Affinage

KCNJ11

ATP-sensitive inward rectifier potassium channel 11 · UniProt Q14654

Length
390 aa
Mass
43.5 kDa
Annotated
2026-06-10
100 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KCNJ11 encodes Kir6.2, the pore-forming subunit of the ATP-sensitive potassium (K(ATP)) channel that couples cellular metabolic state to membrane excitability across pancreatic beta-cells, neurons, and cardiomyocytes (PMID:9144288, PMID:10868950). Kir6.2 assembles combinatorially with sulfonylurea receptor isoforms — SUR1 for the beta-cell/neuronal channel, SUR2A for the cardiac sarcolemmal channel, and SUR2B for the smooth-muscle channel — and the choice of SUR partner specifies the tissue-specific pharmacology and gating of the resulting channel (PMID:8798681, PMID:10093054, PMID:11282890). ATP inhibition is conferred intrinsically by Kir6.2 itself, as a C-terminally truncated Kir6.2 forms ATP-sensitive channels in the absence of SUR1 (PMID:9144288); positively charged and polar residues distributed across both the N-terminus (R50) and C-terminus (K185, R192, R201) form the nucleotide-binding/transduction surface, with the N- and C-termini cooperating to drive pore closure (PMID:9831713, PMID:12524280). Channel opening is promoted by PIP2 binding to a defined set of N-terminal, transmembrane, and C-terminal residues that antagonizes ATP inhibition (PMID:12034765, PMID:17673911), and a cryoEM structure of an open-state channel resolves both a canonical and a non-canonical SUR1–Kir6.2 interface PIP2 site, linking pore opening to a cytoplasmic-domain twist and widening of the ATP pocket (PMID:38509107). The Kir6.2 N-terminus and a discrete SUR1–Kir6.2 interface (SUR1-E203/Kir6.2-Q52, SUR1 residues 196–288) physically couple SUR1 drug binding to pore gating (PMID:19351728, PMID:22802363), and the N-terminus is also required for high-affinity binding of sulfonylurea-class drugs such as repaglinide (PMID:15678092). Channel activity is further tuned by phosphorylation — PKA activates via Ser372, PKC inhibits via Ser372-dependent internalization, and CaMKII inhibits via Thr224 — and by palmitoylation at Cys166, which enhances PIP2 sensitivity (PMID:10469651, PMID:22207763, PMID:24101510, PMID:32332165). In beta-cells, K(ATP) channels set the resting potential and gate glucose- and sulfonylurea-induced depolarization, Ca2+ entry, and insulin secretion (PMID:10868950); in the heart, sarcolemmal Kir6.2 channels mediate responses to channel openers and contribute to ischemic-preconditioning energetic protection (PMID:11282890, PMID:12598229). Gain-of-function KCNJ11 mutations reduce ATP sensitivity and cause permanent neonatal diabetes, with the most severe open-state-stabilizing mutations producing DEND syndrome, whereas a Kir6.2 M2-domain mutation causes persistent hyperinsulinemic hypoglycemia of infancy (PMID:8923010, PMID:15115830, PMID:15583126).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1996 High

    Established that Kir6.2 is a necessary subunit of the beta-cell K(ATP) channel and that its assembly with SUR isoforms generates tissue-specific channels, framing the channel as a combinatorial heteromer.

    Evidence Genetic sequencing of a PHHI family plus functional reconstitution of Kir6.2 with SUR1 and with the novel SUR2B isoform; patch-clamp

    PMID:8798681 PMID:8923010

    Open questions at the time
    • Did not resolve where on Kir6.2 ATP acts
    • Stoichiometry and structural arrangement of the heteromer not defined
  2. 1997 High

    Resolved the long-standing question of whether ATP inhibition resides on Kir6.2 or SUR1 by showing a C-terminally truncated Kir6.2 forms ATP-sensitive channels alone, localizing the ATP-inhibitory site to the pore subunit while SUR1 confers sulfonylurea/diazoxide/Mg-ADP responsiveness.

    Evidence Truncation mutagenesis (ΔC26) of Kir6.2 expressed in Xenopus oocytes; patch-clamp

    PMID:9144288

    Open questions at the time
    • Did not identify the specific ATP-contacting residues
    • Mechanism of SUR1-Kir6.2 functional coupling unresolved
  3. 1999 High

    Mapped the ATP-inhibitory and coupling determinants to specific Kir6.2 regions — the N-terminus couples SUR1 drug binding to pore closure, and N- and C-terminal residues (R50, plus C-terminal sites) cooperate in ATP transduction — and identified PKA Ser372 phosphorylation as an activating modulation.

    Evidence N-terminal deletion and point mutagenesis, PKA phosphorylation assays in oocyte homogenates and intact cells, patch-clamp

    PMID:10381582 PMID:10469651 PMID:9831713

    Open questions at the time
    • Atomic geometry of the ATP site not yet defined
    • Did not establish full set of nucleotide-contacting residues
  4. 2001 High

    Demonstrated by knockout and rescue that Kir6.2 is the obligate pore of the cardiac sarcolemmal K(ATP) channel but is dispensable in arterial smooth muscle, defining its tissue distribution in vivo.

    Evidence Kir6.2-knockout mice, gene-transfer rescue, patch-clamp and contractile assays

    PMID:11282890

    Open questions at the time
    • Did not address cardiac mitochondrial K(ATP) contribution
    • SUR partner specificity in vivo not dissected here
  5. 2000 High

    Established physiologically that beta-cell K(ATP) channels set resting potential and are required for glucose- and sulfonylurea-coupled insulin secretion, beta-cell survival, and islet architecture.

