SLC6A8 (creatine transporter 1, CRT/CT1) is a sodium- and chloride-dependent plasma membrane creatine transporter of the SLC6 (SNF/neurotransmitter:sodium symporter) family. The 635-residue, 12-transmembrane protein couples the inward electrochemical gradients of Na+ and Cl- to import creatine into cells with a stoichiometry of approximately 2 Na+ : 1 Cl- : 1 creatine, generating an electrogenic, high-affinity (micromolar Km) uptake that is highly specific for creatine and closely related guanidino compounds; it does not transport choline or the neurotransmitter GABA despite its family relationship to GABA, taurine and betaine transporters. It is the transport arm of the creatine/phosphocreatine energy-buffer system, distributing blood-borne creatine to tissues with high and fluctuating energy demand. It is most strongly expressed in skeletal muscle, kidney and heart, with lower expression in brain, and is also present in intestine and other epithelia; in polarized epithelial cells (intestine, kidney) it localizes to the apical plasma membrane. It mediates creatine entry into the brain across the blood-brain barrier. Loss-of-function variants cause X-linked cerebral creatine deficiency syndrome 1 (creatine transporter deficiency), characterized by intellectual disability, severe speech delay, behavioral abnormalities and seizures.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: SLC6A8 is an integral plasma membrane transporter; the plasma membrane is where it acts. Well supported and consistent with experimental localization. Reason: Correct cellular location for the transporter, corroborated by experimental (IMP/IDA) localization to the plasma membrane / apical plasma membrane. Supporting Evidence: PMID:22644605 All mutants were properly targeted to the plasma membrane in both systems. |
| GO:0006865 amino acid transport | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Creatine is a guanidino compound, not an amino acid, and the established substrate of SLC6A8 is creatine. This IBA term is an imprecise, family-level generalization that mischaracterizes the cargo. Reason: Over-broad/family-derived annotation; the specific, experimentally established transported substrate is creatine (GO:0015881), not amino acids. Better captured by creatine transmembrane transport. |
| GO:0035725 sodium ion transmembrane transport | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: SLC6A8 cotransports Na+ together with creatine, so it does participate in sodium ion transmembrane transport, but this is a generic by-product of the symport mechanism rather than its core dedicated function. Reason: Mechanistically true (Na+ is co-transported) but generic; the core function is creatine symport. Retain as a non-core mechanistic annotation. Supporting Evidence: PMID:9882430 induced a Na+- and Cl--dependent creatine uptake activity |
| GO:0005332 gamma-aminobutyric acid:sodium:chloride symporter activity | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: This IBA annotation, propagated from GABA/monoamine transporter relatives in the SLC6 family, assigns the wrong substrate. SLC6A8 transports creatine, not GABA; GABA does not inhibit creatine uptake, indicating it is not a substrate. Reason: Wrong-substrate over-annotation derived from family phylogeny. The experimentally verified molecular function is creatine:sodium symporter activity (GO:0005309). GABA is not transported. Supporting Evidence: PMID:12433955 More distant structural analogues of creatine, such as GABA, choline, glycine, beta-alanine, taurine and betaine, had no effect on intestinal creatine uptake, indicating a high substrate specificity of the creatine transporter |
| GO:0005309 creatine:sodium symporter activity | IEA GO_REF:0000120 | ACCEPT | Summary: Correct core molecular function, here assigned electronically. Strongly supported by multiple experimental annotations and the UniProt catalytic activity. Reason: Accurate molecular function; this is the core activity of SLC6A8. Corroborated by independent IDA/IMP evidence. |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Correct plasma membrane localization, assigned electronically and supported experimentally. Reason: Correct cellular location; redundant with experimental plasma membrane annotations. |
| GO:0006836 neurotransmitter transport | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Creatine is not a classical neurotransmitter and SLC6A8 is a creatine transporter, not a neurotransmitter transporter. This term derives from the InterPro signature shared with the neurotransmitter:sodium symporter family. Reason: Family-signature (InterPro) over-annotation; the transported cargo is creatine, not a neurotransmitter. Better represented by creatine transmembrane transport. |
