Affinage

KCNJ11

ATP-sensitive inward rectifier potassium channel 11 · UniProt Q14654

Length
390 aa
Mass
43.5 kDa
Annotated
2026-04-28
100 papers in source corpus 33 papers cited in narrative 33 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KCNJ11 (Kir6.2) encodes the pore-forming subunit of ATP-sensitive potassium (K_ATP) channels, coupling cellular metabolic status to membrane excitability across pancreatic islet cells, cardiomyocytes, and neurons. Kir6.2 assembles as a tetramer with four sulfonylurea receptor subunits (SUR1 or SUR2A) to form an octameric channel complex; ATP directly inhibits the channel by binding a site composed of N-terminal (R50) and C-terminal (K185, R201) residues on Kir6.2, while MgADP activation and sulfonylurea-mediated closure are transduced through SUR, with the Kir6.2 N-terminus required for coupling drug binding to pore gating (PMID:9144288, PMID:12805206, PMID:12524280, PMID:22083559). Channel open probability is further tuned by PIP2 binding to a distributed site spanning both termini and the transmembrane domain, by palmitoylation at Cys166 that enhances PIP2 sensitivity, by PKA phosphorylation at Ser372, by CaMKII phosphorylation at Thr224 scaffolded by βIV-spectrin, and by intracellular pH sensed through His175 (PMID:17673911, PMID:32332165, PMID:10469651, PMID:24101510, PMID:12205184). Gain-of-function mutations that reduce ATP sensitivity cause permanent neonatal diabetes—with severity ranging from isolated diabetes (R201C/H) to diabetes with developmental delay, epilepsy, and neonatal diabetes (DEND syndrome; Q52R, V59G, I296L)—while loss-of-function mutations (e.g., F55L) cause congenital hyperinsulinism; in the heart, Kir6.2-containing channels mediate ischemic preconditioning and stress-induced cardioprotection (PMID:15583126, PMID:16332676, PMID:12598229).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1997 High

    Whether the ATP-inhibitory site resides on the pore subunit or the accessory SUR was unknown; truncation of the Kir6.2 C-terminus produced functional ATP-sensitive channels without SUR1, establishing that Kir6.2 itself harbors the primary ATP gate.

    Evidence Expression of Kir6.2ΔC26 in Xenopus oocytes; electrophysiology

    PMID:9144288

    Open questions at the time
    • Exact residues forming the ATP binding pocket not yet identified
    • SUR contribution to ATP sensitivity modulation not fully dissected
  2. 1997 High

    The identity of pore-lining residues and their influence on gating was unresolved; N160 was shown to line the pore and mediate inward rectification, and its mutation altered ATP sensitivity indirectly by changing open probability rather than ATP binding affinity.

    Evidence Site-directed mutagenesis of N160 in Kir6.2/SUR1; electrophysiology in COSm6 cells

    PMID:9236207

    Open questions at the time
    • Full pore structure unknown at this resolution
    • How open probability modulates apparent ATP sensitivity only conceptually understood
  3. 1999 High

    The contribution of Kir6.2 structural domains to ATP binding and gating was mapped: the N-terminus controls interburst gating and couples SUR1 drug binding to pore closure, while R50 in the N-terminus cooperates with C-terminal E179 for ATP inhibition.

    Evidence Systematic N-terminal deletions, R50 mutagenesis, and synergy analysis in Xenopus oocytes; single-channel kinetics

    PMID:10049691 PMID:10381582 PMID:9831713

    Open questions at the time
    • Direct contact between R50 and ATP not yet proven by accessibility methods
    • Mechanism coupling N-terminal conformational change to SUR1 drug binding unresolved
  4. 1999 Medium

    How the channel assembles with different SUR isoforms was unclear; the Kir6.2 proximal C-terminus and M2 domain were shown to mediate physical association with SUR2A, defining the cardiac channel assembly interface.

    Evidence Co-immunoprecipitation of in vitro-translated Kir6.2 and SUR2A; C-terminal deletion mutants

    PMID:10093054

    Open questions at the time
    • In vitro translation system may not recapitulate native assembly
    • No reciprocal mapping on SUR2A side
  5. 1999 High

    Whether Kir6.2 channel activity is regulated by second-messenger cascades was unknown; PKA was shown to phosphorylate Kir6.2 at Ser372 downstream of Gs-coupled receptors, increasing channel activity.

    Evidence Mutagenesis of PKA sites; phosphorylation assays in oocytes and intact cells; electrophysiology

    PMID:10469651

    Open questions at the time
    • Physiological context of PKA-mediated regulation in beta-cell insulin secretion not directly tested
    • Whether other kinases also target Kir6.2 unknown
  6. 2000 High

    The in vivo role of Kir6.2 in beta-cell physiology was unproven; Kir6.2 knockout and dominant-negative transgenic mice demonstrated that K_ATP channels set beta-cell resting potential and are required for glucose- and sulfonylurea-stimulated insulin secretion.