    Evidence Dominant-negative (G132S) transgenic and Kir6.2-knockout mice; insulin secretion, electrophysiology, calcium imaging

    PMID:10868950

    Open questions at the time
    • Did not define molecular basis of survival/architecture defects
    • Human disease relevance addressed only later
  6. 2003 High

    Defined the electrostatic chemistry of nucleotide inhibition by showing C-terminal K185 and R201 contact phosphate groups (R201 stabilizing the closed state via the alpha-phosphate), and located the C-terminal phospholipid/PIP2-interacting helix.

    Evidence Systematic site-directed mutagenesis, GFP-fragment membrane association, patch-clamp

    PMID:12034765 PMID:12524280

    Open questions at the time
    • Did not provide a structural model of the nucleotide pocket
    • Coupling between PIP2 site and ATP site inferred functionally
  7. 2005 High

    Identified the PIP2 binding residues across N-terminus, transmembrane, and C-terminus and showed PIP2 opens the channel while reducing ATP binding, establishing PIP2 as the physiological antagonist of ATP inhibition.

    Evidence Homology modelling and docking validated by mutagenesis and patch-clamp (reported 2007; multiple residue mutants)

    PMID:17673911

    Open questions at the time
    • Model-based site assignment lacked an experimental structure at the time
    • Number and arrangement of PIP2 sites unresolved
  8. 2004 High

    Connected Kir6.2 mechanism to human disease by showing heterozygous gain-of-function KCNJ11 mutations reduce ATP sensitivity to cause permanent neonatal diabetes (and DEND syndrome), and dissected two mechanistic classes — direct impairment of ATP binding/transduction versus indirect bias toward the open state.

    Evidence KCNJ11 patient sequencing, heterologous expression of mutant Kir6.2/SUR1, patch-clamp with kinetic analysis, in vivo secretion tests

    PMID:15115830 PMID:15583126 PMID:15864298 PMID:15962003 PMID:17021801

    Open questions at the time
    • Did not establish atomic explanation for open-state stabilization until cryoEM
    • Genotype–phenotype severity correlation defined functionally, not structurally
  9. 2006 High

    Validated the disease mechanism in a native beta-cell context, showing inducible R201H expression collapses ATP sensitivity, abolishes metabolic channel closure, electrical activity, and insulin secretion.

    Evidence Tetracycline-inducible R201H expression in INS-1 cells; patch-clamp; insulin secretion assay

    PMID:17065345

    Open questions at the time
    • Single mutation in a cell line, not in vivo human islet
    • Did not address neuronal DEND phenotype mechanism
  10. 2009 High

    Defined a physical SUR1–Kir6.2 coupling interface, showing Kir6.2 N-terminal residues 28–32 interact with SUR1 residues 196–288 to transmit drug binding into gating.

    Evidence Co-immunoprecipitation of fragments plus in-frame deletion mutagenesis and patch-clamp

    PMID:19351728

    Open questions at the time
    • Interface mapped by deletion/co-IP, not by structure
    • Did not define full interface contact map
  11. 2012 High

    Pinpointed a precise SUR1-E203/Kir6.2-Q52 contact controlling ATP sensitivity, using disulfide cross-linking to lock the channel closed and proving close physical proximity at a functionally critical interface.

    Evidence Cysteine mutagenesis and disulfide cross-linking; patch-clamp in Xenopus oocytes

    PMID:22802363

    Open questions at the time
    • Did not resolve full interface geometry
    • Relationship to PIP2 site addressed only by later cryoEM
  12. 2013 High

    Extended channel regulation to multivalent phosphorylation and scaffolding, showing βIV-spectrin targets CaMKII to phosphorylate Kir6.2-Thr224 (inhibitory), ankyrin-B controls cardiac Kir6.2 surface expression and gating, and PKC inhibits via Ser372-driven internalization.

    Evidence In vitro kinase assays, site-directed mutagenesis, co-IP, transgenic mice, patch-clamp

    PMID:20610380 PMID:22207763 PMID:24101510

    Open questions at the time
    • Interplay between competing Ser372 PKA/PKC effects not fully integrated
    • Physiological stimuli triggering each modification incompletely defined
  13. 2020 High

    Added lipid post-translational regulation, showing palmitoylation at Cys166 promotes opening by enhancing PIP2 sensitivity and that clinical Cys166 variants behave as gain-of-function, mimicking palmitoylation.

    Evidence Acyl-biotin exchange, C166 mutagenesis, patch-clamp in multiple cell types

    PMID:32332165

    Open questions at the time
    • Enzymes mediating Kir6.2 palmitoylation/depalmitoylation not identified
    • Dynamic regulation in vivo not established
  14. 2024 High

    Provided the structural basis for gating by solving an open-state cryoEM structure of a Kir6.2-Q52R channel, revealing tandem canonical and non-canonical PIP2 sites at the SUR1–Kir6.2 interface and a cytoplasmic-domain twist that widens the ATP pocket, with Q52R stabilizing the open state via cation-π bonding to SUR1-W51.

    Evidence CryoEM structure determination with functional mutagenesis and patch-clamp validation

    PMID:38509107

    Open questions at the time
    • Closed/ATP-bound conformational transition not fully captured here
    • Structural basis of every disease mutation not individually resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple regulatory inputs — ATP, PIP2, palmitoylation, and competing PKA/PKC/CaMKII phosphorylation — are integrated dynamically at a single channel in different tissues, and how trafficking/degradation (ubiquitin-proteasome, ankyrin/spectrin scaffolds) tunes channel density in vivo, remains incompletely defined.
  • Quantitative model of competing modifications absent
  • Tissue-specific regulatory hierarchy not resolved
  • In vivo degradation control of channel abundance underexplored

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0008289 lipid binding 3 GO:0140313 molecular sequestering activity 3
Localization
GO:0005886 plasma membrane 5 GO:0005739 mitochondrion 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-382551 Transport of small molecules 2 R-HSA-397014 Muscle contraction 2 R-HSA-112316 Neuronal System 1
Partners
ABCC8ABCC9ANK2CAMK2DPRKAA1PRKACAPRKCASPTBN4
Complex memberships
K(ATP) channel (Kir6.2/SUR1)Kir6.2/SUR2A cardiac K(ATP) channelKir6.2/SUR2B smooth-muscle K(ATP) channelankyrin-B/Na,K-ATPase/K(ATP) membrane complex

