SLC12A2 encodes NKCC1 (Na-K-2Cl cotransporter 1), an electroneutral secondary-active cation-chloride cotransporter of the SLC12 family that imports one Na+, one K+ and two Cl- ions across the plasma membrane using the inwardly directed Na+ gradient established by the Na/K-ATPase. It is a homodimeric multi-pass membrane protein with 12 transmembrane helices and large cytoplasmic N- and C-terminal domains, and is inhibited by the loop diuretics bumetanide and furosemide. Transport activity is switched on by phosphorylation of N-terminal threonines by the SPAK (STK39) and OSR1 (OXSR1) kinases acting downstream of WNK kinases. NKCC1 is broadly expressed and in epithelia resides mainly on the basolateral membrane, where it mediates the ion-uptake step for transepithelial salt and fluid secretion; in the inner ear it is essential for endolymph K+ secretion. By accumulating chloride it sets the intracellular Cl- concentration, which in immature neurons renders GABA-A signaling depolarizing, and it drives regulatory volume increase and cell-volume homeostasis. Loss-of-function variants cause sensorineural deafness (DFNA78) and the multisystem Kilquist and Delpire-McNeill syndromes.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:17721439 Structural insights into the recognition of substrates and a... | REMOVE | Summary: Interaction with OXSR1 (OSR1) kinase, reported from structural work on OSR1 substrate recognition. Reason: Bare "protein binding" is uninformative and is removed by the protein-binding policy. The partner here (OXSR1/OSR1, the activating Ser/Thr kinase) is already captured more informatively by GO:0120283 protein serine/threonine kinase binding on this gene. |
| GO:0005515 protein binding | IPI PMID:22570591 Regulation of brain tumor dispersal by NKCC1 through a novel... | REMOVE | Summary: Interaction with ezrin (EZR) linking NKCC1 to the cortical cytoskeleton during glioma dispersal. Reason: Bare "protein binding" is uninformative (protein-binding policy). The ezrin interaction is real but there is no evidence-backed specific MF term for it; it is recorded in the notes rather than as a generic uninformative MF. |
| GO:0005515 protein binding | IPI PMID:24555568 WNK1-OSR1 kinase-mediated phospho-activation of Na+-K+-2Cl- ... | REMOVE | Summary: Second report of the NKCC1-ezrin (EZR) interaction, in WNK1-OSR1-driven glioma migration. Reason: Duplicate generic protein-binding annotation to ezrin; removed as uninformative per the protein-binding policy. Removal does not dispute the reported interaction. |
| GO:0005886 plasma membrane | IDA PMID:7629105 Primary structure, functional expression, and chromosomal lo... | ACCEPT | Summary: NKCC1 is a plasma-membrane cotransporter; activity shown at the cell surface by functional expression. Reason: The protein is a multi-pass plasma-membrane transporter whose activity is measured at the cell surface; a core location. Supporting Evidence: UniProtKB:P55011 SUBCELLULAR LOCATION: Basolateral cell membrane |
| GO:0005886 plasma membrane | TAS PMID:7629105 Primary structure, functional expression, and chromosomal lo... | ACCEPT | Summary: Plasma-membrane localization asserted from the original cloning/characterization. Reason: Consistent with the established role of NKCC1 as a plasma-membrane cotransporter. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-426086 | ACCEPT | Summary: Reactome places the Na+,K+,2Cl- cotransport reaction at the plasma membrane. Reason: Core plasma-membrane location of the cotransporter. Supporting Evidence: Reactome:R-HSA-426086 Two Cl- ions are electroneutrally transported into cells with a Na+ ion and a K+ ion. |
| GO:0006811 monoatomic ion transport | IEA GO_REF:0000002 | TOO GENERAL | Summary: Generic ion-transport term from InterPro2GO mapping. Reason: True but uninformative given the specific ion transmembrane transport terms asserted here (GO:0035725, GO:0071805, GO:1902476), which entail generic monoatomic ion transport. |
| GO:0006813 potassium ion transport | IEA GO_REF:0000107 | TOO GENERAL | Summary: Potassium transport from Ensembl Compara ortholog transfer. Reason: Entailed by the more specific GO:0071805 potassium ion transmembrane transport asserted elsewhere. |
| GO:0006814 sodium ion transport | IEA GO_REF:0000107 | TOO GENERAL | Summary: Sodium transport from Ensembl Compara ortholog transfer. Reason: Entailed by the more specific GO:0035725 sodium ion transmembrane transport asserted elsewhere. |
| GO:0006821 chloride transport | IBA GO_REF:0000033 | TOO GENERAL | Summary: Phylogenetic inference that CCC-family members transport chloride. Reason: The phylogenetic chloride-transport claim is sound (self in WITH/FROM reflects experimental grounding on NKCC1), but the term is less specific than GO:1902476 chloride transmembrane transport asserted elsewhere, which entails it. |
