KCNJ11 encodes Kir6.2, the pore-forming subunit of the ATP-sensitive potassium (KATP) channel. Four Kir6.2 subunits form an inward-rectifier K+-selective pore that assembles with four sulfonylurea receptor subunits (SUR1/ABCC8 in pancreatic beta cells and neurons; SUR2A/SUR2B/ABCC9 in cardiac, skeletal and smooth muscle) into a hetero-octameric channel at the plasma membrane. Cytoplasmic ATP binding to Kir6.2 closes the pore, whereas MgADP acting through SUR opens it, so the channel couples cellular energy state to membrane excitability. In beta cells, rising glucose metabolism increases the ATP/ADP ratio and closes KATP channels, depolarizing the membrane and triggering calcium-dependent insulin secretion; open channels hold the cell hyperpolarized and restrain insulin release. Loss-of-function variants cause congenital hyperinsulinism (familial hyperinsulinemic hypoglycemia type 2), whereas gain-of-function variants that reduce ATP sensitivity cause transient or permanent neonatal diabetes, sometimes with developmental delay and epilepsy (DEND) reflecting neuronal and muscle KATP channels.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005242 inward rectifier potassium channel activity | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT inference that Kir6.2 contributes to inward rectifier potassium channel activity, the family-level activity of Kir channels. Reason: Kir6.2 is the pore-forming inward rectifier subunit of the KATP channel; the inward rectifier parent activity is correct, and the contributes_to qualifier reflects that the functional channel is the Kir6.2/SUR hetero-octamer. The more specific ATP-sensitive activity GO:0015272 is captured as core. Supporting Evidence: file:human/KCNJ11/KCNJ11-uniprot.txt Inward rectifier potassium channel that forms the pore of ATP-sensitive potassium channels (KATP), regulating potassium permeability as a function of cytoplasmic ATP and ADP concentrations in many different cells PMID:7502040 Coexpression with the sulfonylurea receptor SUR reconstituted an inwardly rectifying potassium conductance of 76 picosiemens that was sensitive to adenosine triphosphate (ATP) (IKATP) |
| GO:0005242 inward rectifier potassium channel activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic mapping to inward rectifier potassium channel activity. Reason: Correct parent of the core ATP-sensitive inward rectifier activity; Kir6.2 forms the K+-selective inward rectifier pore. Supporting Evidence: file:human/KCNJ11/KCNJ11-uniprot.txt Inward rectifier potassium channel that forms the pore of ATP-sensitive potassium channels (KATP), regulating potassium permeability as a function of cytoplasmic ATP and ADP concentrations in many different cells PMID:7502040 Coexpression with the sulfonylurea receptor SUR reconstituted an inwardly rectifying potassium conductance of 76 picosiemens that was sensitive to adenosine triphosphate (ATP) (IKATP) |
| GO:0005249 voltage-gated potassium channel activity | IDA PMID:19805355 Dual role of K ATP channel C-terminal motif in membrane targ... | MODIFY | Summary: IDA to voltage-gated potassium channel activity from a study of Kir6.2 membrane targeting by ankyrin-B. Kir6.2 is a ligand (ATP/ADP)-gated inward rectifier, not a voltage-gated (Kv-type) channel. Reason: Kir6.2 lacks a voltage-sensor domain; its gating is controlled by intracellular adenine nucleotides and PIP2, and rectification arises from internal Mg2+/polyamine block. The assayed channel activity is better captured by ATP-activated (ATP-sensitive) inward rectifier potassium channel activity. Proposed replacements: ATP-activated inward rectifier potassium channel activity Supporting Evidence: file:human/KCNJ11/KCNJ11-uniprot.txt Inward rectifier potassium channel that forms the pore of ATP-sensitive potassium channels (KATP), regulating potassium permeability as a function of cytoplasmic ATP and ADP concentrations in many different cells PMID:19805355 the C-terminal domain of Kir6.2 contains a motif conferring membrane targeting in primary excitable cells |
| GO:0005249 voltage-gated potassium channel activity | IEA GO_REF:0000117 | MODIFY | Summary: ARBA electronic annotation to voltage-gated potassium channel activity. Reason: Kir6.2 is an ATP-sensitive inward rectifier rather than a voltage-gated channel; replace with the specific KATP pore activity. Proposed replacements: ATP-activated inward rectifier potassium channel activity Supporting Evidence: file:human/KCNJ11/KCNJ11-uniprot.txt Inward rectifier potassium channel that forms the pore of ATP-sensitive potassium channels (KATP), regulating potassium permeability as a function of cytoplasmic ATP and ADP concentrations in many different cells PMID:7502040 Coexpression with the sulfonylurea receptor SUR reconstituted an inwardly rectifying potassium conductance of 76 picosiemens that was sensitive to adenosine triphosphate (ATP) (IKATP) |
| GO:0005515 protein binding | IPI PMID:19805355 Dual role of K ATP channel C-terminal motif in membrane targ... | REMOVE | Summary: Bare protein binding (IPI) with ankyrin-B (Q01484) from the Kir6.2 membrane-targeting study. Reason: Bare protein binding conveys no functional information; the ankyrin-B interaction is captured more informatively by the existing ankyrin binding (GO:0030506) annotation. Removal does not imply the interaction is false. Supporting Evidence: PMID:19805355 Kir6.2 lacking this motif displays aberrant channel targeting due to loss of association with the membrane adapter ankyrin-B (AnkB) |