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 Kir6.2 is the primary subunit of the K(ATP) channel at which ATP acts to mediate channel inhibition; truncation of the C-terminus of Kir6.2 (ΔC26) produces ATP-sensitive K+ channels in the absence of SUR1, demonstrating the ATP-inhibitory site resides on Kir6.2. SUR1 is required for sensitivity to sulfonylureas, diazoxide, and activation by Mg-ADP. Truncation mutagenesis of Kir6.2 expressed in Xenopus oocytes; electrophysiology (patch-clamp) Nature High 9144288
1996 Kir6.2 co-expression with SUR1 reconstitutes the beta-cell K(ATP) channel; a homozygous L147P mutation in Kir6.2 (disrupting the M2 transmembrane domain) causes familial persistent hyperinsulinemic hypoglycemia of infancy (PHHI), demonstrating Kir6.2 is a necessary subunit for normal regulated insulin release. Genetic sequencing, functional reconstitution by coexpression of Kir6.2 and SUR1 Human molecular genetics High 8923010
1996 A novel SUR isoform (SUR2B) co-expressed with Kir6.2 reconstitutes smooth muscle-type K(ATP) channels that are activated by diazoxide and pinacidil, establishing that tissue-specific K(ATP) channel phenotypes arise from combinatorial assembly of Kir6.2 with different SUR isoforms. Heterologous coexpression in mammalian cell line; patch-clamp electrophysiology The Journal of biological chemistry High 8798681
1999 The N-terminus of Kir6.2 is involved in coupling sulfonylurea binding at SUR1 to closure of the Kir6.2 pore; N-terminal deletions (ΔN5, ΔN9, ΔN14) increase open probability, reduce ATP sensitivity, and abolish high-affinity tolbutamide block when co-expressed with SUR1, but do not alter intrinsic Kir6.2 gating in the absence of SUR1. N-terminal deletion and site-directed mutagenesis of Kir6.2; patch-clamp in Xenopus oocytes The Journal of physiology High 10381582
1999 The R50 residue in the N-terminus of Kir6.2 is important for ATP inhibition; R50S/A/G mutations substantially reduce ATP sensitivity (Ki increased from 117 µM to 800 µM–3.8 mM). Combining N-terminal (R50S) and C-terminal (E179Q) mutations has additive effects, suggesting N- and C-termini cooperate to mediate channel closure by ATP. Site-directed mutagenesis; patch-clamp of excised membrane patches from Xenopus oocytes The Journal of physiology High 9831713
1999 PKA directly phosphorylates Kir6.2 at Ser372 in the C-terminus and SUR1 at Ser1571; phosphorylation of Kir6.2 at Ser372 increases channel activity, while phosphorylation of SUR1 modulates basal channel properties (burst duration, interburst interval, open probability) and surface expression. PKA stimulation via Gs-coupled receptors can phosphorylate Kir6.2 in intact cells. Site-directed mutagenesis of PKA consensus sequences; phosphorylation assays in Xenopus oocyte homogenates and intact cells; electrophysiology The EMBO journal High 10469651
1999 Kir6.2 physically associates with SUR2A to form the cardiac K(ATP) channel; co-immunoprecipitation of in vitro-translated proteins demonstrated direct physical interaction. The proximal C-terminus and M2 transmembrane domain of Kir6.2 are required for assembly with SUR2A, while the distal 37 amino acids of the C-terminus are not. Co-immunoprecipitation of in vitro-translated Kir6.2 deletion mutants with SUR2A Journal of molecular and cellular cardiology Medium 10093054
2001 Kir6.2 is the pore-forming subunit mediating sarcolemmal K(ATP) channel activity in ventricular cardiomyocytes; Kir6.2-knockout mice lack electrophysiological and contractile responses to K+ channel openers (pinacidil, P-1075) in the heart. In contrast, Kir6.2 plays no role in arterial smooth muscle K(ATP) channels, where only Kir6.1 is expressed. Genetic knockout (Kir6.2-KO mice); patch-clamp electrophysiology; gene transfer rescue experiment; contractile function assays Circulation research High 11282890
2000 In pancreatic beta-cells, Kir6.2 subunits form the K+ ion-permeable pore and primarily confer ATP inhibition; dominant-negative Kir6.2-G132S expression and Kir6.2 knockout mice establish that K(ATP) channels are the major determinant of beta-cell resting membrane potential, are required for both glucose- and sulfonylurea-induced membrane depolarization, Ca2+ entry, and insulin secretion, and are important for beta-cell survival and islet architecture. Transgenic dominant-negative mice (Kir6.2-G132S); Kir6.2 knockout mice; insulin secretion assays; electrophysiology; calcium imaging Diabetes High 10868950
2002 The C-terminus of Kir6.2 associates with lipid membranes via a conserved domain; systematic mutagenesis of D307–F315 identifies residues E308, I309, W311, and F315 on one face of a conserved alpha-helix as critical determinants of phospholipid (PIP2) interaction and K(ATP) channel activity. GFP-tagged fragment membrane association assay; site-directed mutagenesis; patch-clamp electrophysiology The Journal of general physiology High 12034765
2003 Positively charged residues K185 and R201 in the C-terminus of Kir6.2 are critical for channel inhibition by adenine nucleotides via electrostatic interaction with phosphate groups; R201 interacts with the alpha-phosphate to stabilize a closed state, while K185 interacts with the beta-phosphate in a state-independent manner. R192 (C-terminus) and R50 (N-terminus) also contribute to ATP sensitivity. Site-directed mutagenesis; patch-clamp of Xenopus oocytes Biophysical journal High 12524280
2003 Kir6.2 knockout abolishes ischemic preconditioning-induced protection of myocardial bioenergetics; preconditioned wild-type hearts showed significantly higher ATP turnover, synthesis rate, and creatine kinase-catalyzed phosphotransfer than Kir6.2-KO hearts, demonstrating that sarcolemmal K(ATP) channels (via Kir6.2) are integral to ischemic preconditioning-induced cardiac energetic protection. Kir6.2 knockout mice; 18O-assisted 31P-NMR spectroscopy; ischemia-reperfusion protocol American journal of physiology. Heart and circulatory physiology High 12598229