| GO:0006821 chloride transport | IEA GO_REF:0000107 | TOO GENERAL | Summary: Chloride transport from Ensembl Compara ortholog transfer. Reason: Entailed by the more specific GO:1902476 chloride transmembrane transport asserted elsewhere. |
| GO:0006883 intracellular sodium ion homeostasis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: NKCC1 contributes to intracellular Na+ balance; ISS from the mouse ortholog Slc12a2 (P55012). Reason: NKCC1 imports Na+ and participates in Na+ homeostasis, but Na+ is cotransported and NKCC1 is not a primary determinant of its level; peripheral to the chloride-accumulation/volume roles. |
| GO:0006884 cell volume homeostasis | ISS GO_REF:0000024 | ACCEPT | Summary: Cell-volume homeostasis; ISS from NKCC1 orthologs. Reason: Regulation of ionic balance and cell volume (regulatory volume increase) is a core, well-established NKCC1 function. Supporting Evidence: UniProtKB:P55011 Plays a vital role in the regulation of ionic balance and cell volume |
| GO:0006884 cell volume homeostasis | ISS GO_REF:0000024 | ACCEPT | Summary: Cell-volume homeostasis; ISS from NKCC1 orthologs. Reason: Regulation of ionic balance and cell volume (regulatory volume increase) is a core, well-established NKCC1 function. Supporting Evidence: UniProtKB:P55011 Plays a vital role in the regulation of ionic balance and cell volume |
| GO:0006884 cell volume homeostasis | TAS PMID:27782176 Functional kinomics establishes a critical node of volume-se... | ACCEPT | Summary: Volume-sensitive regulation of cation-Cl- cotransporters including NKCC1. Reason: Core NKCC1 function; cell-volume regulation is the central physiological output of its ion accumulation. Supporting Evidence: PMID:27782176 Cell volume homeostasis requires the dynamically regulated transport of ions |
| GO:0006972 hyperosmotic response | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NKCC1 is activated by cell shrinkage/hyperosmotic stress to drive regulatory volume increase. Reason: A classic effector of the hyperosmotic/shrinkage response (via WNK-SPAK/OSR1), but a conditional response rather than its defining activity. |
| GO:0007214 gamma-aminobutyric acid signaling pathway | ISS PMID:16227993 NKCC1 transporter facilitates seizures in the developing bra... | KEEP AS NON CORE | Summary: By accumulating Cl-, NKCC1 sets the Cl- gradient that determines GABA-A receptor polarity (depolarizing in immature neurons). Reason: NKCC1 modulates GABAergic signaling upstream by setting intracellular Cl-, rather than performing a step of GABA signaling itself; a key but non-core neuronal role. Supporting Evidence: PMID:16227993 activation of Cl(-)-permeable GABA(A) receptors (GABA(A)-R) excites neurons as a result of elevated intracellular Cl(-) levels |
| GO:0007214 gamma-aminobutyric acid signaling pathway | ISS PMID:16227993 NKCC1 transporter facilitates seizures in the developing bra... | KEEP AS NON CORE | Summary: By accumulating Cl-, NKCC1 sets the Cl- gradient that determines GABA-A receptor polarity (depolarizing in immature neurons). Reason: NKCC1 modulates GABAergic signaling upstream by setting intracellular Cl-, rather than performing a step of GABA signaling itself; a key but non-core neuronal role. Supporting Evidence: PMID:16227993 activation of Cl(-)-permeable GABA(A) receptors (GABA(A)-R) excites neurons as a result of elevated intracellular Cl(-) levels |
| GO:0008511 sodium:potassium:chloride symporter activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of Na:K:Cl symporter activity for the NKCC clade. Reason: The core molecular function of NKCC1, grounded experimentally (self in WITH/FROM reflects direct evidence on NKCC1; donor Q13621 is NKCC2). Supporting Evidence: UniProtKB:P55011 Reaction=K(+)(out) + 2 chloride(out) + Na(+)(out) = K(+)(in) + 2 |
| GO:0008511 sodium:potassium:chloride symporter activity | IDA PMID:33597714 The structural basis of function and regulation of neuronal ... | ACCEPT | Summary: Structural and functional characterization of NKCC1 Na-K-Cl cotransport. Reason: Direct evidence for the core cotransport activity. Supporting Evidence: PMID:33597714 NKCC and KCC transporters mediate coupled transport of Na++K++Cl- and K++Cl- across the plasma membrane |
| GO:0008511 sodium:potassium:chloride symporter activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated assignment of the Na-K-Cl symporter activity. Reason: Correct core molecular function, consistent with experimental and structural evidence. |