| GO:0005515 protein binding | IPI PMID:19805355 Dual role of K ATP channel C-terminal motif in membrane targ... | REMOVE | Summary: Bare protein binding (IPI) with SUR1 (Q09428-1). Reason: Bare protein binding conveys no functional information; the Kir6.2-SUR1 association is captured by membership in the inward rectifying potassium channel complex (GO:0008282) and transmembrane transporter binding. Removal does not imply the interaction is false. Supporting Evidence: PMID:29286281 human pancreatic KATP channel, containing the ABC transporter SUR1 and the inward-rectifier K+ channel Kir6.2 |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Bare protein binding from the HuRI high-throughput yeast two-hybrid map (partner Q96B26). Reason: High-throughput binary interaction with no established functional consequence for Kir6.2; bare protein binding is uninformative. Removal does not imply the interaction is false. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005524 ATP binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic ortholog transfer of ATP binding. Reason: Kir6.2 binds ATP at its cytoplasmic domain, which closes the channel; this ligand binding is a mechanistic component of the core ATP-sensitive channel activity rather than a separate core function. Supporting Evidence: PMID:12860923 mutation of three positively charged residues, R50, K185 and R201, impairs the ability of ATP to close the channel |
| GO:0005524 ATP binding | ISS PMID:12860923 Molecular mechanism for ATP-dependent closure of the K+ chan... | KEEP AS NON CORE | Summary: ATP binding supported by mutagenesis of Kir6.2 ATP-site residues (R50, K185, R201). Reason: The paper shows these residues mediate ATP-dependent closure, consistent with direct ATP binding to Kir6.2; captured as a sub-aspect of the core gating mechanism. Supporting Evidence: PMID:12860923 mutation of three positively charged residues, R50, K185 and R201, impairs the ability of ATP to close the channel |
| GO:0005737 cytoplasm | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Electronic ortholog transfer of cytoplasm (is_active_in). Reason: Kir6.2 is a multi-pass integral membrane channel that acts at the plasma membrane; its cytoplasmic domain faces the cytosol but the protein is not active as a cytoplasmic protein. Supporting Evidence: file:human/KCNJ11/KCNJ11-uniprot.txt Inward rectifier potassium channel that forms the pore of ATP-sensitive potassium channels (KATP), regulating potassium permeability as a function of cytoplasmic ATP and ADP concentrations in many different cells PMID:19805355 the C-terminal domain of Kir6.2 contains a motif conferring membrane targeting in primary excitable cells |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Plasma membrane localization of Kir6.2. Reason: Kir6.2 is a multi-pass channel subunit that functions at the plasma membrane (sarcolemma in muscle, beta-cell plasma membrane); this is its core location. Supporting Evidence: PMID:19805355 the C-terminal domain of Kir6.2 contains a motif conferring membrane targeting in primary excitable cells PMID:20610380 cardiac sarcolemmal K(ATP) channels directly associate with ankyrin-B in heart via the K(ATP) channel alpha-subunit Kir6.2 |
| GO:0005886 plasma membrane | IDA PMID:19805355 Dual role of K ATP channel C-terminal motif in membrane targ... | ACCEPT | Summary: IDA plasma membrane localization from Kir6.2 C-terminal targeting-motif experiments. Reason: The study directly assesses Kir6.2 targeting to the plasma membrane via its ankyrin-B-binding motif; core location. Supporting Evidence: PMID:19805355 the C-terminal domain of Kir6.2 contains a motif conferring membrane targeting in primary excitable cells PMID:19805355 Kir6.2 lacking this motif displays aberrant channel targeting due to loss of association with the membrane adapter ankyrin-B (AnkB) |
| GO:0005886 plasma membrane | IEA GO_REF:0000107 | ACCEPT | Summary: Plasma membrane localization of Kir6.2. Reason: Kir6.2 is a multi-pass channel subunit that functions at the plasma membrane (sarcolemma in muscle, beta-cell plasma membrane); this is its core location. Supporting Evidence: PMID:19805355 the C-terminal domain of Kir6.2 contains a motif conferring membrane targeting in primary excitable cells PMID:20610380 cardiac sarcolemmal K(ATP) channels directly associate with ankyrin-B in heart via the K(ATP) channel alpha-subunit Kir6.2 |
| GO:0005886 plasma membrane | TAS PMID:8923010 Mutation of the pancreatic islet inward rectifier Kir6.2 als... | ACCEPT | Summary: TAS plasma membrane localization in the context of the beta-cell KATP channel. Reason: Beta-cell KATP channels act at the plasma membrane, where their closure initiates depolarization and insulin release. Supporting Evidence: PMID:8923010 Closure of ATP-sensitive potassium channels in pancreatic islet beta-cells initiates a cascade of events that leads to insulin secretion. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-1296024 | ACCEPT | Summary: Plasma membrane localization of Kir6.2. Reason: Kir6.2 is a multi-pass channel subunit that functions at the plasma membrane (sarcolemma in muscle, beta-cell plasma membrane); this is its core location. Supporting Evidence: PMID:19805355 the C-terminal domain of Kir6.2 contains a motif conferring membrane targeting in primary excitable cells PMID:20610380 cardiac sarcolemmal K(ATP) channels directly associate with ankyrin-B in heart via the K(ATP) channel alpha-subunit Kir6.2 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-1369017 | ACCEPT | Summary: Plasma membrane localization of Kir6.2. Reason: Kir6.2 is a multi-pass channel subunit that functions at the plasma membrane (sarcolemma in muscle, beta-cell plasma membrane); this is its core location. Supporting Evidence: PMID:19805355 the C-terminal domain of Kir6.2 contains a motif conferring membrane targeting in primary excitable cells PMID:20610380 cardiac sarcolemmal K(ATP) channels directly associate with ankyrin-B in heart via the K(ATP) channel alpha-subunit Kir6.2 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-265682 | ACCEPT | Summary: Plasma membrane localization of Kir6.2. Reason: Kir6.2 is a multi-pass channel subunit that functions at the plasma membrane (sarcolemma in muscle, beta-cell plasma membrane); this is its core location. Supporting Evidence: PMID:19805355 the C-terminal domain of Kir6.2 contains a motif conferring membrane