| GO:0015812 gamma-aminobutyric acid transport | IEA GO_REF:0000108 | MARK AS OVER ANNOTATED | Summary: Inferred logically from the (incorrect for this gene) GABA symporter molecular function. Since SLC6A8 does not transport GABA, this process annotation is also incorrect. Reason: Downstream of the erroneous GO:0005332 GABA symporter annotation; GABA is not a substrate of SLC6A8. Supporting Evidence: PMID:12433955 More distant structural analogues of creatine, such as GABA, choline, glycine, beta-alanine, taurine and betaine, had no effect on intestinal creatine uptake |
| GO:0016020 membrane | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Generic membrane localization, true but uninformative given the more specific plasma membrane / apical plasma membrane annotations. Reason: Correct but non-specific; subsumed by the plasma membrane annotation. Retained as a high-level location. |
| GO:0016324 apical plasma membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: In polarized epithelia (intestine, kidney) SLC6A8 is apical. Correct context-specific localization, also supported experimentally by immunohistochemistry in enterocytes. Reason: Accurate for polarized epithelial cells but context-specific; the gene-wide core location is plasma membrane. Supporting Evidence: PMID:12433955 CRT protein was mainly associated with the apical membrane of the enterocytes |
| GO:0006600 creatine metabolic process | TAS Reactome:R-HSA-71288 | KEEP AS NON CORE | Summary: SLC6A8 is the transport step of cellular creatine handling and so participates in the creatine metabolic process. Reasonable high-level process annotation. Reason: Accurate process context (creatine distribution within metabolism) but broader than the specific creatine transmembrane transport process that is the gene's core role. |
| GO:0005309 creatine:sodium symporter activity | ISS PMID:25531585 Negative regulation of the creatine transporter SLC6A8 by SP... | ACCEPT | Summary: Core molecular function, supported here by sequence/ortholog similarity. Correct. Reason: Accurate core molecular function; consistent with direct experimental evidence. |
| GO:0005309 creatine:sodium symporter activity | IMP PMID:17465020 Functional characterization of missense variants in the crea... | ACCEPT | Summary: Functional (creatine uptake) characterization of SLC6A8 missense variants establishes the creatine:sodium symporter activity by mutational analysis. Strong support for the core molecular function. Reason: Direct experimental (IMP) support for the core molecular function via variant analysis. |
| GO:0005309 creatine:sodium symporter activity | IMP PMID:22644605 Functional and electrophysiological characterization of four... | ACCEPT | Summary: Electrophysiological and transport characterization of non-truncating SLC6A8 mutants directly demonstrates electrogenic, Na+/Cl--coupled creatine symport activity. Reason: Strong direct experimental (IMP) support; loss of activity in mutants confirms the function. Supporting Evidence: PMID:22644605 Mutations led to the complete loss of both electrogenic and transport activities |
| GO:0005309 creatine:sodium symporter activity | IMP PMID:25861866 Estimated carrier frequency of creatine transporter deficien... | ACCEPT | Summary: Functional creatine-uptake characterization of novel SLC6A8 missense variants supports the creatine:sodium symporter molecular function. Reason: Direct experimental (IMP) support for the core molecular function. |
| GO:0005309 creatine:sodium symporter activity | IDA PMID:7945388 The cloning and expression of a human creatine transporter. | ACCEPT | Summary: Heterologous expression of the cloned human creatine transporter produced sodium-dependent creatine uptake, directly demonstrating the activity. Reason: Direct assay (IDA) of the core molecular function in a heterologous system. Supporting Evidence: PMID:7945388 Transient expression of the hCRT-BS2M in COS-7 cells demonstrates sodium dependent [14C]creatine uptake with a KM value of 14.9 +/- 3.0 microM |
| GO:0005309 creatine:sodium symporter activity | IDA PMID:7953292 Cloning, pharmacological characterization, and genomic local... | ACCEPT | Summary: The cloned human creatine transporter mediated high-affinity creatine uptake with no transport of choline, directly establishing creatine symport activity and specificity. Reason: Direct assay (IDA) of the core molecular function with demonstrated substrate specificity. Supporting Evidence: PMID:7953292 mediated high affinity (Km = 77 +/- 6 microM) creatine uptake, which was blocked by creatine analogs with high affinity. There was no specific transport of choline |
| GO:0005309 creatine:sodium symporter activity | IDA PMID:9882430 Molecular characterization of the human CRT-1 creatine trans... | ACCEPT | Summary: Expression of the human heart CRT-1 cDNA in Xenopus oocytes induced Na+- and Cl--dependent creatine uptake, directly demonstrating the symporter activity. Reason: Direct assay (IDA) establishing Na+/Cl--dependent creatine symport. Supporting Evidence: PMID:9882430 induced a Na+- and Cl--dependent creatine uptake activity that saturated with a Km of approximately 20 microM for creatine |