| GO:0008511 sodium:potassium:chloride symporter activity | TAS PMID:7629105 Primary structure, functional expression, and chromosomal lo... | ACCEPT | Summary: Original functional expression of the bumetanide-sensitive Na-K-Cl cotransporter established this activity. Reason: Foundational experimental support for the core molecular function. Supporting Evidence: UniProtKB:P55011 Cation-chloride cotransporter which mediates the |
| GO:0008511 sodium:potassium:chloride symporter activity | TAS Reactome:R-HSA-426086 | ACCEPT | Summary: Reactome reaction: NKCC1 cotransports Na+, K+, 2Cl- into the cytosol. Reason: Core molecular function of NKCC1 as represented in the Reactome pathway. Supporting Evidence: Reactome:R-HSA-426086 Two Cl- ions are electroneutrally transported into cells with a Na+ ion and a K+ ion. |
| GO:0008519 ammonium channel activity | IDA PMID:12946942 Ammonium effects on colonic Cl- secretion: anomalous mole fr... | MARK AS OVER ANNOTATED | Summary: NH4+ is transported by NKCC1, shown by anomalous mole-fraction competition with K+ on bumetanide-sensitive uptake. Reason: The data show NH4+ is carried by the cotransporter in place of K+ (secondary active symport), not by facilitated diffusion through a pore; GO:0008519 is defined as a channel, which NKCC1 is not. The activity is the symporter (GO:0008511) with NH4+ as a K+ surrogate. Supporting Evidence: PMID:12946942 Similar anomalous behavior was also observed for inhibition of bumetanide-sensitive 36Cl- uptake, e.g., Na+-K+-2Cl- -cotransporter (NKCC-1). |
| GO:0008519 ammonium channel activity | IDA PMID:18032481 Ammonium transport in the colonic crypt cell line, T84: role... | MARK AS OVER ANNOTATED | Summary: NH4+ transported on NKCC1 nearly as well as K+ (bumetanide-sensitive 86Rb uptake) in T84 colonic cells. Reason: NH4+ substitutes for K+ on the cotransporter; this is carrier-mediated symport, not channel activity. GO:0008519 mischaracterizes the mechanism. Supporting Evidence: PMID:18032481 NH(4)(+) was transported on NKCC1 in T84 cells nearly as well as K(+) as determined by bumetanide-sensitive (86)Rb-uptake. |
| GO:0009925 basal plasma membrane | IDA PMID:17478539 Dynamic and differential regulation of NKCC1 by calcium and ... | ACCEPT | Summary: Basolateral (basal) membrane localization in native human colonic crypt epithelium. Reason: Consistent with the established basolateral localization of NKCC1 in secretory epithelia, underlying transepithelial secretion. Supporting Evidence: PMID:17478539 Unstimulated NKCC1 was expressed on basolateral membranes |
| GO:0010818 T cell chemotaxis | IMP PMID:27400149 WNK1 kinase balances T cell adhesion versus migration in viv... | KEEP AS NON CORE | Summary: SLC12A2 acts as the downstream effector of the WNK1-OXSR1/STK39 pathway promoting T-cell migration. Reason: Experimentally implicated in T-cell migration as the cotransporter effector of WNK1 signaling, likely via volume regulation for motility; a cell-type-specific, non-core role. Supporting Evidence: PMID:27400149 it acts as a positive regulator of migration via the kinases OXSR1 and STK39 and the ion co-transporter SLC12A2 |
| GO:0015079 potassium ion transmembrane transporter activity | ISS GO_REF:0000024 | TOO GENERAL | Summary: Potassium transmembrane transporter activity; ISS from mouse Slc12a2 ortholog. Reason: NKCC1 transports K+ only as part of coupled Na-K-Cl symport; the standalone single-ion transporter MF is entailed by and less informative than GO:0008511. |
| GO:0015377 chloride:monoatomic cation symporter activity | IDA PMID:7629105 Primary structure, functional expression, and chromosomal lo... | TOO GENERAL | Summary: Chloride:cation symporter activity, the parent class of the Na-K-Cl symporter. Reason: Correct but less specific than GO:0008511 (its direct descendant) accepted as the core MF. |
| GO:0015377 chloride:monoatomic cation symporter activity | IEA GO_REF:0000002 | TOO GENERAL | Summary: Chloride:cation symporter activity from InterPro2GO mapping. Reason: Entailed by the specific GO:0008511 symporter activity asserted as core. |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: Generic membrane localization. Reason: NKCC1 is a plasma-membrane protein; refine the generic membrane term to plasma membrane (the gene already carries GO:0005886 and the more specific basolateral GO:0016323). Proposed replacements: plasma membrane |
| GO:0016020 membrane | RCA PMID:7629105 Primary structure, functional expression, and chromosomal lo... | MODIFY | Summary: Generic membrane localization. Reason: NKCC1 is a plasma-membrane protein; refine the generic membrane term to plasma membrane (the gene already carries GO:0005886 and the more specific basolateral GO:0016323). Proposed replacements: plasma membrane |