targeting in primary excitable cells PMID:20610380 cardiac sarcolemmal K(ATP) channels directly associate with ankyrin-B in heart via the K(ATP) channel alpha-subunit Kir6.2 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5678261 | ACCEPT | Summary: Plasma membrane localization of Kir6.2. Reason: Kir6.2 is a multi-pass channel subunit that functions at the plasma membrane (sarcolemma in muscle, beta-cell plasma membrane); this is its core location. Supporting Evidence: PMID:19805355 the C-terminal domain of Kir6.2 contains a motif conferring membrane targeting in primary excitable cells PMID:20610380 cardiac sarcolemmal K(ATP) channels directly associate with ankyrin-B in heart via the K(ATP) channel alpha-subunit Kir6.2 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5678418 | ACCEPT | Summary: Plasma membrane localization of Kir6.2. Reason: Kir6.2 is a multi-pass channel subunit that functions at the plasma membrane (sarcolemma in muscle, beta-cell plasma membrane); this is its core location. Supporting Evidence: PMID:19805355 the C-terminal domain of Kir6.2 contains a motif conferring membrane targeting in primary excitable cells PMID:20610380 cardiac sarcolemmal K(ATP) channels directly associate with ankyrin-B in heart via the K(ATP) channel alpha-subunit Kir6.2 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5683113 | ACCEPT | Summary: Plasma membrane localization of Kir6.2. Reason: Kir6.2 is a multi-pass channel subunit that functions at the plasma membrane (sarcolemma in muscle, beta-cell plasma membrane); this is its core location. Supporting Evidence: PMID:19805355 the C-terminal domain of Kir6.2 contains a motif conferring membrane targeting in primary excitable cells PMID:20610380 cardiac sarcolemmal K(ATP) channels directly associate with ankyrin-B in heart via the K(ATP) channel alpha-subunit Kir6.2 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9650858 | ACCEPT | Summary: Plasma membrane localization of Kir6.2. Reason: Kir6.2 is a multi-pass channel subunit that functions at the plasma membrane (sarcolemma in muscle, beta-cell plasma membrane); this is its core location. Supporting Evidence: PMID:19805355 the C-terminal domain of Kir6.2 contains a motif conferring membrane targeting in primary excitable cells PMID:20610380 cardiac sarcolemmal K(ATP) channels directly associate with ankyrin-B in heart via the K(ATP) channel alpha-subunit Kir6.2 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9652580 | ACCEPT | Summary: Plasma membrane localization of Kir6.2. Reason: Kir6.2 is a multi-pass channel subunit that functions at the plasma membrane (sarcolemma in muscle, beta-cell plasma membrane); this is its core location. Supporting Evidence: PMID:19805355 the C-terminal domain of Kir6.2 contains a motif conferring membrane targeting in primary excitable cells PMID:20610380 cardiac sarcolemmal K(ATP) channels directly associate with ankyrin-B in heart via the K(ATP) channel alpha-subunit Kir6.2 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9691566 | ACCEPT | Summary: Plasma membrane localization of Kir6.2. Reason: Kir6.2 is a multi-pass channel subunit that functions at the plasma membrane (sarcolemma in muscle, beta-cell plasma membrane); this is its core location. Supporting Evidence: PMID:19805355 the C-terminal domain of Kir6.2 contains a motif conferring membrane targeting in primary excitable cells PMID:20610380 cardiac sarcolemmal K(ATP) channels directly associate with ankyrin-B in heart via the K(ATP) channel alpha-subunit Kir6.2 |
| GO:0006006 glucose metabolic process | IMP PMID:15115830 Activating mutations in the gene encoding the ATP-sensitive ... | MODIFY | Summary: IMP to glucose metabolic process from patients with activating KCNJ11 mutations (permanent neonatal diabetes). Reason: Kir6.2 does not catalyse or transport glucose metabolites; the mutations disturb insulin secretion and hence systemic glucose homeostasis. Glucose homeostasis is the appropriate process. Proposed replacements: glucose homeostasis Supporting Evidence: PMID:15115830 Because ATP-sensitive potassium (K(ATP)) channels mediate glucose-stimulated insulin secretion from the pancreatic beta cells PMID:15115830 Heterozygous activating mutations in the gene encoding Kir6.2 cause permanent neonatal diabetes and may also be associated with developmental delay, muscle weakness, and epilepsy. |
| GO:0006006 glucose metabolic process | IMP PMID:8923010 Mutation of the pancreatic islet inward rectifier Kir6.2 als... | MODIFY | Summary: IMP to glucose metabolic process from a loss-of-function KCNJ11 mutation causing persistent hyperinsulinemic hypoglycemia of infancy. Reason: The phenotype reflects dysregulated insulin release and blood glucose, not a role in cellular glucose metabolism; glucose homeostasis is the accurate process. Proposed replacements: glucose homeostasis Supporting Evidence: PMID:8923010 Closure of ATP-sensitive potassium channels in pancreatic islet beta-cells initiates a cascade of events that leads to insulin secretion. PMID:8923010 Kir6.2 is necessary, although not sufficient, for normal regulation of insulin release |
| GO:0006813 potassium ion transport | IEA GO_REF:0000002 | ACCEPT | Summary: Electronic annotation to potassium ion transport. Reason: Correct general process for a K+-selective channel pore subunit; the specific term potassium ion transmembrane transport is used in core functions. Supporting Evidence: file:human/KCNJ11/KCNJ11-uniprot.txt Inward rectifier potassium channel that forms the pore of ATP-sensitive potassium channels (KATP), regulating potassium permeability as a function of cytoplasmic ATP and ADP concentrations in many different cells |
