterium
  evidence_type: IMP
  original_reference_id: PMID:18005709
  qualifier: involved_in
  review:
    summary: OCTN2-dependent uptake of the Bacillus subtilis quorum-sensing peptide
      CSF in intestinal epithelia links the transporter to host responses to
      commensal bacteria. A downstream, tissue-specific biology of OCTN2's cationic-
      peptide transport, not a core transporter function.
    action: KEEP_AS_NON_CORE
    reason: Genuine but peripheral role (mediating uptake of a bacterial signaling
      peptide) downstream of OCTN2's transport activity; non-core.
    supported_by:
    - reference_id: PMID:18005709
      supporting_text: OCTN2-mediated CSF transport serves as an example of a
        host-bacterial interaction that allows the host to monitor and respond to
        changes in the behavior or composition of colonic flora.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5625674
  qualifier: located_in
  review:
    summary: Reactome-asserted plasma-membrane localization of SLC22A5. Consistent
      with the established core localization.
    action: ACCEPT
    reason: Reactome pathway assertion matching well-established plasma-membrane
      localization.
    supported_by:
    - reference_id: PMID:17509700
      supporting_text: OCTN2 was expressed on the plasma membrane with robust
        N-glycosylation
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    summary: High-throughput proteomic detection of OCTN2 among proteins in human
      urinary exosomes. Incidental proteomic co-purification (renal epithelial
      membrane proteins are commonly recovered in urinary exosomes); not a functional
      subcellular location.
    action: MARK_AS_OVER_ANNOTATED
    reason: Exosome detection is a mass-spectrometry co-occurrence consistent with
      shedding of apical renal membrane proteins; it does not indicate a functional
      exosomal role and over-annotates the localization.
    supported_by:
    - reference_id: PMID:19056867
      supporting_text: Normal human urine contains large numbers of exosomes
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-165026
  qualifier: located_in
  review:
    summary: Reactome-asserted plasma-membrane localization of SLC22A5 (in the
      carnitine transport reaction). Consistent with core localization.
    action: ACCEPT
    reason: Reactome assertion matching established plasma-membrane localization.
    supported_by:
    - reference_id: PMID:33334877
      supporting_text: OCTN2 must interact with the surrounding lipid microenvironment
        to function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-549297
  qualifier: located_in
  review:
    summary: Reactome-asserted plasma-membrane localization of SLC22A5 (in the
      carnitine/Na+ cotransport reaction). Consistent with core localization.
    action: ACCEPT
    reason: Reactome assertion matching established plasma-membrane localization.
    supported_by:
    - reference_id: PMID:17509700
      supporting_text: OCTN2 was expressed on the plasma membrane with robust
        N-glycosylation
- term:
    id: GO:0060731
    label: positive regulation of intestinal epithelial structure maintenance
  evidence_type: IMP
  original_reference_id: PMID:18005709
  qualifier: involved_in
  review:
    summary: OCTN2-mediated uptake of the bacterial CSF peptide induces cytoprotective
      heat shock proteins that prevent oxidant-induced intestinal epithelial injury
      and loss of barrier function, linking OCTN2 to intestinal homeostasis. A
      downstream, tissue-specific process rather than a core transporter function.
    action: KEEP_AS_NON_CORE
    reason: Genuine but peripheral physiological consequence of OCTN2 cationic-peptide
      transport in the intestine; non-core.
    supported_by:
    - reference_id: PMID:18005709
      supporting_text: CSF also induces cytoprotective heat shock proteins (Hsps),
        which prevent oxidant-induced intestinal epithelial cell injury and loss of
        barrier function.
- term:
    id: GO:0070715
    label: sodium-dependent organic cation transport
  evidence_type: IDA
  original_reference_id: PMID:15238359
  qualifier: involved_in
  review:
    summary: OCTN2-mediated Na+-dependent, high-affinity L-carnitine uptake in
      placental brush-border membranes. Carnitine is a zwitterionic organic cation;
      this Na+-dependent organic-cation transport is essentially the core carnitine
      uptake function.
    action: ACCEPT
    reason: Directly demonstrated Na+-dependent organic-cation (carnitine) transport
      by OCTN2; reflects the core function.