2004 Heterozygous activating (gain-of-function) missense mutations in KCNJ11 (Kir6.2) cause permanent neonatal diabetes by reducing ATP-inhibitory sensitivity of K(ATP) channels; the most common mutation (R201H) when co-expressed with SUR1 in Xenopus oocytes greatly reduced the ability of ATP to block mutant channels, hyperpolarizing beta-cells and preventing insulin secretion. Some mutations also cause DEND syndrome (developmental delay, epilepsy, neonatal diabetes). KCNJ11 sequencing; heterologous expression of mutant Kir6.2/SUR1 in Xenopus oocytes; patch-clamp electrophysiology; in vivo insulin secretion tests The New England journal of medicine High 15115830
2004 Neonatal diabetes mutations in Kir6.2 reduce ATP inhibition by two distinct mechanisms: mutations causing diabetes alone (e.g., R201C) directly impair ATP binding/transduction, while mutations causing severe DEND syndrome (e.g., Q52R, V59G) act indirectly by biasing the channel toward the open state. Disease severity correlates with the magnitude of reduction in ATP sensitivity. The slide helix (V59) is implicated in Kir channel gating. Site-directed mutagenesis; heterologous expression in Xenopus oocytes; patch-clamp electrophysiology with kinetic analysis Proceedings of the National Academy of Sciences of the United States of America High 15583126
2005 The I296L mutation at the internal mouth of the Kir6.2 pore (DEND syndrome) increases whole-cell K(ATP) currents by stabilizing the open state of the channel and possibly reducing ATP binding via allosteric effects; kinetic analysis revealed the mutation impairs ATP sensitivity indirectly, implicating this region in Kir-channel gating. Site-directed mutagenesis; expression in Xenopus oocytes; patch-clamp electrophysiology; kinetic analysis EMBO reports High 15864298
2005 Neonatal diabetes mutations Y330C and F333I in Kir6.2 reduce ATP inhibition and alter Kir6.2/SUR1 interactions; Y330C impairs ATP binding directly and stabilizes the open state; F333I alters ATP binding/transduction directly and dramatically enhances stimulatory MgATP effects mediated via SUR1. At least three SUR1 subunits must bind/hydrolyse MgATP to open F333I mutant channels. Site-directed mutagenesis; heterologous expression in Xenopus oocytes; patch-clamp electrophysiology The EMBO journal High 15962003
2005 High-affinity repaglinide binding requires both SUR1 and Kir6.2; repaglinide binds with ~150-fold higher affinity to SUR1 co-expressed with Kir6.2 compared to SUR1 alone. N-terminal deletion of Kir6.2 (ΔN14) abolishes this affinity enhancement, indicating the Kir6.2 N-terminus is required for high-affinity repaglinide binding and functional inhibition. Glibenclamide binding affinity depends primarily on SUR1. Radioligand binding assay ([3H]repaglinide, [3H]glibenclamide); N-terminal deletion of Kir6.2; patch-clamp electrophysiology British journal of pharmacology High 15678092
2006 Six novel Kir6.2 mutations (H46Y, N48D, E227K, E229K, E292G, V252A) causing neonatal diabetes all reduce K(ATP) channel inhibition by MgATP; E227K and E229K enhance intrinsic open probability (indirectly reducing ATP sensitivity), while H46Y, N48D, E292G, and V252A likely affect ATP binding directly, as they lie near the predicted ATP-binding site. None substantially altered tolbutamide sensitivity. Heterologous expression of mutant Kir6.2/SUR1 in Xenopus oocytes; patch-clamp electrophysiology Pflugers Archiv : European journal of physiology High 17021801
2006 Induction of the R201H Kir6.2 mutation in INS-1 beta-cells strongly reduces K(ATP) channel ATP sensitivity (IC50 from ~20 µM to ~2 mM), prevents metabolic substrate-induced channel closure, abolishes electrical activity and insulin secretion, directly demonstrating that Kir6.2 gain-of-function mutations cause neonatal diabetes by hyperpolarizing beta-cells. Stable tetracycline-regulated expression in INS-1 cells; patch-clamp electrophysiology; insulin secretion assay Diabetes High 17065345
2007 The G53D Kir6.2 mutation reduces channel ATP sensitivity, causing intermediate DEND syndrome; G53D channels co-expressed with SUR1 (pancreatic/neuronal isoform) show high-affinity block by gliclazide, but G53D channels with SUR2A (skeletal muscle isoform) are insensitive to gliclazide while remaining sensitive to glibenclamide, explaining why glibenclamide but not gliclazide improved motor function in a DEND patient. Reconstitution of mutant Kir6.2/SUR1 or Kir6.2/SUR2A in Xenopus oocytes; patch-clamp electrophysiology; clinical treatment assessment The Journal of clinical endocrinology and metabolism High 18073297
2007 PIP2 binds to Kir6.2 at a site involving residues K39, N41, R54 (N-terminus), K67 (transmembrane domain), and R176, R177, E179, R301 (C-terminus), identified by homology modelling and validated by mutagenesis; PIP2 increases channel opening and decreases ATP binding and channel inhibition. Homology modelling; ligand docking; site-directed mutagenesis; patch-clamp electrophysiology in Xenopus oocytes The EMBO journal High 17673911
2009 Residues 28–32 in the N-terminus of Kir6.2 physically and functionally interact with SUR1 (specifically residues 196–288 of SUR1); an in-frame deletion of residues 28–32 impairs coupling between SUR1 and Kir6.2, increases intrinsic open probability, reduces ATP sensitivity, and disrupts co-immunoprecipitation with SUR1 N-terminal fragments. Co-immunoprecipitation; heterologous expression in Xenopus oocytes; patch-clamp electrophysiology The Journal of clinical endocrinology and metabolism High 19351728