| GO:0008282 inward rectifying potassium channel | IDA PMID:19805355 Dual role of K ATP channel C-terminal motif in membrane targ... | ACCEPT | Summary: Kir6.2 is part of the inward rectifying potassium channel (KATP) complex. Reason: The KATP channel is a hetero-octamer of four Kir6.2 pore subunits and four SUR regulatory subunits; GO:0008282 explicitly covers this complex. Supporting Evidence: PMID:19805355 the C-terminal domain of Kir6.2 contains a motif conferring membrane targeting in primary excitable cells file:human/KCNJ11/KCNJ11-uniprot.txt In pancreatic cells, it forms KATP channels with ABCC8/SUR1 |
| GO:0008282 inward rectifying potassium channel | IDA PMID:20610380 Ankyrin-B regulates Kir6.2 membrane expression and function ... | ACCEPT | Summary: Kir6.2 is part of the inward rectifying potassium channel (KATP) complex. Reason: The KATP channel is a hetero-octamer of four Kir6.2 pore subunits and four SUR regulatory subunits; GO:0008282 explicitly covers this complex. Supporting Evidence: PMID:20610380 cardiac sarcolemmal K(ATP) channels directly associate with ankyrin-B in heart via the K(ATP) channel alpha-subunit Kir6.2 |
| GO:0008282 inward rectifying potassium channel | IEA GO_REF:0000107 | ACCEPT | Summary: Kir6.2 is part of the inward rectifying potassium channel (KATP) complex. Reason: The KATP channel is a hetero-octamer of four Kir6.2 pore subunits and four SUR regulatory subunits; GO:0008282 explicitly covers this complex. Supporting Evidence: file:human/KCNJ11/KCNJ11-uniprot.txt In pancreatic cells, it forms KATP channels with ABCC8/SUR1 |
| GO:0008282 inward rectifying potassium channel | IPI PMID:29286281 Molecular structure of human KATP in complex with ATP and AD... | ACCEPT | Summary: Kir6.2 is part of the inward rectifying potassium channel (KATP) complex. Reason: The KATP channel is a hetero-octamer of four Kir6.2 pore subunits and four SUR regulatory subunits; GO:0008282 explicitly covers this complex. Supporting Evidence: PMID:29286281 human pancreatic KATP channel, containing the ABC transporter SUR1 and the inward-rectifier K+ channel Kir6.2 file:human/KCNJ11/KCNJ11-uniprot.txt In pancreatic cells, it forms KATP channels with ABCC8/SUR1 |
| GO:0008282 inward rectifying potassium channel | ISS GO_REF:0000024 | ACCEPT | Summary: Kir6.2 is part of the inward rectifying potassium channel (KATP) complex. Reason: The KATP channel is a hetero-octamer of four Kir6.2 pore subunits and four SUR regulatory subunits; GO:0008282 explicitly covers this complex. Supporting Evidence: PMID:7502040 these pancreatic beta cell potassium channels are a complex composed of at least two subunits--BIR, a member of the inward rectifier potassium channel family, and SUR |
| GO:0009410 response to xenobiotic stimulus | IMP PMID:18073297 The G53D mutation in Kir6.2 (KCNJ11) is associated with neon... | KEEP AS NON CORE | Summary: IMP to response to xenobiotic stimulus, reflecting sulfonylurea block of mutant Kir6.2-containing channels. Reason: Sulfonylurea responsiveness is a pharmacological property of the KATP channel (mediated via SUR) rather than a physiological role of Kir6.2; retained as non-core. Supporting Evidence: PMID:18073297 Reconstituted G53D channels exhibit reduced ATP sensitivity, which is predicted to suppress electrical activity in vivo. PMID:18073297 this improvement is due to inhibition of the neuronal but not skeletal muscle KATP |
| GO:0015272 ATP-activated inward rectifier potassium channel activity | IEA GO_REF:0000120 | ACCEPT | Summary: ATP-activated (ATP-sensitive) inward rectifier potassium channel activity. Reason: This is the defining activity of Kir6.2: it forms the K+ pore of the KATP channel whose opening is inhibited by cytoplasmic ATP and relieved by MgADP via SUR. The GO term definition covers ATP-regulated inward rectifiers despite the "ATP-activated" label. Supporting Evidence: file:human/KCNJ11/KCNJ11-uniprot.txt Inward rectifier potassium channel that forms the pore of ATP-sensitive potassium channels (KATP), regulating potassium permeability as a function of cytoplasmic ATP and ADP concentrations in many different cells PMID:7502040 Coexpression with the sulfonylurea receptor SUR reconstituted an inwardly rectifying potassium conductance of 76 picosiemens that was sensitive to adenosine triphosphate (ATP) (IKATP) |
| GO:0015272 ATP-activated inward rectifier potassium channel activity | ISS GO_REF:0000024 | ACCEPT | Summary: ATP-activated (ATP-sensitive) inward rectifier potassium channel activity. Reason: This is the defining activity of Kir6.2: it forms the K+ pore of the KATP channel whose opening is inhibited by cytoplasmic ATP and relieved by MgADP via SUR. The GO term definition covers ATP-regulated inward rectifiers despite the "ATP-activated" label. Supporting Evidence: file:human/KCNJ11/KCNJ11-uniprot.txt Inward rectifier potassium channel that forms the pore of ATP-sensitive potassium channels (KATP), regulating potassium permeability as a function of cytoplasmic ATP and ADP concentrations in many different cells PMID:7502040 Coexpression with the sulfonylurea receptor SUR reconstituted an inwardly rectifying potassium conductance of 76 picosiemens that was sensitive to adenosine triphosphate (ATP) (IKATP) |
| GO:0015272 ATP-activated inward rectifier potassium channel activity | NAS PMID:28842488 Conserved functional consequences of disease-associated muta... | ACCEPT | Summary: NAS for ATP-sensitive inward rectifier channel activity from a study of slide-helix mutations in Kir6.1 and Kir6.2. Reason: The study measures KATP channel activity and ATP sensitivity of Kir6.2-containing channels by flux and patch clamp; consistent with the core activity. Supporting Evidence: PMID:28842488 results in increased open state stability and hence significantly reduced ATP sensitivity and a marked increase of channel activity in the intact cell irrespective of the identity of the coassembled SUR subunit file:human/KCNJ11/KCNJ11-uniprot.txt Inward rectifier potassium channel that forms the pore of ATP-sensitive potassium channels (KATP), regulating potassium permeability as a function of cytoplasmic ATP and ADP concentrations in many different cells |