    supported_by:
    - reference_id: PMID:15238359
      supporting_text: l-carnitine uptake was sodium and temperature dependent
- term:
    id: GO:0070715
    label: sodium-dependent organic cation transport
  evidence_type: IDA
  original_reference_id: PMID:9685390
  qualifier: involved_in
  review:
    summary: OCTN2 characterized as a sodium-dependent high-affinity carnitine
      (zwitterionic organic cation) transporter. Reflects the core Na+-coupled
      transport mechanism.
    action: ACCEPT
    reason: Directly demonstrated Na+-dependent organic-cation (carnitine) transport;
      reflects the core function/mechanism.
    supported_by:
    - reference_id: PMID:9685390
      supporting_text: OCTN2 is a physiologically important, high affinity
        sodium-carnitine cotransporter in humans.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:15523054
  qualifier: enables
  review:
    summary: OCTN2 binds the PDZ scaffolding protein PDZK1 (interaction data). While
      recorded as generic protein binding, this specific interaction is functionally
      important (PDZK1 stimulates OCTN2 carnitine transport). The informative capture
      is the PDZ-domain-binding annotation (GO:0030165) from the same study.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding is uninformative per curation guidelines; the
      biologically meaningful content (binding PDZK1 via a PDZ motif) is better
      captured by the PDZ domain binding annotation from the same reference.
    supported_by:
    - reference_id: PMID:15523054
      supporting_text: The present findings are the first to identify PDZK1 as a
        functional regulator of OCTN2 through direct interaction with the C terminus.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IC
  original_reference_id: PMID:9618255
  qualifier: located_in
  review:
    summary: Plasma-membrane localization inferred by the curator from the
      demonstrated transport function (OCTN2 mediates TEA transport when expressed in
      HeLa cells). Consistent with the established core localization.
    action: ACCEPT
    reason: Plasma-membrane localization inferred from surface transport function and
      confirmed by later direct evidence; correct.
    supported_by:
    - reference_id: PMID:9618255
      supporting_text: OCTN2 mediates the transport of tetraethylammonium, a
        prototypical organic cation, in a pH-dependent manner.
- term:
    id: GO:0015226
    label: carnitine transmembrane transporter activity
  evidence_type: IDA
  original_reference_id: PMID:9685390
  qualifier: enables
  review:
    summary: Original identification of OCTN2 as a high-affinity Na+-dependent
      carnitine transporter. Core molecular function.
    action: ACCEPT
    reason: Direct experimental demonstration of carnitine transporter activity; core
      molecular function.
    supported_by:
    - reference_id: PMID:9685390
      supporting_text: uptake of L-[3H]carnitine was strongly enhanced in a
        sodium-dependent manner with Km value of 4.34 microM
- term:
    id: GO:0015226
    label: carnitine transmembrane transporter activity
  evidence_type: IMP
  original_reference_id: PMID:9916797
  qualifier: enables
  review:
    summary: Mutational evidence that loss of OCTN2 function causes systemic carnitine
      deficiency (jvs mouse mutation abrogates carnitine transport; human SLC22A5
      mutations in SCD pedigrees). Confirms OCTN2 carnitine transporter activity via
      loss-of-function. Core molecular function.
    action: ACCEPT
    reason: Loss-of-function (disease/mutation) evidence directly supports carnitine
      transporter activity; core molecular function.
    supported_by:
    - reference_id: PMID:9916797
      supporting_text: this mutation abrogates carnitine transport.
- term:
    id: GO:0015651
    label: quaternary ammonium group transmembrane transporter activity
  evidence_type: IDA
  original_reference_id: PMID:9618255
  qualifier: enables
  review:
    summary: OCTN2 mediates transport of the quaternary ammonium compound
      tetraethylammonium (TEA) in a pH-dependent manner when expressed in HeLa cells.
      Correct family-level MF, broader than the specific carnitine activity.
    action: KEEP_AS_NON_CORE
    reason: Genuine quaternary-ammonium (organic cation) transporter activity, but
      the informative core MF is carnitine transmembrane transporter activity.
    supported_by:
    - reference_id: PMID:9618255
      supporting_text: OCTN2 mediates the transport of tetraethylammonium, a
        prototypical organic cation, in a pH-dependent manner.