| GO:0016020 membrane | TAS PMID:7629105 Primary structure, functional expression, and chromosomal lo... | MODIFY | Summary: Generic membrane localization. Reason: NKCC1 is a plasma-membrane protein; refine the generic membrane term to plasma membrane (the gene already carries GO:0005886 and the more specific basolateral GO:0016323). Proposed replacements: plasma membrane |
| GO:0016323 basolateral plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Basolateral membrane localization from UniProt subcellular-location mapping. Reason: Basolateral plasma membrane is the defining, core location of NKCC1 in secretory epithelia. Supporting Evidence: UniProtKB:P55011 SUBCELLULAR LOCATION: Basolateral cell membrane |
| GO:0016323 basolateral plasma membrane | TAS PMID:7629105 Primary structure, functional expression, and chromosomal lo... | ACCEPT | Summary: Basolateral localization of the colonic Na-K-Cl cotransporter. Reason: Core basolateral location consistent with the role in transepithelial secretion. Supporting Evidence: UniProtKB:P55011 SUBCELLULAR LOCATION: Basolateral cell membrane |
| GO:0016324 apical plasma membrane | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Apical membrane localization inferred for the CCC family (members include the apical kidney NKCC2/NCC). Reason: NKCC1 is predominantly basolateral but is apical in specialized epithelia (choroid plexus, inner-ear marginal cells); kept as a non-core, context-specific location rather than removing the phylogenetically supported term. |
| GO:0016324 apical plasma membrane | IDA PMID:17478539 Dynamic and differential regulation of NKCC1 by calcium and ... | KEEP AS NON CORE | Summary: Membrane localization observed during NKCC1 trafficking/recycling in colonic crypt epithelium. Reason: Apical localization is non-core for NKCC1 (basolateral is the principal functional membrane); retained as a context-specific location. |
| GO:0016328 lateral plasma membrane | IDA PMID:17478539 Dynamic and differential regulation of NKCC1 by calcium and ... | KEEP AS NON CORE | Summary: Lateral membrane localization in colonic epithelium (part of the basolateral domain). Reason: Lateral membrane is a sub-domain of the basolateral surface where NKCC1 resides; consistent with its core basolateral location but more granular. |
| GO:0019901 protein kinase binding | IPI PMID:12740379 PASK (proline-alanine-rich STE20-related kinase), a regulato... | MODIFY | Summary: Binding to a PASK/SPAK-type Ste20 kinase that regulates NKCC1. Reason: The partners are the SPAK/OSR1 serine/threonine kinases; refine to the more specific GO:0120283 protein serine/threonine kinase binding, which the gene already carries. Proposed replacements: protein serine/threonine kinase binding |
| GO:0019901 protein kinase binding | IPI PMID:16669787 Functional interactions of the SPAK/OSR1 kinases with their ... | MODIFY | Summary: Binding to the SPAK/OSR1 kinases via RFXV motifs. Reason: OXSR1/OSR1 and STK39/SPAK are Ser/Thr kinases; refine to GO:0120283 protein serine/threonine kinase binding. Proposed replacements: protein serine/threonine kinase binding Supporting Evidence: UniProtKB:P55011 The RFXV motifs mediate binding with OXSR1/OSR1 and STK39/SPAK. |
| GO:0019901 protein kinase binding | IPI PMID:16669787 Functional interactions of the SPAK/OSR1 kinases with their ... | MODIFY | Summary: Binding to the SPAK/OSR1 kinases via RFXV motifs. Reason: OXSR1/OSR1 and STK39/SPAK are Ser/Thr kinases; refine to GO:0120283 protein serine/threonine kinase binding. Proposed replacements: protein serine/threonine kinase binding Supporting Evidence: UniProtKB:P55011 The RFXV motifs mediate binding with OXSR1/OSR1 and STK39/SPAK. |
| GO:0022857 transmembrane transporter activity | IEA GO_REF:0000002 | TOO GENERAL | Summary: Root transporter-activity term from InterPro2GO. Reason: Uninformative given the specific GO:0008511 sodium:potassium:chloride symporter activity accepted as the core MF, which entails transmembrane transporter activity. |
| GO:0030007 intracellular potassium ion homeostasis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Contribution to intracellular K+ balance; ISS from mouse Slc12a2 ortholog. Reason: NKCC1 imports K+ as part of coupled transport, contributing to K+ homeostasis, but secondary to its chloride-accumulation/volume roles. |