| GO:0016020 membrane | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: Electronic annotation to the generic membrane term. Reason: Uninformative parent of the experimentally supported plasma membrane location. Supporting Evidence: file:human/KCNJ11/KCNJ11-uniprot.txt Inward rectifier potassium channel that forms the pore of ATP-sensitive potassium channels (KATP), regulating potassium permeability as a function of cytoplasmic ATP and ADP concentrations in many different cells PMID:19805355 the C-terminal domain of Kir6.2 contains a motif conferring membrane targeting in primary excitable cells |
| GO:0019829 ATPase-coupled monoatomic cation transmembrane transporter activity | ISS GO_REF:0000024 | REMOVE | Summary: ISS annotation to ATPase-coupled monoatomic cation transmembrane transporter activity. Reason: Kir6.2 is a passive, gated K+ channel pore; it has no ATPase domain and does not couple ATP hydrolysis to cation transport. Nucleotide binding inhibits the pore rather than energizing transport. The term describes a different mechanism (a P-type or ABC pump). Supporting Evidence: file:human/KCNJ11/KCNJ11-uniprot.txt Inward rectifier potassium channel that forms the pore of ATP-sensitive potassium channels (KATP), regulating potassium permeability as a function of cytoplasmic ATP and ADP concentrations in many different cells PMID:12860923 mutation of three positively charged residues, R50, K185 and R201, impairs the ability of ATP to close the channel file:human/KCNJ11/KCNJ11-deep-research-falcon.md ATP is an intracellular **inhibitory gating ligand**, not the ion transported through the pore, and Kir6.2 is not an enzyme. |
| GO:0030315 T-tubule | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: T-tubule localization transferred from rodent orthologs. Reason: Muscle KATP channels (Kir6.2 with SUR2A) are present in sarcolemma and T-tubules; plausible tissue-specific location but secondary to the plasma membrane core location. Supporting Evidence: file:human/KCNJ11/KCNJ11-uniprot.txt Can form cardiac and smooth muscle-type KATP channels with ABCC9. |
| GO:0030315 T-tubule | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: T-tubule localization transferred from rodent orthologs. Reason: Muscle KATP channels (Kir6.2 with SUR2A) are present in sarcolemma and T-tubules; plausible tissue-specific location but secondary to the plasma membrane core location. Supporting Evidence: file:human/KCNJ11/KCNJ11-uniprot.txt Can form cardiac and smooth muscle-type KATP channels with ABCC9. |
| GO:0030506 ankyrin binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ankyrin binding transferred from mouse. Reason: Kir6.2 binds ankyrin-B through a C-terminal motif that targets KATP channels to membrane domains; a trafficking interaction, not the core channel function. Supporting Evidence: PMID:19805355 Kir6.2 lacking this motif displays aberrant channel targeting due to loss of association with the membrane adapter ankyrin-B (AnkB) |
| GO:0030506 ankyrin binding | IPI PMID:20610380 Ankyrin-B regulates Kir6.2 membrane expression and function ... | KEEP AS NON CORE | Summary: IPI ankyrin binding (ankyrin-B) in heart. Reason: Direct association of Kir6.2 with ankyrin-B supports KATP membrane expression; supported but secondary to the channel activity. Supporting Evidence: PMID:20610380 cardiac sarcolemmal K(ATP) channels directly associate with ankyrin-B in heart via the K(ATP) channel alpha-subunit Kir6.2 |
| GO:0030955 potassium ion binding | TAS PMID:8923010 Mutation of the pancreatic islet inward rectifier Kir6.2 als... | MARK AS OVER ANNOTATED | Summary: TAS potassium ion binding from the Kir6.2 PHHI mutation paper. Reason: K+ coordination in the selectivity filter is intrinsic to the channel activity; a separate potassium ion binding MF adds no information and is not what the cited paper shows. Supporting Evidence: file:human/KCNJ11/KCNJ11-uniprot.txt Inward rectifier potassium channel that forms the pore of ATP-sensitive potassium channels (KATP), regulating potassium permeability as a function of cytoplasmic ATP and ADP concentrations in many different cells |
| GO:0033198 response to ATP | IDA PMID:15583126 Molecular basis of Kir6.2 mutations associated with neonatal... | KEEP AS NON CORE | Summary: IDA response to ATP: mutant Kir6.2 channels show altered ATP inhibition. Reason: ATP inhibition is the gating mechanism of the core channel activity; the BP "response to ATP" is a weak restatement of that gating and is kept as non-core. Supporting Evidence: PMID:15583126 All mutations increased resting whole-cell K(ATP) currents by reducing channel inhibition by ATP |
| GO:0033198 response to ATP | IDA PMID:18073297 The G53D mutation in Kir6.2 (KCNJ11) is associated with neon... | KEEP AS NON CORE | Summary: IDA response to ATP: mutant Kir6.2 channels show altered ATP inhibition. Reason: ATP inhibition is the gating mechanism of the core channel activity; the BP "response to ATP" is a weak restatement of that gating and is kept as non-core. Supporting Evidence: PMID:18073297 Reconstituted G53D channels exhibit reduced ATP sensitivity, which is predicted to suppress electrical activity in vivo. |
| GO:0034705 potassium channel complex | IEA GO_REF:0000117 | ACCEPT | Summary: Electronic annotation to potassium channel complex. Reason: Correct parent of the KATP inward rectifying potassium channel complex. Supporting Evidence: PMID:7502040 these pancreatic beta cell potassium channels are a complex composed of at least two subunits--BIR, a member of the inward rectifier potassium channel family, and SUR |
| GO:0042391 regulation of membrane potential | IDA PMID:18073297 The G53D mutation in Kir6.2 (KCNJ11) is associated with neon... | ACCEPT | Summary: IDA regulation of membrane potential from reconstituted G53D Kir6.2 channels. Reason: KATP channel activity sets the resting membrane potential of beta cells, neurons and muscle; mutant channels with reduced ATP sensitivity suppress electrical activity. Supporting Evidence: PMID:18073297 Reconstituted G53D channels exhibit reduced ATP sensitivity, which is predicted to suppress electrical activity in vivo. PMID:15583126 increased K(ATP) currents hyperpolarize pancreatic beta cells and impair insulin secretion |