    Evidence Kir6.2 KO and dominant-negative transgenic mice; glucose tolerance, calcium imaging, insulin secretion

    PMID:10868950

    Open questions at the time
    • Compensatory changes in KO mice not fully characterized
    • Role in alpha- and delta-cell physiology not dissected
  7. 2001 High

    Whether Kir6.2 is the essential pore subunit of cardiac sarcolemmal K_ATP channels was uncertain; Kir6.2 KO mice lacked cardiac K_ATP currents and K+ channel opener responses, while vascular Kir6.1-based channels were unaffected, establishing tissue-specific subunit usage.

    Evidence Kir6.2 KO mice; electrophysiology, gene transfer rescue, contractility and vascular studies

    PMID:11282890

    Open questions at the time
    • Whether Kir6.2 also contributes to vascular or mitochondrial channels in vivo not resolved
  8. 2002 High

    PIP2 regulation of Kir6.2 was known but the structural basis was unclear; a conserved C-terminal alpha-helix (residues 306–315) was identified as a phospholipid-interaction domain, and allosteric coupling between pH sensing (His175) and ATP inhibition (Lys185) was demonstrated.

    Evidence GFP-fusion membrane association assay with mutagenesis; pH-titration electrophysiology with H175/K185 mutants

    PMID:12034765 PMID:12205184

    Open questions at the time
    • Full PIP2 binding site not yet mapped
    • Whether pH regulation is physiologically relevant in beta-cells not tested
  9. 2003 High

    The identities of residues directly contacting ATP were unknown; cysteine-scanning and mutagenesis established that R50 contacts the γ-phosphate, K185 the β-phosphate, and R201 the α-phosphate of ATP, defining the complete inhibitory binding site.

    Evidence Cysteine-scanning mutagenesis with charged thiol reagents; electrophysiology with ATP analogs; site-directed mutagenesis with AMP/ADP/ATP

    PMID:12524280 PMID:12805206

    Open questions at the time
    • No atomic-resolution structure of the ATP binding pocket
    • Conformational changes upon ATP binding not directly visualized
  10. 2003 High

    The role of cardiac K_ATP channels in ischemic preconditioning was debated; Kir6.2 KO mice failed to develop preconditioning-induced bioenergetic protection, establishing Kir6.2-containing channels as essential mediators.

    Evidence Kir6.2 KO mice; 18O-assisted 31P-NMR spectroscopy; ischemia-reperfusion with contractile measurements

    PMID:12598229

    Open questions at the time
    • Whether sarcolemmal or mitochondrial Kir6.2 channels mediate preconditioning not distinguished
  11. 2004 High

    The genetic basis of permanent neonatal diabetes was being elucidated; heterozygous gain-of-function KCNJ11 mutations were shown to cause neonatal diabetes by reducing ATP inhibition, with mutation severity correlating to clinical phenotype—mild mutations causing diabetes alone and severe mutations causing DEND syndrome.

    Evidence Heterologous expression of disease mutations in Xenopus oocytes; electrophysiology with simulated heterozygosity

    PMID:15583126

    Open questions at the time
    • Why some mutations cause transient vs permanent neonatal diabetes unknown
    • In vivo confirmation in mouse models not yet done
  12. 2005 High

    Multiple mechanistic advances converged: disease mutations were shown to act both by reducing direct ATP block on Kir6.2 and by enhancing MgATP activation via SUR1; tissue specificity was explained by differential SUR2A vs SUR1 responses; loss-of-function (hyperinsulinism) mutations were shown to reduce PIP2 sensitivity; the first 3D structure of the octameric complex was obtained at 18 Å; and the Kir6.2 N-terminus was required for high-affinity drug binding.

    Evidence Comparative electrophysiology of SUR1 vs SUR2A channels; F55L reconstitution with PIP2 rescue; single-particle EM at 18 Å with ATPase and Rb+ flux validation; radioligand binding with N-terminal deletions

    PMID:15678092 PMID:15864298 PMID:16087682 PMID:16308567 PMID:16332676 PMID:16339180

    Open questions at the time
    • High-resolution structure needed to resolve ATP and PIP2 binding sites
    • How MgATP activation through SUR1 NBDs is mechanistically coupled to Kir6.2 gating unknown
  13. 2007 High

    The full PIP2 binding site was mapped across both termini and the transmembrane domain, revealing a distributed interaction surface involving K39, R54, K67, R176, R177, and R301.

    Evidence Homology modeling with ligand docking validated by systematic mutagenesis and electrophysiology

    PMID:17673911

    Open questions at the time
    • No direct structural visualization of PIP2 bound to Kir6.2
    • Relative contribution of each residue to PIP2 affinity not quantified
  14. 2012 High

    How SUR1 communicates with the Kir6.2 pore was structurally unresolved; charge-swap and cysteine cross-linking between SUR1-E203 and Kir6.2-Q52 demonstrated a direct physical interface that dynamically regulates ATP-dependent gating.