2010 Ankyrin-B directly associates with Kir6.2 in the cardiac sarcolemma; primary cardiomyocytes lacking ankyrin-B display defects in Kir6.2 protein expression, membrane expression, and K(ATP) channel function, as well as altered channel gating. Ankyrin-B forms a membrane complex with K(ATP) channels and the Na/K-ATPase. Co-immunoprecipitation; Western blot; patch-clamp electrophysiology in ankyrin-B deficient primary myocytes; subcellular fractionation The Journal of biological chemistry High 20610380
2011 A Ca2+-dependent PKC inhibits Kir6.2/SUR2B channel complexes by promoting internalization; Ser372 in the distal C-terminus of Kir6.2 is the critical phosphorylation site for this inhibitory effect, distinct from the activating PKA phosphorylation of the same residue. Site-directed mutagenesis (Ser372); biochemical internalization assay; patch-clamp electrophysiology; PKC activator/inhibitor pharmacology The Journal of biological chemistry Medium 22207763
2012 A molecular interaction between SUR1-E203 and Kir6.2-Q52 regulates K(ATP) channel ATP sensitivity; E203K in SUR1 combined with Q52E in Kir6.2 increases ATP sensitivity ~100-fold over wild-type. Cross-linking of E203C (SUR1) and Q52C (Kir6.2) locks the channel in a closed state reversible by reducing agents, demonstrating close proximity and a functionally critical SUR1–Kir6.2 interface. Site-directed mutagenesis; disulfide cross-linking; patch-clamp electrophysiology in Xenopus oocytes The Journal of general physiology High 22802363
2013 βIV-spectrin serves as a scaffold that targets CaMKII to pancreatic islet beta-cells; CaMKII directly phosphorylates Kir6.2 at Thr224, inhibiting K(ATP) channel function and consistent with aberrant insulin regulation. βIV-spectrin mutant mice lacking CaMKII-binding motifs show selective loss of CaMKIIδ and aberrant Kir6.2 phosphorylation. Co-immunoprecipitation; site-directed mutagenesis (T224); patch-clamp electrophysiology; transgenic mice; in vitro kinase assay Proceedings of the National Academy of Sciences of the United States of America High 24101510
2005 Kir6.2 channel protein is degraded via the ubiquitin-proteasome pathway; Kir6.2 has a short half-life (~1.9 h) in COS cells. Proteasome inhibitors (MG132, ALLN, lactacystin) prolong Kir6.2 half-life and increase ubiquitinated Kir6.2, augmenting K(ATP) currents. The Na+ channel blocker aprindine inhibits 20S proteasome activity and similarly stabilizes Kir6.2. Pulse-chase/half-life analysis; proteasome inhibitors; ubiquitination assay; patch-clamp electrophysiology in COS cells and neonatal cardiomyocytes Biochemical and biophysical research communications Medium 15882977
2006 Targeted expression of Kir6.2 in mitochondria increases mitochondrial K+ influx, confers protection against hypoxic stress, and attenuates mitochondrial Ca2+ accumulation; an inactive Kir6.2 mutant abolishes this protection, demonstrating that K+ conductance through Kir6.2 in the inner mitochondrial membrane directly protects against hypoxic injury. Mitochondria-targeted Kir6.2 expression (pCMV/mito/GFP vector); colocalization studies; K+-sensitive fluorescent dye (PBFI AM); mitochondrial Ca2+ imaging (rhod-2); LDH release assay The Journal of physiology Medium 16959852
2014 Kir6.2-containing K(ATP) channels mediate the cardioprotective effects of resveratrol; resveratrol enhances AMPK phosphorylation and promotes physical association of AMPK with Kir6.2. Kir6.2 knockout abolishes cardioprotection by resveratrol in vivo and in vitro. AMPK activator cardioprotection is also lost in Kir6.2 KO, placing Kir6.2 downstream of AMPK in the cardioprotective signaling pathway. Kir6.2 knockout mice; ischemia/reperfusion injury; co-immunoprecipitation (AMPK–Kir6.2); infarct size measurement; neonatal cardiomyocyte assays Cardiovascular diabetology Medium 24498880
2018 SUR1-Kir6.2 (K(ATP)) and SUR1-TRPM4 heteromers are both upregulated in astrocytes after contusion-TBI; FRET imaging demonstrates SUR1-TRPM4 heteromers in endothelium and both SUR1-TRPM4 and SUR1-KIR6.2 heteromers in astrocytes. Antisense knockdown of KIR6.2 (unlike SUR1/TRPM4 knockdown) does not reduce hemorrhagic progression of contusion, indicating SUR1-TRPM4 (not SUR1-KIR6.2) is the primary channel mediating hemorrhagic contusion expansion. FRET imaging; antisense oligodeoxynucleotide (AS-ODN) knockdown; immunohistochemistry; contusion volume measurement Journal of neurotrauma Medium 30160201
2020 Kir6.2 is palmitoylated at Cys166; palmitoylation of Kir6.2 promotes channel opening by enhancing PIP2 sensitivity without affecting surface expression. Mutagenesis of Cys166 prevents palmitoylation effects. Palmitoylation blunts regulation of K(ATP) channels by α1-adrenoreceptor stimulation. Clinical KCNJ11 variants affecting Cys166 show gain-of-function phenotypes consistent with palmitoylation mimicry. Acyl-biotin exchange assay; site-directed mutagenesis (C166); patch-clamp electrophysiology in transfected cells, INS-1 cells, and isolated cardiomyocytes; palmitate preincubation; protein thioesterase inhibition Proceedings of the National Academy of Sciences of the United States of America High 32332165
2024 CryoEM structure of open-state K(ATP) channel (Kir6.2-Q52R neonatal diabetes mutant) reveals two tandem PIP2 binding sites at the SUR1–Kir6.2 interface: a canonical site conserved among PIP2-gated Kir channels and a non-canonical site at the subunit interface. Kir6.2 pore opening is associated with a twist of the cytoplasmic domain and SUR1 N-terminal transmembrane domain rotation that widens the ATP binding pocket. Q52R stabilizes the open state via cation-π bonding with SUR1-W51. Functional studies confirm both PIP2 binding sites determine channel activity. CryoEM structure determination; functional mutagenesis; patch-clamp electrophysiology Nature communications High 38509107