- term:
    id: GO:0015697
    label: quaternary ammonium group transport
  evidence_type: IDA
  original_reference_id: PMID:9618255
  qualifier: involved_in
  review:
    summary: OCTN2 transports the quaternary ammonium organic cation TEA (and
      competing organic cations MPP+, MPTP, methamphetamine). Correct but broad
      process.
    action: KEEP_AS_NON_CORE
    reason: Correct but general organic-cation transport process; the specific process
      is carnitine transmembrane transport.
    supported_by:
    - reference_id: PMID:9618255
      supporting_text: Several organic cations, including the neurotoxins
        1-methyl-4-phenylpyridinium
- term:
    id: GO:0015879
    label: carnitine transport
  evidence_type: IDA
  original_reference_id: PMID:9685390
  qualifier: involved_in
  review:
    summary: OCTN2 identified as the physiologically important high-affinity
      Na+-carnitine cotransporter. Core carnitine transport process.
    action: ACCEPT
    reason: Direct evidence of OCTN2-mediated carnitine transport; core process.
    supported_by:
    - reference_id: PMID:9685390
      supporting_text: OCTN2 is a physiologically important, high affinity
        sodium-carnitine cotransporter in humans.
- term:
    id: GO:0015879
    label: carnitine transport
  evidence_type: IMP
  original_reference_id: PMID:9916797
  qualifier: involved_in
  review:
    summary: Loss-of-function OCTN2 mutations abrogate carnitine transport and cause
      systemic carnitine deficiency, confirming OCTN2's role in carnitine transport.
      Core process.
    action: ACCEPT
    reason: Mutation/disease evidence directly supports OCTN2 involvement in carnitine
      transport; core process.
    supported_by:
    - reference_id: PMID:9916797
      supporting_text: this mutation abrogates carnitine transport.
- term:
    id: GO:0016324
    label: apical plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:17274673
  qualifier: located_in
  review:
    summary: OCTN2 localized to the apical membrane of the human proximal tubule cell
      line Caki-1, where it mediates carnitine reabsorption. Core polarized
      localization in kidney.
    action: ACCEPT
    reason: Directly documented apical plasma-membrane localization in proximal tubule
      cells; correct.
    supported_by:
    - reference_id: PMID:17274673
      supporting_text: an apical membrane expression pattern of OCTN2 in Caki-1 cells
        was discovered.
- term:
    id: GO:0016324
    label: apical plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:18641280
  qualifier: located_in
  review:
    summary: OCTN2 predominantly localized to the apical membranes of human corneal
      and conjunctival epithelial cells, with apical L-carnitine uptake. Apical
      localization consistent across epithelia.
    action: ACCEPT
    reason: Directly documented apical plasma-membrane localization in ocular
      epithelia; correct.
    supported_by:
    - reference_id: PMID:18641280
      supporting_text: OCTN1 and OCTN2 were predominately localized in the apical
        membranes of the cells.
- term:
    id: GO:0030165
    label: PDZ domain binding
  evidence_type: IPI
  original_reference_id: PMID:15523054
  qualifier: enables
  review:
    summary: The OCTN2 C-terminal PDZ-binding motif (last four residues) binds the PDZ
      protein PDZK1 (and NHERF2), and PDZK1 co-expression stimulates OCTN2 carnitine
      transport capacity ~6-fold. An informative, functionally relevant molecular
      function (accessory regulatory interaction).
    action: KEEP_AS_NON_CORE
    reason: A specific, biologically meaningful protein-domain interaction that
      regulates OCTN2 transport; retained as an informative non-core molecular
      function (the core MF remains carnitine transport).
    supported_by:
    - reference_id: PMID:15523054
      supporting_text: a specific interaction of apical transporters OCTN1 and OCTN2,
        but not basolateral transporters OCT1 and OCT2, with PDZK1
- term:
    id: GO:0031526
    label: brush border membrane
  evidence_type: IDA
  original_reference_id: PMID:15238359
  qualifier: located_in
  review:
    summary: OCTN2 detected by Western blot in placental brush-border (but not basal)
      membrane vesicles. Brush-border (apical) localization consistent with the
      transporter's polarized reabsorptive/absorptive role.
    action: ACCEPT
    reason: Directly documented brush-border membrane localization; correct and
      informative (specific apical sub-localization).
    supported_by:
    - reference_id: PMID:15238359
      supporting_text: OCTN2, a high-affinity, Na(+)-dependent carnitine transporter,
        was present in placental BBM but not in isolated basal plasma membrane
        vesicles.