    Evidence Charge-swap mutagenesis and oxidative cross-linking in Xenopus oocytes; electrophysiology

    PMID:22802363

    Open questions at the time
    • Whether additional SUR1–Kir6.2 contact points exist beyond E203–Q52 not known
    • Structural basis at atomic resolution not available
  15. 2013 High

    Whether scaffold proteins recruit kinases to Kir6.2 was unknown; βIV-spectrin was shown to associate with Kir6.2 and recruit CaMKII, which phosphorylates Thr224 to inhibit channel activity, providing a new regulatory mechanism in islets.

    Evidence Co-IP; in vitro kinase assay; T224 mutagenesis; electrophysiology; βIV-spectrin mutant mice

    PMID:24101510

    Open questions at the time
    • Whether CaMKII-mediated phosphorylation regulates Kir6.2 in neurons or heart not tested
    • Signaling cascades upstream of CaMKII at the channel not defined
  16. 2020 High

    Post-translational lipid modification of Kir6.2 was unexplored; palmitoylation at Cys166 was discovered to promote channel opening by enhancing PIP2 sensitivity, adding a lipid-based regulatory layer.

    Evidence Acyl-biotin exchange; patch-clamp in transfected cells, INS-1 cells, and cardiomyocytes; C166 mutagenesis; molecular modeling

    PMID:32332165

    Open questions at the time
    • Which palmitoyl transferase modifies Kir6.2 unknown
    • Whether palmitoylation is dynamically regulated by metabolic state not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions include: the high-resolution structural basis of ATP/PIP2 binding and gating transitions; how palmitoylation is enzymatically regulated; the precise mechanism by which SUR nucleotide-binding domain activation is transduced to Kir6.2 pore opening; and whether Kir6.2 functions in mitochondrial membranes in vivo.
  • No high-resolution cryo-EM structure with bound ATP and PIP2 simultaneously resolved in the timeline
  • Enzymatic palmitoylation/depalmitoylation machinery not identified
  • In vivo evidence for mitochondrial Kir6.2 remains indirect

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0008289 lipid binding 3
Localization
GO:0005886 plasma membrane 4 GO:0005783 endoplasmic reticulum 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-382551 Transport of small molecules 4 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-112316 Neuronal System 1
Partners
ABCC8ABCC9CAMK2ALDHASPTBN4
Complex memberships
K_ATP channel (Kir6.2/SUR1)K_ATP channel (Kir6.2/SUR2A)