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. The New England journal of medicine 863 15115830
1997 Truncation of Kir6.2 produces ATP-sensitive K+ channels in the absence of the sulphonylurea receptor. Nature 671 9144288
2003 Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes. Diabetes 552 12540637
1998 A single BIR domain of XIAP sufficient for inhibiting caspases. The Journal of biological chemistry 508 9525868
1996 A novel sulfonylurea receptor forms with BIR (Kir6.2) a smooth muscle type ATP-sensitive K+ channel. The Journal of biological chemistry 478 8798681
1996 Mutation of the pancreatic islet inward rectifier Kir6.2 also leads to familial persistent hyperinsulinemic hypoglycemia of infancy. Human molecular genetics 343 8923010
2005 Activating mutations in Kir6.2 and neonatal diabetes: new clinical syndromes, new scientific insights, and new therapy. Diabetes 321 16123337
1999 An exegesis of IAPs: salvation and surprises from BIR motifs. Trends in cell biology 290 10407412
2000 The survivin-like C. elegans BIR-1 protein acts with the Aurora-like kinase AIR-2 to affect chromosomes and the spindle midzone. Molecular cell 218 10983970
1999 Caenorhabditis elegans inhibitor of apoptosis protein (IAP) homologue BIR-1 plays a conserved role in cytokinesis. Current biology : CB 205 10209096
1998 Missense mutations in the pancreatic islet beta cell inwardly rectifying K+ channel gene (KIR6.2/BIR): a meta-analysis suggests a role in the polygenic basis of Type II diabetes mellitus in Caucasians. Diabetologia 200 9867219
2004 Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features. Proceedings of the National Academy of Sciences of the United States of America 194 15583126
2009 Update of mutations in the genes encoding the pancreatic beta-cell K(ATP) channel subunits Kir6.2 (KCNJ11) and sulfonylurea receptor 1 (ABCC8) in diabetes mellitus and hyperinsulinism. Human mutation 191 18767144
2006 Mutations in KCNJ11, which encodes Kir6.2, are a common cause of diabetes diagnosed in the first 6 months of life, with the phenotype determined by genotype. Diabetologia 171 16609879
2001 Functional roles of cardiac and vascular ATP-sensitive potassium channels clarified by Kir6.2-knockout mice. Circulation research 158 11282890
1999 PKA-mediated phosphorylation of the human K(ATP) channel: separate roles of Kir6.2 and SUR1 subunit phosphorylation. The EMBO journal 148 10469651
2012 Whole-exome sequencing and high throughput genotyping identified KCNJ11 as the thirteenth MODY gene. PloS one 145 22701567
2005 Distinct BIR domains of cIAP1 mediate binding to and ubiquitination of tumor necrosis factor receptor-associated factor 2 and second mitochondrial activator of caspases. The Journal of biological chemistry 136 16282325
2020 Update of variants identified in the pancreatic β-cell KATP channel genes KCNJ11 and ABCC8 in individuals with congenital hyperinsulinism and diabetes. Human mutation 131 32027066
2000 Diverse roles of K(ATP) channels learned from Kir6.2 genetically engineered mice. Diabetes 128 10868950
2003 Knockout of Kir6.2 negates ischemic preconditioning-induced protection of myocardial energetics. American journal of physiology. Heart and circulatory physiology 113 12598229
2001 Two kinds of BIR-containing protein - inhibitors of apoptosis, or required for mitosis. Journal of cell science 98 11329368
2010 ABCC8 and KCNJ11 molecular spectrum of 109 patients with diazoxide-unresponsive congenital hyperinsulinism. Journal of medical genetics 92 20685672
2006 Mutations in the genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) in diabetes mellitus and hyperinsulinism. Human mutation 90 16416420
2005 A gating mutation at the internal mouth of the Kir6.2 pore is associated with DEND syndrome. EMBO reports 85 15864298
2003 CSC-1: a subunit of the Aurora B kinase complex that binds to the survivin-like protein BIR-1 and the incenp-like protein ICP-1. The Journal of cell biology 83 12707312
2015 KCNJ11: Genetic Polymorphisms and Risk of Diabetes Mellitus. Journal of diabetes research 82 26448950
1999 Involvement of the n-terminus of Kir6.2 in coupling to the sulphonylurea receptor. The Journal of physiology 82 10381582
1997 Sequence variants in the pancreatic islet beta-cell inwardly rectifying K+ channel Kir6.2 (Bir) gene: identification and lack of role in Caucasian patients with NIDDM. Diabetes 79 9032109
2019 Targeting the BIR Domains of Inhibitor of Apoptosis (IAP) Proteins in Cancer Treatment. Computational and structural biotechnology journal 73 30766663
2005 Mutations in the Kir6.2 subunit of the KATP channel and permanent neonatal diabetes: new insights and new treatment. Annals of medicine 73 16019717
2007 The G53D mutation in Kir6.2 (KCNJ11) is associated with neonatal diabetes and motor dysfunction in adulthood that is improved with sulfonylurea therapy. The Journal of clinical endocrinology and metabolism 69 18073297
1999 Physical association between recombinant cardiac ATP-sensitive K+ channel subunits Kir6.2 and SUR2A. Journal of molecular and cellular cardiology 69 10093054
2011 KCNJ11 gene E23K variant and therapeutic response to sulfonylureas. European journal of internal medicine 67 22385882