- term:
    id: GO:0031526
    label: brush border membrane
  evidence_type: ISS
  original_reference_id: PMID:15523054
  qualifier: located_in
  review:
    summary: Brush-border membrane localization supported by sequence-similarity
      transfer (rat Octn2, Q9Z0E8) alongside the demonstrated colocalization of OCTN2
      and PDZK1 in kidney brush-border membranes. Consistent with the direct human
      evidence.
    action: ACCEPT
    reason: Brush-border localization is corroborated directly (placenta,
      OCTN2/PDZK1 colocalization in kidney BBM) and by ISS from the rat ortholog;
      correct.
    supported_by:
    - reference_id: PMID:15523054
      supporting_text: both PDZK1 and OCTN2 are colocalized in brush-border membranes
        of the kidney.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: PMID:9916797
  qualifier: located_in
  review:
    summary: Author-asserted plasma-membrane localization of the carnitine transporter
      (membrane-physiological studies indicated a plasma-membrane carnitine transport
      defect in SCD). Consistent with the established core localization.
    action: ACCEPT
    reason: Traceable author statement of plasma-membrane carnitine transporter
      localization, corroborated by extensive direct evidence.
    supported_by:
    - reference_id: PMID:9916797
      supporting_text: a defect of the carnitine transport system in the plasma
        membrane in SCD patients
core_functions:
- description: Sodium-coupled, high-affinity import of L-carnitine across the plasma
    membrane. OCTN2 symports one Na+ with one (R)-carnitine molecule, enabling cellular
    uptake and renal reabsorption of carnitine that supplies the mitochondrial
    carnitine shuttle for long-chain fatty-acid beta-oxidation.
  molecular_function:
    id: GO:0015226
    label: carnitine transmembrane transporter activity
  directly_involved_in:
  - id: GO:1902603
    label: carnitine transmembrane transport
  locations:
  - id: GO:0005886
    label: plasma membrane
  - id: GO:0016324
    label: apical plasma membrane
  supported_by:
  - reference_id: PMID:9685390
    supporting_text: OCTN2 is a physiologically important, high affinity
      sodium-carnitine cotransporter in humans.
  - reference_id: PMID:10966938
    supporting_text: hOCTN2 mediates electrogenic Na(+)-dependent stereoselective
      high-affinity transport of L-carnitine and Na(+).
- description: Stereospecific (R)-carnitine transmembrane transporter activity,
    demonstrated directly in heterologous systems and native epithelia and lost in
    disease-causing SLC22A5 mutants; this is the specific-substrate resolution of the
    core carnitine transport function.
  molecular_function:
    id: GO:1901235
    label: (R)-carnitine transmembrane transporter activity
  directly_involved_in:
  - id: GO:1902270
    label: (R)-carnitine transmembrane transport
  locations:
  - id: GO:0005886
    label: plasma membrane
  supported_by:
  - reference_id: PMID:9916797
    supporting_text: this mutation abrogates carnitine transport.
  - reference_id: PMID:17509700
    supporting_text: A novel organic cation transporter OCTN2 is indispensable for
      carnitine transport across plasma membrane
- description: Sodium-dependent transport of carnitine and other zwitterionic/cationic
    organic solutes; the Na+-coupled symport mechanism underlies OCTN2's high-affinity
    carnitine uptake, while OCTN2 also transports organic cations more weakly in a
    Na+-independent manner (polyspecific secondary activity).
  molecular_function:
    id: GO:0015226
    label: carnitine transmembrane transporter activity
  directly_involved_in:
  - id: GO:0070715
    label: sodium-dependent organic cation transport
  locations:
  - id: GO:0016324
    label: apical plasma membrane
  supported_by:
  - reference_id: PMID:10454528
    supporting_text: it transports carnitine only in the presence of Na(+)
  - reference_id: PMID:15238359
    supporting_text: l-carnitine uptake was sodium and temperature dependent
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10454528
  title: Functional characteristics and tissue distribution pattern of organic cation
    transporter 2 (OCTN2), an organic cation/carnitine transporter.
  findings:
  - statement: OCTN2 transports organic cations independently of Na+ but transports
      carnitine only in the presence of Na+; short-chain acylcarnitines are also
      substrates; disease mutations M352R and P478L abolish transport.
    supporting_text: OCTN2 transports organic cations without involving Na(+), but it
      transports carnitine only in the presence of Na(+).