| GO:0005886 plasma membrane | IMP PMID:22644605 Functional and electrophysiological characterization of four... | ACCEPT | Summary: Immunofluorescence/western blot localization of wild-type and mutant SLC6A8 to the plasma membrane. Correct core localization. Reason: Direct experimental support for plasma membrane localization. Supporting Evidence: PMID:22644605 All mutants were properly targeted to the plasma membrane in both systems |
| GO:0016324 apical plasma membrane | IDA PMID:12433955 Human, rat and chicken small intestinal Na+ - Cl- -creatine ... | KEEP AS NON CORE | Summary: Immunohistochemistry localized CRT to the apical membrane of enterocytes, establishing apical localization in polarized epithelia. Reason: Accurate context-specific (polarized epithelium) localization; the gene-wide core location is plasma membrane. Supporting Evidence: PMID:12433955 CRT protein was mainly associated with the apical membrane of the enterocytes |
| GO:0005309 creatine:sodium symporter activity | TAS Reactome:R-HSA-200396 | ACCEPT | Summary: Core molecular function captured via Reactome pathway curation. Correct. Reason: Accurate core molecular function; consistent with experimental evidence. |
| GO:0015881 creatine transmembrane transport | IMP PMID:25861866 Estimated carrier frequency of creatine transporter deficien... | ACCEPT | Summary: Functional creatine-uptake assays of SLC6A8 variants support the gene's involvement in creatine transmembrane transport. This is the core biological process. Reason: Direct experimental support for the core transport process; this is a primary core process for SLC6A8. |
| GO:0005308 creatine transmembrane transporter activity | NAS PMID:8661037 Identification of a testis-expressed creatine transporter ge... | ACCEPT | Summary: Correct molecular function but more general than the substrate-and-coupling-specific GO:0005309 (creatine:sodium symporter activity) that is experimentally supported. Reason: Accurate parent molecular function; retained as a correct (if broader) term. The more precise creatine:sodium symporter activity (GO:0005309) is recorded as the core molecular function in core_functions; GO:0005308 is kept as an accepted parent rather than modified away, since it is not wrong. |
| GO:0015881 creatine transmembrane transport | NAS PMID:8661037 Identification of a testis-expressed creatine transporter ge... | ACCEPT | Summary: Correct core biological process, asserted from the literature. Accurate. Reason: Accurate core transport process; corroborated by experimental IMP evidence. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-200396 | ACCEPT | Summary: Correct plasma membrane localization captured via Reactome curation. Reason: Accurate core location; redundant with experimental plasma membrane annotations. |
| GO:0005309 creatine:sodium symporter activity | TAS PMID:7953292 Cloning, pharmacological characterization, and genomic local... | ACCEPT | Summary: Core molecular function captured from the cloning/characterization paper. Reason: Accurate core molecular function; the same paper provides direct IDA support. |
| GO:0006936 muscle contraction | TAS PMID:8661155 The genomic organization of a human creatine transporter (CR... | MARK AS OVER ANNOTATED | Summary: SLC6A8 supplies creatine to skeletal and cardiac muscle for the phosphocreatine energy buffer, an upstream physiological role rather than direct participation in the contraction machinery. The cited reference (PMID:8661155) is a genomic-organization paper that does not establish a role in contraction (flagged MISCITED in its reference_review). Reason: Indirect, downstream physiological consequence (creatine supply supports muscle energy metabolism); not a core molecular activity of the transporter and not direct involvement in the contractile process. The sole cited reference does not support a contraction role, so this is over-annotated rather than a supportable non-core function. |
| GO:0016020 membrane | TAS PMID:7953292 Cloning, pharmacological characterization, and genomic local... | KEEP AS NON CORE | Summary: Generic membrane localization; subsumed by the more specific plasma membrane annotations. Reason: Correct but non-specific; retained as a high-level location. |
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Download this section (compressed HTML)Q: Does SLC6A8 transport guanidinoacetate (the GAMT substrate) to any physiologically relevant degree, or is it strictly selective for creatine among the guanidino compounds?
Experiment: Side-by-side radiolabeled/LC-MS uptake assays in SLC6A8-expressing cells comparing creatine, guanidinoacetate, GABA, taurine and betaine, with Na+/Cl- dependence and competition controls, to quantify substrate selectivity.
Hypothesis: SLC6A8 selectively imports creatine and does not efficiently transport guanidinoacetate or other amino acids/neurotransmitters.
Type: transport assay
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