2004 Hyperinsulinism of infancy: novel ABCC8 and KCNJ11 mutations and evidence for additional locus heterogeneity. The Journal of clinical endocrinology and metabolism 66 15579781
2010 Permanent neonatal diabetes due to activating mutations in ABCC8 and KCNJ11. Reviews in endocrine & metabolic disorders 65 20922570
2007 Identification of the PIP2-binding site on Kir6.2 by molecular modelling and functional analysis. The EMBO journal 64 17673911
2005 Common variants in the ATP-sensitive K+ channel genes KCNJ11 (Kir6.2) and ABCC8 (SUR1) in relation to glucose intolerance: population-based studies and meta-analyses. Diabetic medicine : a journal of the British Diabetic Association 62 15842514
1997 A BIR motif containing gene of African swine fever virus, 4CL, is nonessential for growth in vitro and viral virulence. Virology 62 9143281
2007 Polymorphisms of KCNJ11 (Kir6.2 gene) are associated with Type 2 diabetes and hypertension in the Korean population. Diabetic medicine : a journal of the British Diabetic Association 56 17257281
2004 Current status of the E23K Kir6.2 polymorphism: implications for type-2 diabetes. Human genetics 56 15565284
2005 Kir6.2 mutations causing neonatal diabetes provide new insights into Kir6.2-SUR1 interactions. The EMBO journal 55 15962003
2002 Structural and functional determinants of conserved lipid interaction domains of inward rectifying Kir6.2 channels. The Journal of general physiology 54 12034765
2006 Functional analysis of six Kir6.2 (KCNJ11) mutations causing neonatal diabetes. Pflugers Archiv : European journal of physiology 52 17021801
2005 Focus on Kir6.2: a key component of the ATP-sensitive potassium channel. Journal of molecular and cellular cardiology 52 15910877
1999 Involvement of the N-terminus of Kir6.2 in the inhibition of the KATP channel by ATP. The Journal of physiology 52 9831713
2008 Association of KCNJ11 and ABCC8 genetic polymorphisms with response to repaglinide in Chinese diabetic patients. Acta pharmacologica Sinica 51 18664331
2021 Linagliptin, a DPP-4 inhibitor, ameliorates Aβ (1-42) peptides induced neurodegeneration and brain insulin resistance (BIR) via insulin receptor substrate-1 (IRS-1) in rat model of Alzheimer's disease. Neuropharmacology 50 34119519
2010 Ankyrin-B regulates Kir6.2 membrane expression and function in heart. The Journal of biological chemistry 49 20610380
2005 The BIR domain of IAP-like protein 2 is conformationally unstable: implications for caspase inhibition. The Biochemical journal 46 15485395
2018 The SERK3 elongated allele defines a role for BIR ectodomains in brassinosteroid signalling. Nature plants 45 29735985
2018 Sulfonylurea Receptor 1, Transient Receptor Potential Cation Channel Subfamily M Member 4, and KIR6.2:Role in Hemorrhagic Progression of Contusion. Journal of neurotrauma 43 30160201
2007 Origin of de novo KCNJ11 mutations and risk of neonatal diabetes for subsequent siblings. The Journal of clinical endocrinology and metabolism 41 17327377
2003 NN414, a SUR1/Kir6.2-selective potassium channel opener, reduces blood glucose and improves glucose tolerance in the VDF Zucker rat. Diabetes 41 14514634
2003 Molecular basis for Kir6.2 channel inhibition by adenine nucleotides. Biophysical journal 39 12524280
2006 A Kir6.2 mutation causing neonatal diabetes impairs electrical activity and insulin secretion from INS-1 beta-cells. Diabetes 36 17065345
1998 Cloning of the promoters for the beta-cell ATP-sensitive K-channel subunits Kir6.2 and SUR1. Diabetes 34 9703328
2020 Palmitoylation of the KATP channel Kir6.2 subunit promotes channel opening by regulating PIP2 sensitivity. Proceedings of the National Academy of Sciences of the United States of America 33 32332165
2011 Characterization of ABCC8 and KCNJ11 gene mutations and phenotypes in Korean patients with congenital hyperinsulinism. European journal of endocrinology 32 21422196
2017 XIAP BIR domain suppresses miR-200a expression and subsequently promotes EGFR protein translation and anchorage-independent growth of bladder cancer cell. Journal of hematology & oncology 31 28057023
2011 Threonine 48 in the BIR domain of survivin is critical to its mitotic and anti-apoptotic activities and can be phosphorylated by CK2 in vitro. Cell cycle (Georgetown, Tex.) 29 21252625
2000 Pharmacology of human sulphonylurea receptor SUR1 and inward rectifier K(+) channel Kir6.2 combination expressed in HEK-293 cells. British journal of pharmacology 29 10742287
2012 Engineered interaction between SUR1 and Kir6.2 that enhances ATP sensitivity in KATP channels. The Journal of general physiology 28 22802363
2024 Structure of an open KATP channel reveals tandem PIP2 binding sites mediating the Kir6.2 and SUR1 regulatory interface. Nature communications 27 38509107
2014 Quantitative assessment of the effect of KCNJ11 gene polymorphism on the risk of type 2 diabetes. PloS one 27 24710510
2013 βIV-Spectrin and CaMKII facilitate Kir6.2 regulation in pancreatic beta cells. Proceedings of the National Academy of Sciences of the United States of America 27 24101510
2005 Kir6.2-dependent high-affinity repaglinide binding to beta-cell K(ATP) channels. British journal of pharmacology 27 15678092
2004 Pore loop-mutated rat KIR6.1 and KIR6.2 suppress KATP current in rat cardiomyocytes. American journal of physiology. Heart and circulatory physiology 27 15044189