| GO:0030321 transepithelial chloride transport | IDA PMID:12946942 Ammonium effects on colonic Cl- secretion: anomalous mole fr... | ACCEPT | Summary: NKCC1 provides the basolateral Cl- entry step for transepithelial Cl- secretion (bumetanide-sensitive, cAMP-stimulated) in colonic epithelium. Reason: A core physiological process for NKCC1 in secretory epithelia; it executes the rate-limiting basolateral chloride uptake step of transepithelial secretion. Supporting Evidence: PMID:12946942 on cAMP-stimulated Cl- secretion in the colonic cell line T84. In HEPES-buffered solutions, application of basolateral NH4+ resulted in a reduced level of Cl- secretory current |
| GO:0030644 intracellular chloride ion homeostasis | ISS GO_REF:0000024 | ACCEPT | Summary: NKCC1 accumulates Cl- and is a principal determinant of intracellular Cl- concentration; ISS from mouse ortholog. Reason: Setting intracellular Cl- is a core NKCC1 function (e.g. underlies the depolarizing GABA response in immature neurons). Supporting Evidence: PMID:16227993 The Na(+)-K(+)-2Cl(-) cotransporter (NKCC1) facilitates the accumulation of Cl(-) in neurons. |
| GO:0030644 intracellular chloride ion homeostasis | TAS PMID:16227993 NKCC1 transporter facilitates seizures in the developing bra... | ACCEPT | Summary: Control of neuronal intracellular Cl- by NKCC1. Reason: Core NKCC1 function; it accumulates chloride and sets the Cl- gradient in neurons. Supporting Evidence: PMID:16227993 The Na(+)-K(+)-2Cl(-) cotransporter (NKCC1) facilitates the accumulation of Cl(-) in neurons. |
| GO:0030659 cytoplasmic vesicle membrane | IDA PMID:17478539 Dynamic and differential regulation of NKCC1 by calcium and ... | KEEP AS NON CORE | Summary: NKCC1 is seen in cytoplasmic vesicles during its Ca2+-dependent cycle of internalization, degradation and re-expression. Reason: Vesicular localization reflects a trafficking/recycling intermediate, not the functional membrane; peripheral to transport. Supporting Evidence: PMID:17478539 the lysosome inhibitor chloroquine promoted accumulation of NKCC1 vesicles |
| GO:0031253 cell projection membrane | TAS PMID:11940529 Contribution of Na(+)-K(+)-Cl(-) cotransporter to high-[K(+)... | KEEP AS NON CORE | Summary: Localization to cell projection membranes in astrocytes. Reason: A cell-type-specific localization in astrocytes; peripheral to the core basolateral/plasma-membrane location. |
| GO:0035633 maintenance of blood-brain barrier | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Role in blood-brain barrier maintenance; ISS from mouse ortholog. Reason: NKCC1 at brain endothelium/astrocytes contributes to BBB ion and water handling, but this is a tissue-level, non-core role. |
| GO:0035633 maintenance of blood-brain barrier | TAS PMID:27782176 Functional kinomics establishes a critical node of volume-se... | KEEP AS NON CORE | Summary: Volume-sensitive CCC regulation node relevant to brain/BBB. Reason: Non-core tissue-level contribution; retained as peripheral. |
| GO:0035725 sodium ion transmembrane transport | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of sodium transmembrane transport for the NKCC clade. Reason: NKCC1 imports Na+ across the plasma membrane as part of its coupled cotransport; a core transport process. |
| GO:0035865 cellular response to potassium ion | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Cellular response to potassium; ISS from NKCC1 orthologs. Reason: NKCC1 participates in responses to altered extracellular K+ (e.g. high-K+ astrocyte swelling), but this is a conditional, non-core response. |
| GO:0035865 cellular response to potassium ion | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Cellular response to potassium; ISS from NKCC1 orthologs. Reason: NKCC1 participates in responses to altered extracellular K+ (e.g. high-K+ astrocyte swelling), but this is a conditional, non-core response. |
| GO:0043005 neuron projection | IDA PMID:16227993 NKCC1 transporter facilitates seizures in the developing bra... | KEEP AS NON CORE | Summary: NKCC1 localization in neuronal projections. Reason: A neuronal localization relevant to its role in setting intracellular Cl-; peripheral to the core location. |
| GO:0043025 neuronal cell body | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic inference of neuronal cell-body localization. Reason: Neuronal localization consistent with NKCC1's role in neurons; peripheral to the core location. |
| GO:0043025 neuronal cell body | IDA PMID:16227993 NKCC1 transporter facilitates seizures in the developing bra... | KEEP AS NON CORE | Summary: NKCC1 localization in neuronal cell bodies (developing cortex/hippocampus). Reason: Non-core neuronal localization; supports the neuronal Cl- accumulation role. |
| GO:0043025 neuronal cell body | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Neuronal cell-body localization; ISS from mouse ortholog. Reason: Non-core neuronal localization. |