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Abstract confirms OCTN2 as a dual Na+-independent organic cation /
      Na+-dependent carnitine transporter; PMID matches title.
- id: PMID:10966938
  title: Functional and pharmacological characterization of human Na(+)-carnitine
    cotransporter hOCTN2.
  findings:
  - statement: hOCTN2 is an electrogenic Na+-dependent, stereoselective, high-affinity
      L-carnitine cotransporter (Km ~4.8 uM) that also transports betaine and is
      inhibited by emetine, quinidine and verapamil.
    supporting_text: hOCTN2 mediates electrogenic Na(+)-dependent stereoselective
      high-affinity transport of L-carnitine and Na(+).
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Electrophysiological characterization; supports the Na+-symport
      mechanism and betaine transport.
- id: PMID:15238359
  title: L-Carnitine transport in human placental brush-border membranes is mediated
    by the sodium-dependent organic cation transporter OCTN2.
  findings:
  - statement: OCTN2 protein is present in placental brush-border (but not basal)
      membranes and mediates Na+-dependent, high-affinity L-carnitine uptake for
      maternofetal transport.
    supporting_text: OCTN2, a high-affinity, Na(+)-dependent carnitine transporter,
      was present in placental BBM but not in isolated basal plasma membrane vesicles.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Supports carnitine transporter activity and brush-border (apical)
      localization.
- id: PMID:15523054
  title: PDZK1 directly regulates the function of organic cation/carnitine transporter
    OCTN2.
  findings:
  - statement: The OCTN2 C-terminal PDZ-binding motif (last four residues) binds
      PDZK1; PDZK1 co-expression stimulates OCTN2 carnitine transport capacity ~6-fold,
      and the two colocalize in kidney brush-border membranes.
    supporting_text: The present findings are the first to identify PDZK1 as a
      functional regulator of OCTN2 through direct interaction with the C terminus.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes the functionally meaningful PDZ-domain (PDZK1)
      interaction; supersedes the bare protein-binding IPI.
- id: PMID:17274673
  title: OCTN2-mediated carnitine uptake in a newly discovered human proximal tubule
    cell line (Caki-1).
  findings:
  - statement: OCTN2 shows an apical membrane expression pattern in human proximal
      tubule Caki-1 cells and mediates Na+-dependent high-affinity carnitine uptake,
      consistent with renal tubular carnitine reabsorption.
    supporting_text: an apical membrane expression pattern of OCTN2 in Caki-1 cells
      was discovered.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Supports apical/renal localization and carnitine reabsorption role.
- id: PMID:17509700
  title: OCTN2VT, a splice variant of OCTN2, does not transport carnitine because
    of the retention in the endoplasmic reticulum caused by insertion of 24 amino
    acids in the first extracellular loop of OCTN2.
  findings:
  - statement: The functional OCTN2 is a plasma-membrane, N-glycosylated carnitine
      transporter; the OCTN2VT splice variant (isoform 3) is retained in the ER,
      poorly glycosylated, and cannot take up carnitine.
    supporting_text: OCTN2VT was retained in the endoplasmic reticulum (ER) with poor
      N-glycosylation. In addition, the retention in the ER caused no carnitine uptake
      into the cells.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Distinguishes plasma-membrane functional OCTN2 from ER-retained,
      transport-dead isoform 3.
- id: PMID:17855766
  title: Transport of butyryl-L-carnitine, a potential prodrug, via the carnitine
    transporter OCTN2 and the amino acid transporter ATB(0,+).
  findings:
  - statement: OCTN2 is a high-affinity, low-capacity transporter for butyryl-L-carnitine
      (electrogenic, Na+-dependent), in addition to L-carnitine.
    supporting_text: OCTN2 is a high-affinity/low-capacity transporter
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Supports acyl-carnitine (butyryl-carnitine) transport by OCTN2.
- id: PMID:18005709
  title: The Bacillus subtilis quorum-sensing molecule CSF contributes to intestinal
    homeostasis via OCTN2, a host cell membrane transporter.
  findings:
  - statement: OCTN2 is an apical intestinal organic cation transporter that takes up
      the B. subtilis quorum-sensing pentapeptide CSF, inducing cytoprotective heat
      shock proteins and contributing to intestinal homeostasis.
    supporting_text: These effects of CSF depend on its uptake by an apical membrane
      organic cation transporter-2 (OCTN2).