| GO:0044325 transmembrane transporter binding | IPI PMID:20610380 Ankyrin-B regulates Kir6.2 membrane expression and function ... | KEEP AS NON CORE | Summary: IPI transmembrane transporter binding (SUR2/ABCC9, O60706) in heart. Reason: Kir6.2 assembles with SUR subunits (ABCC8 or ABCC9) to form KATP channels; this subunit interaction is captured by complex membership and is non-core as an MF. Supporting Evidence: file:human/KCNJ11/KCNJ11-uniprot.txt Can form cardiac and smooth muscle-type KATP channels with ABCC9. PMID:20610380 cardiac sarcolemmal K(ATP) channels directly associate with ankyrin-B in heart via the K(ATP) channel alpha-subunit Kir6.2 |
| GO:0044325 transmembrane transporter binding | IPI PMID:20610380 Ankyrin-B regulates Kir6.2 membrane expression and function ... | KEEP AS NON CORE | Summary: IPI transmembrane transporter binding (SUR1/ABCC8, Q09428). Reason: Kir6.2-SUR1 co-assembly is required to form functional beta-cell KATP channels; captured by complex membership and non-core as an MF. Supporting Evidence: file:human/KCNJ11/KCNJ11-uniprot.txt In pancreatic cells, it forms KATP channels with ABCC8/SUR1 PMID:29286281 human pancreatic KATP channel, containing the ABC transporter SUR1 and the inward-rectifier K+ channel Kir6.2 |
| GO:0046676 negative regulation of insulin secretion | IEA GO_REF:0000107 | ACCEPT | Summary: Electronic ortholog annotation to negative regulation of insulin secretion. Reason: Open KATP channels hold the beta-cell membrane hyperpolarized and restrain insulin release; loss of Kir6.2 function causes hyperinsulinism. Supporting Evidence: PMID:8923010 Closure of ATP-sensitive potassium channels in pancreatic islet beta-cells initiates a cascade of events that leads to insulin secretion. PMID:15583126 increased K(ATP) currents hyperpolarize pancreatic beta cells and impair insulin secretion |
| GO:0046676 negative regulation of insulin secretion | IMP PMID:8923010 Mutation of the pancreatic islet inward rectifier Kir6.2 als... | ACCEPT | Summary: IMP: a homozygous loss-of-function Kir6.2 mutation causes familial persistent hyperinsulinemic hypoglycemia of infancy. Reason: Loss of Kir6.2 causes unregulated insulin secretion, directly supporting a role for the channel in restraining insulin release. Supporting Evidence: PMID:8923010 Closure of ATP-sensitive potassium channels in pancreatic islet beta-cells initiates a cascade of events that leads to insulin secretion. PMID:8923010 Kir6.2 is necessary, although not sufficient, for normal regulation of insulin release |
| GO:0050796 regulation of insulin secretion | IMP PMID:15115830 Activating mutations in the gene encoding the ATP-sensitive ... | ACCEPT | Summary: IMP regulation of insulin secretion from activating KCNJ11 mutations causing neonatal diabetes. Reason: Gain- and loss-of-function Kir6.2 variants respectively suppress and derepress insulin secretion; KATP channels couple beta-cell metabolism to insulin release. Supporting Evidence: PMID:15115830 Because ATP-sensitive potassium (K(ATP)) channels mediate glucose-stimulated insulin secretion from the pancreatic beta cells PMID:15583126 increased K(ATP) currents hyperpolarize pancreatic beta cells and impair insulin secretion |
| GO:0050877 nervous system process | IMP PMID:15115830 Activating mutations in the gene encoding the ATP-sensitive ... | KEEP AS NON CORE | Summary: IMP nervous system process from DEND-spectrum patients with activating KCNJ11 mutations. Reason: Neuronal KATP channels contribute to neuronal excitability, and activating mutations cause developmental delay and epilepsy; a real but tissue-specific, broadly worded process kept as non-core. Supporting Evidence: PMID:15115830 Heterozygous activating mutations in the gene encoding Kir6.2 cause permanent neonatal diabetes and may also be associated with developmental delay, muscle weakness, and epilepsy. |
| GO:0050877 nervous system process | IMP PMID:18073297 The G53D mutation in Kir6.2 (KCNJ11) is associated with neon... | KEEP AS NON CORE | Summary: IMP nervous system process from DEND-spectrum patients with activating KCNJ11 mutations. Reason: Neuronal KATP channels contribute to neuronal excitability, and activating mutations cause developmental delay and epilepsy; a real but tissue-specific, broadly worded process kept as non-core. Supporting Evidence: PMID:18073297 this improvement is due to inhibition of the neuronal but not skeletal muscle KATP |
| GO:0055085 transmembrane transport | ISS GO_REF:0000024 | MODIFY | Summary: ISS annotation to generic transmembrane transport. Reason: Too general; the specific process is potassium ion transmembrane transport. Proposed replacements: potassium ion transmembrane transport Supporting Evidence: file:human/KCNJ11/KCNJ11-uniprot.txt Inward rectifier potassium channel that forms the pore of ATP-sensitive potassium channels (KATP), regulating potassium permeability as a function of cytoplasmic ATP and ADP concentrations in many different cells |
| GO:0071805 potassium ion transmembrane transport | NAS PMID:28842488 Conserved functional consequences of disease-associated muta... | ACCEPT | Summary: NAS potassium ion transmembrane transport. Reason: Kir6.2 forms the K+-conducting pore of KATP channels; core process. Supporting Evidence: file:human/KCNJ11/KCNJ11-uniprot.txt Inward rectifier potassium channel that forms the pore of ATP-sensitive potassium channels (KATP), regulating potassium permeability as a function of cytoplasmic ATP and ADP concentrations in many different cells PMID:28842488 results in increased open state stability and hence significantly reduced ATP sensitivity and a marked increase of channel activity in the intact cell irrespective of the identity of the coassembled SUR subunit |