| GO:0044297 cell body | ISS GO_REF:0000024 | TOO GENERAL | Summary: Generic cell-body localization; ISS from mouse ortholog. Reason: Entailed by the more specific GO:0043025 neuronal cell body asserted elsewhere. |
| GO:0044298 cell body membrane | TAS PMID:11940529 Contribution of Na(+)-K(+)-Cl(-) cotransporter to high-[K(+)... | KEEP AS NON CORE | Summary: Cell-body membrane localization in astrocytes. Reason: A cell-type-specific sub-cellular membrane localization; peripheral to the core location. |
| GO:0045795 positive regulation of cell volume | IEA GO_REF:0000107 | ACCEPT | Summary: NKCC1 drives cell swelling / regulatory volume increase by importing ions and osmotically obligated water. Reason: Increasing cell volume (regulatory volume increase) is a direct, core output of NKCC1 ion accumulation. Supporting Evidence: UniProtKB:P55011 Plays a vital role in the regulation of ionic balance and cell volume |
| GO:0046873 metal ion transmembrane transporter activity | IDA PMID:15347682 Characterization of a novel interaction between the secretor... | TOO GENERAL | Summary: Transport of metal ions (Na+, K+) by NKCC1. Reason: Na+/K+ are the metal-ion substrates, but this broad MF is entailed by and less informative than GO:0008511 accepted as core. |
| GO:0046873 metal ion transmembrane transporter activity | IDA PMID:7629105 Primary structure, functional expression, and chromosomal lo... | TOO GENERAL | Summary: Metal-ion (Na+/K+) transport by the cotransporter. Reason: Entailed by the specific GO:0008511 symporter activity asserted as the core MF. |
| GO:0051087 protein-folding chaperone binding | IPI PMID:15347682 Characterization of a novel interaction between the secretor... | KEEP AS NON CORE | Summary: NKCC1 C-terminus associates with the chaperone Hsp90 during biogenesis. Reason: A real chaperone interaction (the specific partner, Hsp90, is also captured by GO:0051879); supports NKCC1 folding/trafficking and is peripheral (non-core) to the transport function. Supporting Evidence: PMID:15347682 evidence is presented for the first time that hsp90 associates with the cytosolic C terminus of NKCC1 |
| GO:0051879 Hsp90 protein binding | IPI PMID:15347682 Characterization of a novel interaction between the secretor... | KEEP AS NON CORE | Summary: Direct interaction between the NKCC1 cytosolic C-terminus and Hsp90 (P07900), implicated in carrier biogenesis/surface expression. Reason: A real, specific protein interaction supporting NKCC1 folding/trafficking; peripheral to the transport function itself. Supporting Evidence: PMID:15347682 evidence is presented for the first time that hsp90 associates with the cytosolic C terminus of NKCC1 |
| GO:0055085 transmembrane transport | IEA GO_REF:0000002 | TOO GENERAL | Summary: Root transmembrane-transport process term from InterPro2GO. Reason: Uninformative given the specific ion transmembrane transport processes asserted (Na+/K+/Cl-), which entail it. |
| GO:0061044 negative regulation of vascular wound healing | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Indirect role in vascular wound healing; ISS from mouse ortholog. Reason: A specific downstream/indirect physiological phenotype transferred by ISS; retained as a peripheral, non-core role. |
| GO:0070062 extracellular exosome | HDA PMID:19199708 Proteomic analysis of human parotid gland exosomes by multid... | KEEP AS NON CORE | Summary: Detection of NKCC1 in parotid-gland exosomes by proteomics. Reason: High-throughput proteomic detection in exosomes is common for abundant plasma-membrane proteins; peripheral to the functional location. |
| GO:0070062 extracellular exosome | HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote... | KEEP AS NON CORE | Summary: Detection of NKCC1 in B-cell exosomes by proteomics. Reason: Proteomic exosome detection; non-core location. |
| GO:0070634 transepithelial ammonium transport | IDA PMID:18032481 Ammonium transport in the colonic crypt cell line, T84: role... | KEEP AS NON CORE | Summary: NKCC1 supports basolateral NH4+ loading contributing to secretory-direction NH4+ transport in colonic crypt cells. Reason: NKCC1 carries NH4+ as a K+ surrogate, contributing to transepithelial ammonium handling; a genuine but non-core, promiscuity-based role. Supporting Evidence: PMID:18032481 NH(4)(+) transport in the secretory direction was supported by basolateral NH(4)(+) loading on NKCC1 |
| GO:0071805 potassium ion transmembrane transport | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of potassium transmembrane transport across the CCC family. Reason: NKCC1 imports K+ across the plasma membrane as part of its coupled cotransport; a core transport process. |