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Supports apical intestinal localization and a polyspecific
      cationic-peptide transport role (non-core).
- id: PMID:18641280
  title: Expression and localization of carnitine/organic cation transporter OCTN1
    and OCTN2 in ocular epithelium.
  findings:
  - statement: OCTN2 is expressed and predominantly apically localized in human
      corneal and conjunctival epithelial cells, mediating apical L-carnitine uptake.
    supporting_text: OCTN1 and OCTN2 were predominately localized in the apical
      membranes of the cells.
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Supports apical localization in ocular epithelia.
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings:
  - statement: Large-scale proteomic profiling of human urinary exosomes; OCTN2 is
      among detected renal-epithelial membrane proteins (incidental co-purification).
    supporting_text: Normal human urine contains large numbers of exosomes
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput proteomics; exosome detection is incidental, not a
      functional localization.
- id: PMID:20722056
  title: Cytokine regulation of OCTN2 expression and activity in small and large intestine.
  findings:
  - statement: Intestinal OCTN2 apical expression and Na+-dependent carnitine uptake
      are increased by IFN-gamma and TNF-alpha; siRNA knockdown confirms >80% of
      Na+-dependent carnitine uptake is OCTN2-dependent.
    supporting_text: more than 80% of Na+-dependent carnitine uptake is due to OCTN2
      in Caco2BBE cells
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; supports carnitine transport, apical
      localization, and cytokine (IFN-gamma/TNF) regulation.
- id: PMID:23567998
  title: Transport of gabapentin by LAT1 (SLC7A5).
  findings:
  - statement: Gabapentin is transported by LAT1 (SLC7A5) at the blood-brain barrier
      and was negative for OCT-like transport; the abstract does not document an
      OCTN2 quaternary-ammonium transport assay.
    supporting_text: Gabapentin was negative for OCT like transport and LAT2 activity
  reference_review:
    relevance: LOW
    correctness: UNVERIFIED
    review_notes: Paper is about LAT1/gabapentin; the ARUK-UCL OCTN2 IDA cannot be
      verified from the abstract-only cache (full text unavailable). Annotation left
      UNDECIDED.
- id: PMID:23877104
  title: Functional expression of organic cation/carnitine transporter 2 (OCTN2/SLC22A5)
    in human brain capillary endothelial cell line hCMEC/D3, a human blood-brain barrier
    model.
  findings:
  - statement: OCTN2 siRNA knockdown dramatically suppresses Na+-dependent L-carnitine
      uptake in human brain endothelial cells, showing OCTN2 mediates carnitine
      transport at the human blood-brain barrier.
    supporting_text: OCTN2 is involved in L-carnitine transport at the human BBB.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Experimental (siRNA) evidence for OCTN2 carnitine transport at the
      BBB; underpins the BBB-transport annotations.
- id: PMID:26590417
  title: Establishment and Dysfunction of the Blood-Brain Barrier.
  findings:
  - statement: General review of blood-brain barrier physiology and dysfunction;
      cited (NAS) for OCTN2's role in transport across the BBB.
    supporting_text: Establishment and Dysfunction of the Blood-Brain Barrier.
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Review-based NAS support; weak. The experimental BBB evidence is
      PMID:23877104.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings:
  - statement: Proteome-scale binary interactome mapping; source of a high-throughput
      OCTN2 protein-binding annotation (HMGCS1) without independent functional
      validation.
    supporting_text: Architecture of the human interactome defines protein communities
      and disease networks
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; the OCTN2 interaction is uninformative
      bare protein binding.
- id: PMID:30280653
  title: 'Blood-Brain Barrier: From Physiology to Disease and Back.'
  findings:
  - statement: General blood-brain barrier review; cited (NAS) for OCTN2's role in
      transport across the BBB.
    supporting_text: 'Blood-Brain Barrier: From Physiology to Disease and Back.'
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Review-based NAS support; weak. Experimental BBB evidence is
      PMID:23877104.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings:
  - statement: Proteome-scale binary (Y2H) interactome map; source of high-throughput
      OCTN2 protein-binding annotations (keratins, KRTAP6-3, MTUS2, NOTCH2NLC) without
      functional validation.
    supporting_text: A reference map of the human binary protein interactome
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput Y2H; keratin/KAP partners are common artifacts;
      uninformative bare protein binding.