| GO:0098797 plasma membrane protein complex | IEA GO_REF:0000117 | ACCEPT | Summary: Electronic annotation to plasma membrane protein complex. Reason: Correct parent: the KATP channel is a plasma membrane protein complex. Supporting Evidence: file:human/KCNJ11/KCNJ11-uniprot.txt In pancreatic cells, it forms KATP channels with ABCC8/SUR1 PMID:19805355 the C-terminal domain of Kir6.2 contains a motif conferring membrane targeting in primary excitable cells |
| GO:0099505 regulation of presynaptic membrane potential | IEA GO_REF:0000108 | MARK AS OVER ANNOTATED | Summary: Electronic annotation to regulation of presynaptic membrane potential, inferred from the SynGO-style molecular function annotations. Reason: KATP channels regulate membrane potential in neurons, but no evidence here localizes Kir6.2 action specifically to presynaptic terminals; the source MF annotations derive from a urethral smooth-muscle study. The general regulation of membrane potential term is retained instead. Supporting Evidence: PMID:18945825 investigated the molecular basis of the pore of K(ATP) channels of pig urethral smooth muscle cells PMID:18073297 Reconstituted G53D channels exhibit reduced ATP sensitivity, which is predicted to suppress electrical activity in vivo. |
| GO:0099508 voltage-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential | IDA PMID:18945825 ATP-sensitive K+ channels in pig urethral smooth muscle cell... | MODIFY | Summary: Annotation to voltage-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential from a study of KATP channels in pig urethral smooth muscle cells and recombinant Kir6.x concatemers in HEK293 cells. Reason: The cited study characterizes inward-rectifying KATP channel pores containing Kir6.2 in smooth muscle and heterologous cells; it does not address presynaptic membranes, and Kir6.2 is a nucleotide-gated inward rectifier rather than a voltage-gated channel. The channel activity measured is ATP-sensitive inward rectifier potassium channel activity. Proposed replacements: ATP-activated inward rectifier potassium channel activity Supporting Evidence: PMID:18945825 investigated the molecular basis of the pore of K(ATP) channels of pig urethral smooth muscle cells PMID:18945825 heteroconcatemeric Kir6.1-Kir6.2 K(ATP) channels also showed strong inward rectification at positive membrane potentials |
| GO:0099508 voltage-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential | IEA GO_REF:0000117 | MODIFY | Summary: ARBA electronic annotation to voltage-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential. Reason: Kir6.2 is a nucleotide-gated inward rectifier; replace with its specific channel activity. Proposed replacements: ATP-activated inward rectifier potassium channel activity Supporting Evidence: file:human/KCNJ11/KCNJ11-uniprot.txt Inward rectifier potassium channel that forms the pore of ATP-sensitive potassium channels (KATP), regulating potassium permeability as a function of cytoplasmic ATP and ADP concentrations in many different cells |
| GO:0099508 voltage-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential | IMP PMID:18945825 ATP-sensitive K+ channels in pig urethral smooth muscle cell... | MODIFY | Summary: Annotation to voltage-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential from a study of KATP channels in pig urethral smooth muscle cells and recombinant Kir6.x concatemers in HEK293 cells. Reason: The cited study characterizes inward-rectifying KATP channel pores containing Kir6.2 in smooth muscle and heterologous cells; it does not address presynaptic membranes, and Kir6.2 is a nucleotide-gated inward rectifier rather than a voltage-gated channel. The channel activity measured is ATP-sensitive inward rectifier potassium channel activity. Proposed replacements: ATP-activated inward rectifier potassium channel activity Supporting Evidence: PMID:18945825 investigated the molecular basis of the pore of K(ATP) channels of pig urethral smooth muscle cells PMID:18945825 heteroconcatemeric Kir6.1-Kir6.2 K(ATP) channels also showed strong inward rectification at positive membrane potentials |
| GO:0099508 voltage-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential | NAS PMID:18945825 ATP-sensitive K+ channels in pig urethral smooth muscle cell... | MODIFY | Summary: Annotation to voltage-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential from a study of KATP channels in pig urethral smooth muscle cells and recombinant Kir6.x concatemers in HEK293 cells. Reason: The cited study characterizes inward-rectifying KATP channel pores containing Kir6.2 in smooth muscle and heterologous cells; it does not address presynaptic membranes, and Kir6.2 is a nucleotide-gated inward rectifier rather than a voltage-gated channel. The channel activity measured is ATP-sensitive inward rectifier potassium channel activity. Proposed replacements: ATP-activated inward rectifier potassium channel activity Supporting Evidence: PMID:18945825 investigated the molecular basis of the pore of K(ATP) channels of pig urethral smooth muscle cells PMID:18945825 heteroconcatemeric Kir6.1-Kir6.2 K(ATP) channels also showed strong inward rectification at positive membrane potentials |