| GO:0071944 cell periphery | IDA PMID:16227993 NKCC1 transporter facilitates seizures in the developing bra... | TOO GENERAL | Summary: Cell-periphery localization (parent of plasma membrane). Reason: Entailed by the more specific plasma-membrane/basolateral-membrane locations asserted elsewhere. |
| GO:0071944 cell periphery | ISS GO_REF:0000024 | TOO GENERAL | Summary: Cell-periphery localization; ISS from mouse ortholog. Reason: Entailed by the specific plasma-membrane location. |
| GO:0071944 cell periphery | ISS PMID:15347682 Characterization of a novel interaction between the secretor... | TOO GENERAL | Summary: Cell-periphery localization; ISS. Reason: Entailed by the specific plasma-membrane location asserted elsewhere. |
| GO:0072488 ammonium transmembrane transport | IDA PMID:12946942 Ammonium effects on colonic Cl- secretion: anomalous mole fr... | KEEP AS NON CORE | Summary: NH4+ transmembrane transport on NKCC1 (as K+ surrogate), shown by anomalous mole-fraction behavior. Reason: A genuine but secondary (substrate-substitution) transport activity; non-core relative to Na-K-Cl cotransport. Supporting Evidence: PMID:12946942 The competitive effect with K+ exhibits anomalous mole fraction behavior. |
| GO:0072488 ammonium transmembrane transport | IDA PMID:18032481 Ammonium transport in the colonic crypt cell line, T84: role... | KEEP AS NON CORE | Summary: NH4+ transported on NKCC1 nearly as well as K+ in T84 cells. Reason: Secondary substrate (NH4+ for K+) transport; non-core. Supporting Evidence: PMID:18032481 NH(4)(+) was transported on NKCC1 in T84 cells nearly as well as K(+) as determined by bumetanide-sensitive (86)Rb-uptake. |
| GO:0098658 inorganic anion import across plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Chloride import across the plasma membrane; ISS from mouse ortholog. Reason: NKCC1 imports Cl- (two per cycle) into the cell; a core directional transport process accurately described by this term. |
| GO:0098659 inorganic cation import across plasma membrane | IDA PMID:15347682 Characterization of a novel interaction between the secretor... | TOO GENERAL | Summary: Import of inorganic cations (Na+/K+) across the plasma membrane. Reason: True, but entailed by the more specific GO:0098719 sodium ion import and GO:1990573 potassium ion import asserted elsewhere. |
| GO:0098659 inorganic cation import across plasma membrane | IDA PMID:7629105 Primary structure, functional expression, and chromosomal lo... | TOO GENERAL | Summary: Cation (Na+/K+) import across the plasma membrane. Reason: Entailed by the specific sodium and potassium import terms asserted in this review. |
| GO:0098719 sodium ion import across plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Sodium import across the plasma membrane; ISS from mouse ortholog. Reason: NKCC1 imports Na+ into the cell; an accurate, specific directional transport process and part of the core activity. |
| GO:0120283 protein serine/threonine kinase binding | IEA GO_REF:0000117 | ACCEPT | Summary: Serine/threonine kinase binding from an ARBA machine-learning model. Reason: The term is correct and informative: NKCC1 docks the SPAK/OSR1 Ser/Thr kinases via its RFXV motifs, as shown experimentally. Supporting Evidence: UniProtKB:P55011 The RFXV motifs mediate binding with OXSR1/OSR1 and STK39/SPAK. |
| GO:0120283 protein serine/threonine kinase binding | IPI PMID:21423148 MO25 is a master regulator of SPAK/OSR1 and MST3/MST4/YSK1 p... | ACCEPT | Summary: Interaction with the SPAK/OSR1 Ser/Thr kinases. Reason: Specific, informative MF capturing NKCC1 docking of its activating Ser/Thr kinases. Supporting Evidence: UniProtKB:P55011 The RFXV motifs mediate binding with OXSR1/OSR1 and STK39/SPAK. |
| GO:0120283 protein serine/threonine kinase binding | IPI PMID:21423148 MO25 is a master regulator of SPAK/OSR1 and MST3/MST4/YSK1 p... | ACCEPT | Summary: Interaction with the SPAK/OSR1 Ser/Thr kinases. Reason: Specific, informative MF capturing NKCC1 docking of its activating Ser/Thr kinases. Supporting Evidence: UniProtKB:P55011 The RFXV motifs mediate binding with OXSR1/OSR1 and STK39/SPAK. |
| GO:0150003 regulation of spontaneous synaptic transmission | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Modulation of synaptic transmission via control of neuronal intracellular Cl-; ISS from mouse ortholog. Reason: NKCC1 influences synaptic transmission indirectly by setting the Cl- gradient; an upstream, non-core neuronal role. |
| GO:0150003 regulation of spontaneous synaptic transmission | ISS PMID:16227993 NKCC1 transporter facilitates seizures in the developing bra... | KEEP AS NON CORE | Summary: Modulation of synaptic transmission via Cl- accumulation; ISS. Reason: Indirect upstream role via intracellular Cl-; non-core. |