- id: PMID:33124720
  title: Deorphaning a solute carrier 22 family member, SLC22A15, through functional
    genomic studies.
  findings:
  - statement: In deorphaning SLC22A15, OCTN2 (SLC22A5) is used as a reference
      zwitterion transporter; dimethylglycine is noted to interact with SLC22A5 and
      betaine is a known SLC22A5 substrate.
    supporting_text: Dimethylglycine, known to interact with SLC22A5
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Full text available; OCTN2 is a comparator. Betaine transport by
      OCTN2 is directly shown in PMID:10966938; dimethylglycine interaction is cited
      here.
- id: PMID:33334877
  title: Cholesterol stimulates the cellular uptake of L-carnitine by the carnitine/organic
    cation transporter novel 2 (OCTN2).
  findings:
  - statement: OCTN2 is responsible for cellular carnitine uptake in most tissues and
      resides in the plasma membrane; membrane cholesterol modulates its L-carnitine
      transport.
    supporting_text: The carnitine/organic cation transporter novel 2 (OCTN2) is
      responsible for the cellular uptake of carnitine in most tissues.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; supports plasma-membrane localization and
      carnitine transporter activity (cholesterol-regulated).
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings:
  - statement: Proteome-scale affinity-purification interactome (BioPlex); source of a
      high-throughput OCTN2 protein-binding annotation without functional validation.
    supporting_text: Dual proteome-scale networks reveal cell-specific remodeling of
      the human interactome
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; uninformative bare protein binding.
- id: PMID:35307651
  title: Localization of Xenobiotic Transporters Expressed at the Human Blood-Testis
    Barrier.
  findings:
  - statement: At the human blood-testis barrier, OCTN2 localizes to Sertoli-cell
      basal membranes and peritubular myoid cells, consistent with a role in transport
      across the barrier.
    supporting_text: OCTN2, multidrug resistance protein (MRP) 3, MRP6, and MRP7
      localized to SC basal membranes and peritubular myoid cells (PMCs)
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Full text available; supports basal-membrane (Sertoli cell)
      localization at the blood-testis barrier.
- id: PMID:9618255
  title: cDNA sequence, transport function, and genomic organization of human OCTN2,
    a new member of the organic cation transporter family.
  findings:
  - statement: OCTN2 is a 557-aa, 12-transmembrane organic cation transporter (chr
      5q31) that mediates pH-dependent transport of tetraethylammonium and other
      organic cations (including neurotoxins MPP+/MPTP).
    supporting_text: OCTN2 mediates the transport of tetraethylammonium, a prototypical
      organic cation, in a pH-dependent manner.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Original human OCTN2 cloning; supports organic cation (quaternary
      ammonium) transport and multipass membrane topology.
- id: PMID:9685390
  title: Molecular and functional identification of sodium ion-dependent, high affinity
    human carnitine transporter OCTN2.
  findings:
  - statement: OCTN2 is a high-affinity (Km 4.34 uM), Na+-dependent human carnitine
      cotransporter, strongly expressed in kidney, skeletal muscle, heart and placenta.
    supporting_text: OCTN2 is a physiologically important, high affinity
      sodium-carnitine cotransporter in humans.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Foundational identification of OCTN2 as the Na+-dependent carnitine
      transporter.
- id: PMID:9916797
  title: Primary systemic carnitine deficiency is caused by mutations in a gene encoding
    sodium ion-dependent carnitine transporter.
  findings:
  - statement: Loss-of-function mutations in SLC22A5/OCTN2 (in jvs mice and human SCD
      pedigrees) abrogate carnitine transport and cause systemic primary carnitine
      deficiency.
    supporting_text: this mutation abrogates carnitine transport.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes SLC22A5 as the systemic carnitine deficiency gene via
      loss of carnitine transport.
- id: Reactome:R-HSA-165026
  title: OCTN2 / SLC22A5 transports CAR from extracellular space to cytosol
  findings: []
- id: Reactome:R-HSA-549127
  title: SLC-mediated transport of organic cations
  findings: []
- id: Reactome:R-HSA-549297
  title: SLC22A4, 5,15,16 cotransport CAR, Na+ from extracellular region to cytosol
  findings: []
- id: Reactome:R-HSA-5625674
  title: Defective SLC22A5 does not cotransport CAR, Na+ from extracellular region
    to cytosol
  findings: []