2018 Cognitive, Neurological, and Behavioral Features in Adults With KCNJ11 Neonatal Diabetes. Diabetes care 26 30377186
2016 Psychiatric morbidity in children with KCNJ11 neonatal diabetes. Diabetic medicine : a journal of the British Diabetic Association 26 27086753
2011 Regulation of the ATP-sensitive potassium channel subunit, Kir6.2, by a Ca2+-dependent protein kinase C. The Journal of biological chemistry 26 22207763
2007 Gene-gene interactions between HNF4A and KCNJ11 in predicting Type 2 diabetes in women. Diabetic medicine : a journal of the British Diabetic Association 25 17894829
2012 Role of melanoma inhibitor of apoptosis (ML-IAP) protein, a member of the baculoviral IAP repeat (BIR) domain family, in the regulation of C-RAF kinase and cell migration. The Journal of biological chemistry 24 22711539
2017 KCNJ11, ABCC8 and TCF7L2 polymorphisms and the response to sulfonylurea treatment in patients with type 2 diabetes: a bioinformatics assessment. BMC medical genetics 23 28587604
2015 Correlation between KCNQ1 and KCNJ11 gene polymorphisms and type 2 and post-transplant diabetes mellitus in the Asian Indian population. Genes & diseases 23 30258870
2012 Association of KCNJ11 E23K gene polymorphism with hypoglycemia in sulfonylurea-treated type 2 diabetic patients. Diabetes research and clinical practice 23 22591706
2016 ATP Sensitive Potassium Channels in the Skeletal Muscle Function: Involvement of the KCNJ11(Kir6.2) Gene in the Determination of Mechanical Warner Bratzer Shear Force. Frontiers in physiology 22 27242541
2019 Association of KCNJ11 rs5219 gene polymorphism with type 2 diabetes mellitus in a population of Syria: a case-control study. BMC medical genetics 21 31195986
2015 Association of KCNJ11 (E23K) gene polymorphism with susceptibility to type 2 diabetes in Iranian patients. Advanced biomedical research 21 25625107
2014 Kir6.2-containing ATP-sensitive K(+) channel is required for cardioprotection of resveratrol in mice. Cardiovascular diabetology 21 24498880
2006 Targeted expression of Kir6.2 in mitochondria confers protection against hypoxic stress. The Journal of physiology 21 16959852
2013 E23K variant in KCNJ11 gene is associated with susceptibility to type 2 diabetes in the Mauritanian population. Primary care diabetes 20 24332549
2011 Importance of the Kir6.2 N-terminus for the interaction of glibenclamide and repaglinide with the pancreatic K(ATP) channel. Naunyn-Schmiedeberg's archives of pharmacology 20 22083559
2007 Reduced expression of Kir6.2/SUR2A subunits explains KATP deficiency in K+-depleted rats. Neuromuscular disorders : NMD 20 17825556
2005 Proteasomal degradation of Kir6.2 channel protein and its inhibition by a Na+ channel blocker aprindine. Biochemical and biophysical research communications 20 15882977
2022 Risk of type 2 diabetes and KCNJ11 gene polymorphisms: a nested case-control study and meta-analysis. Scientific reports 19 36456687
2019 Structure-Activity Relationships, Pharmacokinetics, and Pharmacodynamics of the Kir6.2/SUR1-Specific Channel Opener VU0071063. The Journal of pharmacology and experimental therapeutics 19 31201216
2015 Replication of KCNJ11 (p.E23K) and ABCC8 (p.S1369A) Association in Russian Diabetes Mellitus 2 Type Cohort and Meta-Analysis. PloS one 19 25955821
2013 Kir6.2 limits Ca(2+) overload and mitochondrial oscillations of ventricular myocytes in response to metabolic stress. American journal of physiology. Heart and circulatory physiology 19 24014680
2000 Sulfonylurea receptor 1 and Kir6.2 expression in the novel human insulin-secreting cell line NES2Y. Diabetes 19 10866047
2008 ATP-sensitive K+ channels in pig urethral smooth muscle cells are heteromultimers of Kir6.1 and Kir6.2. American journal of physiology. Renal physiology 18 18945825
2006 Diabetes and hypoglycaemia in young children and mutations in the Kir6.2 subunit of the potassium channel: therapeutic consequences. Diabetes & metabolism 18 17296510
2020 Continuous spectrum of glucose dysmetabolism due to the KCNJ11 gene mutation-Case reports and review of the literature. Journal of diabetes 17 32935446
2018 Kir6.2 Deficiency Promotes Mesencephalic Neural Precursor Cell Differentiation via Regulating miR-133b/GDNF in a Parkinson's Disease Mouse Model. Molecular neurobiology 17 29564810
2009 An in-frame deletion in Kir6.2 (KCNJ11) causing neonatal diabetes reveals a site of interaction between Kir6.2 and SUR1. The Journal of clinical endocrinology and metabolism 17 19351728
1998 Suppression of KATP currents by gene transfer of a dominant negative Kir6.2 construct. Pflugers Archiv : European journal of physiology 16 9799413
2022 Association of KCNJ11 and ABCC8 single-nucleotide polymorphisms with type 2 diabetes mellitus in a Kinh Vietnamese population. Medicine 15 36401380
2018 ADIPOQ, KCNJ11 and TCF7L2 polymorphisms in type 2 diabetes in Kyrgyz population: A case-control study. Journal of cellular and molecular medicine 15 30467975
2008 The evolution of BIR domain and its containing proteins. FEBS letters 15 18948100
2006 Cerebral glucose transporters expression and spatial learning in the K-ATP Kir6.2(-/-) knockout mice. Behavioural brain research 15 16797737

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