| GO:1990573 potassium ion import across plasma membrane | IBA GO_REF:0000033 | MODIFY | Summary: Annotation to potassium ion import across plasma membrane. Reason: Inward rectification describes the conductance asymmetry of Kir channels, but physiologically open KATP channels carry outward K+ current that hyperpolarizes beta cells, neurons and myocytes. A directional "import" term misrepresents the role; the non-directional potassium ion transmembrane transport is appropriate. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000205946 SUPPORTS TRANSFER Kir-family ancestral node; K+ conduction across the plasma membrane is genuinely inherited by Kir6.2, so the node placement is not disputed. The directional "import" term is the problem for KATP channels, whose physiological current is mainly K+ efflux. UniProtKB:Q14654 SUPPORTS TRANSFER The target itself appears among the sources through its own experimental annotation; this is expected for an IBD node and is not circular. Proposed replacements: potassium ion transmembrane transport Supporting Evidence: file:human/KCNJ11/KCNJ11-uniprot.txt Inward rectifier potassium channel that forms the pore of ATP-sensitive potassium channels (KATP), regulating potassium permeability as a function of cytoplasmic ATP and ADP concentrations in many different cells PMID:15583126 increased K(ATP) currents hyperpolarize pancreatic beta cells and impair insulin secretion file:human/KCNJ11/KCNJ11-deep-research-falcon.md In a pancreatic Ξ²-cell, an open channel permits KβΊ efflux down the prevailing electrochemical gradient, holding the plasma membrane relatively hyperpolarized. |
| GO:1990573 potassium ion import across plasma membrane | IDA PMID:19805355 Dual role of K ATP channel C-terminal motif in membrane targ... | MODIFY | Summary: IDA potassium ion import across plasma membrane from Kir6.2 targeting experiments. Reason: The channel conducts K+ across the plasma membrane, but physiologically KATP channels mediate K+ efflux that hyperpolarizes the cell; the non-directional transmembrane transport term is accurate. Proposed replacements: potassium ion transmembrane transport Supporting Evidence: PMID:19805355 the C-terminal domain of Kir6.2 contains a motif conferring membrane targeting in primary excitable cells PMID:15583126 increased K(ATP) currents hyperpolarize pancreatic beta cells and impair insulin secretion file:human/KCNJ11/KCNJ11-deep-research-falcon.md In a pancreatic Ξ²-cell, an open channel permits KβΊ efflux down the prevailing electrochemical gradient, holding the plasma membrane relatively hyperpolarized. |
| GO:1990573 potassium ion import across plasma membrane | IEA GO_REF:0000120 | MODIFY | Summary: Annotation to potassium ion import across plasma membrane. Reason: Inward rectification describes the conductance asymmetry of Kir channels, but physiologically open KATP channels carry outward K+ current that hyperpolarizes beta cells, neurons and myocytes. A directional "import" term misrepresents the role; the non-directional potassium ion transmembrane transport is appropriate. Proposed replacements: potassium ion transmembrane transport Supporting Evidence: file:human/KCNJ11/KCNJ11-uniprot.txt Inward rectifier potassium channel that forms the pore of ATP-sensitive potassium channels (KATP), regulating potassium permeability as a function of cytoplasmic ATP and ADP concentrations in many different cells PMID:15583126 increased K(ATP) currents hyperpolarize pancreatic beta cells and impair insulin secretion file:human/KCNJ11/KCNJ11-deep-research-falcon.md In a pancreatic Ξ²-cell, an open channel permits KβΊ efflux down the prevailing electrochemical gradient, holding the plasma membrane relatively hyperpolarized. |
| GO:1990573 potassium ion import across plasma membrane | ISS GO_REF:0000024 | MODIFY | Summary: Annotation to potassium ion import across plasma membrane. Reason: Inward rectification describes the conductance asymmetry of Kir channels, but physiologically open KATP channels carry outward K+ current that hyperpolarizes beta cells, neurons and myocytes. A directional "import" term misrepresents the role; the non-directional potassium ion transmembrane transport is appropriate. Proposed replacements: potassium ion transmembrane transport Supporting Evidence: file:human/KCNJ11/KCNJ11-uniprot.txt Inward rectifier potassium channel that forms the pore of ATP-sensitive potassium channels (KATP), regulating potassium permeability as a function of cytoplasmic ATP and ADP concentrations in many different cells PMID:15583126 increased K(ATP) currents hyperpolarize pancreatic beta cells and impair insulin secretion file:human/KCNJ11/KCNJ11-deep-research-falcon.md In a pancreatic Ξ²-cell, an open channel permits KβΊ efflux down the prevailing electrochemical gradient, holding the plasma membrane relatively hyperpolarized. |
| GO:1990573 potassium ion import across plasma membrane | ISS GO_REF:0000114 | MODIFY | Summary: Annotation to potassium ion import across plasma membrane. Reason: Inward rectification describes the conductance asymmetry of Kir channels, but physiologically open KATP channels carry outward K+ current that hyperpolarizes beta cells, neurons and myocytes. A directional "import" term misrepresents the role; the non-directional potassium ion transmembrane transport is appropriate. Proposed replacements: potassium ion transmembrane transport Supporting Evidence: file:human/KCNJ11/KCNJ11-uniprot.txt Inward rectifier potassium channel that forms the pore of ATP-sensitive potassium channels (KATP), regulating potassium permeability as a function of cytoplasmic ATP and ADP concentrations in many different cells PMID:15583126 increased K(ATP) currents hyperpolarize pancreatic beta cells and impair insulin secretion file:human/KCNJ11/KCNJ11-deep-research-falcon.md In a pancreatic Ξ²-cell, an open channel permits KβΊ efflux down the prevailing electrochemical gradient, holding the plasma membrane relatively hyperpolarized. |
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Download this section (compressed HTML)Q: How do the stoichiometric contributions of individual mutant Kir6.2 subunits within the tetramer determine whether a variant causes isolated neonatal diabetes or the DEND spectrum, and can this predict sulfonylurea responsiveness?
Q: Do mitochondrial or intracellular pools of Kir6.2 reported in some tissues contribute functionally, or are they trafficking intermediates?
Experiment: Systematic deep mutational scanning of Kir6.2 co-expressed with SUR1 measuring surface expression, ATP IC50 and open probability, to classify hyperinsulinism (loss-of-function) versus neonatal diabetes (gain-of-function) variants.
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