| GO:0150003 regulation of spontaneous synaptic transmission | ISS PMID:16227993 NKCC1 transporter facilitates seizures in the developing bra... | KEEP AS NON CORE | Summary: Modulation of synaptic transmission via Cl- accumulation; ISS. Reason: Indirect upstream role via intracellular Cl-; non-core. |
| GO:0150003 regulation of spontaneous synaptic transmission | ISS PMID:16227993 NKCC1 transporter facilitates seizures in the developing bra... | KEEP AS NON CORE | Summary: Modulation of synaptic transmission via Cl- accumulation; ISS. Reason: Indirect upstream role via intracellular Cl-; non-core. |
| GO:0150104 transport across blood-brain barrier | NAS PMID:30280653 Blood-Brain Barrier: From Physiology to Disease and Back. | KEEP AS NON CORE | Summary: Ion transport at the blood-brain barrier, asserted in a review. Reason: NKCC1 at brain endothelium participates in ion/water movement across the BBB; a non-core tissue-level role, and the support is a review (NAS). |
| GO:1902476 chloride transmembrane transport | ISS GO_REF:0000024 | ACCEPT | Summary: Chloride transmembrane transport; ISS from mouse ortholog. Reason: NKCC1 transports Cl- across the plasma membrane (two per cycle); a core transport process. |
| GO:1902476 chloride transmembrane transport | NAS PMID:16227993 NKCC1 transporter facilitates seizures in the developing bra... | ACCEPT | Summary: Chloride transmembrane transport asserted for NKCC1. Reason: Core chloride transport process consistent with the cotransport mechanism. |
| GO:1902476 chloride transmembrane transport | TAS Reactome:R-HSA-426117 | ACCEPT | Summary: Reactome: cation-coupled chloride cotransport across the membrane. Reason: Core chloride transmembrane transport process. Supporting Evidence: Reactome:R-HSA-426117 membrane proteins that cotranslocate chloride (Cl-) with either Na+, K+, or both cations electroneutrally |
| GO:1903561 extracellular vesicle | HDA PMID:24769233 Proteomic analysis of cerebrospinal fluid extracellular vesi... | TOO GENERAL | Summary: Detection of NKCC1 in cerebrospinal-fluid extracellular vesicles by proteomics. Reason: Entailed by the more specific GO:0070062 extracellular exosome asserted elsewhere; both reflect proteomic detection in secreted vesicles. |
| GO:1904450 positive regulation of aspartate secretion | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Role in excitatory amino acid (aspartate) release; ISS from mouse ortholog, consistent with NKCC1's contribution to high-K+-induced EAA release in astrocytes. Reason: An indirect, context-specific downstream effect of NKCC1-driven swelling; non-core. |
| GO:1904464 regulation of matrix metallopeptidase secretion | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Role in matrix metallopeptidase secretion; ISS from mouse ortholog. Reason: A specific indirect/pleiotropic downstream phenotype transferred by ISS; peripheral, non-core. |
| GO:1990573 potassium ion import across plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Potassium import across the plasma membrane; ISS from mouse ortholog. Reason: NKCC1 imports K+ into the cell; an accurate, specific directional transport process and part of the core activity. |
| GO:1990869 cellular response to chemokine | IMP PMID:27400149 WNK1 kinase balances T cell adhesion versus migration in viv... | KEEP AS NON CORE | Summary: SLC12A2 is required for chemokine-driven T-cell responses as the effector of the WNK1-OXSR1/STK39 pathway. Reason: Experimentally implicated in chemokine-induced T-cell migration via WNK1 signaling; a cell-type-specific, non-core role. Supporting Evidence: PMID:27400149 it acts as a positive regulator of migration via the kinases OXSR1 and STK39 and the ion co-transporter SLC12A2 |
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Download this section (compressed HTML)Q: In which human epithelia is NKCC1 apically rather than basolaterally localized, and what trafficking determinants (e.g. phosphorylation, scaffold interactions) specify its polarity?
Q: Is NH4+ transport by NKCC1 physiologically significant in vivo, or primarily an in vitro manifestation of K+-site promiscuity?
Experiment: Quantify endogenous NKCC1-mediated NH4+ flux versus K+ flux in polarized epithelia using isotopic (14C-methylammonium / 86Rb) uptake with bumetanide controls, to establish the in vivo relevance of ammonium transport.
Experiment: Define NKCC1 membrane polarity determinants by domain swapping and phosphosite mutagenesis in polarized epithelial models (e.g. choroid plexus vs colonic crypt), tracking apical versus basolateral targeting.
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