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 Truncation of Kir6.2 (removing the last 26 C-terminal residues) allows it to form functional ATP-sensitive K+ channels in the absence of SUR1, demonstrating that the primary ATP inhibitory site resides on Kir6.2, while SUR1 is required for sensitivity to sulphonylureas, diazoxide, and activation by Mg-ADP. Heterologous expression of truncated Kir6.2 (Kir6.2ΔC26) in Xenopus oocytes; electrophysiology Nature High 9144288
1997 Asparagine 160 (N160) in Kir6.2 lines the pore and contributes to inward rectification by interacting with Mg2+ and spermine; mutation of N160 also alters ATP sensitivity indirectly by changing the open probability of the channel (the energy of the open state), rather than directly affecting ATP binding. Site-directed mutagenesis of N160 in Kir6.2/SUR1 channels expressed in COSm6 cells; electrophysiology The Journal of general physiology High 9236207
1999 PKA phosphorylates Kir6.2 at Ser372 in the C-terminus in intact cells following Gs-coupled receptor stimulation, and this phosphorylation increases K(ATP) channel activity; phosphorylation of SUR1 at Ser1571 by PKA modulates basal channel properties by decreasing burst duration and interburst interval and increasing surface channel number. Mutagenesis of PKA consensus sites in SUR1 and Kir6.2; phosphorylation assays in Xenopus oocyte homogenates and intact cells; electrophysiology The EMBO journal High 10469651
1999 The N-terminus of Kir6.2 is involved in coupling sulphonylurea binding to SUR1 to closure of the Kir6.2 pore; deletion of 14 N-terminal amino acids (ΔN14) raises open probability, reduces ATP sensitivity, and abolishes high-affinity tolbutamide block when co-expressed with SUR1, without altering intrinsic Kir6.2 properties when expressed alone. N-terminal deletion and site-directed mutagenesis of Kir6.2; macroscopic current recording in excised patches from Xenopus oocytes The Journal of physiology High 10381582
1999 Arginine 50 (R50) in the N-terminus of Kir6.2 is required for normal ATP inhibition; mutation R50S reduces ATP sensitivity ~7-fold; combining N-terminal (R50S) and C-terminal (E179Q) mutations synergistically increases ATP insensitivity, indicating both termini cooperate in ATP-inhibitory gating. Site-directed mutagenesis at R50 and other N-terminal residues of Kir6.2ΔC26; electrophysiology in Xenopus oocytes The Journal of physiology High 9831713
1999 N-terminal truncations of Kir6.2 nearly eliminate transitions to interburst closed states, producing extremely high open probability; this reduces apparent ATP sensitivity consistent with the N-terminus controlling interburst gating through a closed state that preferentially binds inhibitory ATP. N-terminal truncation constructs of Kir6.2/SUR1; patch-clamp electrophysiology in heterologous cells Biochemical and biophysical research communications High 10049691
1999 Kir6.2 physically associates with SUR2A to form the cardiac K(ATP) channel; the proximal C-terminus and M2 transmembrane domain of Kir6.2 are required for this subunit association, while the distal C-terminal 37 amino acids are dispensable. Co-immunoprecipitation of in vitro-translated Kir6.2 and SUR2A; C-terminal deletion mutants Journal of molecular and cellular cardiology Medium 10093054
1997 Kir6.2 protein is localized to the plasma membrane of pancreatic islet alpha-, beta-, and delta-cells as determined by immunofluorescence and in situ hybridization, and is absent from exocrine pancreas. In situ hybridization and immunofluorescence on mouse pancreatic sections; co-staining with insulin, glucagon, and somatostatin antibodies Diabetes Medium 9287044
2000 Kir6.2 knockout mice and dominant-negative Kir6.2 transgenic mice demonstrate that K(ATP) channels are the major determinant of beta-cell resting membrane potential; both glucose- and sulphonylurea-induced membrane depolarization, calcium rises, and insulin secretion require closure of K(ATP) channels; K(ATP) channels are also important for beta-cell survival and islet architecture. Kir6.2 knockout and dominant-negative transgenic mice; glucose tolerance tests, calcium imaging, insulin secretion assays Diabetes High 10868950
2001 Kir6.2 subunit mediates the depression of cardiac excitability and contractility induced by K+ channel openers (pinacidil, P-1075); ventricular cells from Kir6.2 knockout mice lack sarcolemmal K(ATP) channels and do not respond to K+ channel openers, while arterial smooth muscle K(ATP) channels (composed of Kir6.1) are unaffected. Kir6.2 knockout mice; electrophysiology, gene transfer rescue, contractility assays, vascular smooth muscle studies Circulation research High 11282890
2003 Cysteine-scanning mutagenesis identified R50 (N-terminus) and K185 (C-terminus) as residues that interact directly with ATP in the Kir6.2 binding site; K185 interacts primarily with the beta-phosphate and R50 with the gamma-phosphate of ATP. Cysteine-scanning mutagenesis of Kir6.2 combined with charged thiol-modifying reagents (MTSEA/MTSES); electrophysiology; molecular modeling The EMBO journal High 12805206
2002 Kir6.2 mRNA and protein are widely expressed in rat brain neurons (including mitral cells, pontine nucleus, motor nuclei) and in glial cells (astrocytes and oligodendrocytes); immunoelectron microscopy shows Kir6.2 protein localizes to endoplasmic reticulum, Golgi apparatus, and plasma membranes of neurons and glia. Immunohistochemistry, in situ hybridization, double staining with GFAP, immunoelectron microscopy Brain research. Molecular brain research Medium 12007828
2003 R201 and K185 in the C-terminus of Kir6.2 mediate inhibition by adenine nucleotides via electrostatic interactions with phosphate groups; R201 interacts with the alpha-phosphate to stabilize a closed configuration, and K185 interacts with the beta-phosphate to destabilize channel openings in a state-independent fashion. Site-directed mutagenesis at R201, K185, R192, R50; patch-clamp electrophysiology with ATP, ADP, AMP Biophysical journal High 12524280
2002 Allosteric modulation of Kir6.2 by intracellular H+ and ATP involves His175 (proton sensing) and Lys185 (ATP sensing); mutation of His175 eliminates pH effects on ATP sensitivity, and K185E eliminates the ATP-dependent modulation of pH sensitivity, demonstrating direct interaction between the two regulatory sites. Site-directed mutagenesis (H175, K185) in Kir6.2+/-SUR1; patch-clamp electrophysiology over pH range The Journal of physiology High 12205184
2003 Kir6.2-knockout mice lack ischemic preconditioning-induced protection of myocardial bioenergetics (ATP turnover, creatine kinase-catalyzed phosphotransfer, and contractile recovery), establishing that Kir6.2-containing K(ATP) channels are integral to preconditioning-induced cardiac energetic protection. Kir6.2 KO mice; 18O-assisted 31P-NMR spectroscopy; ischemia-reperfusion protocol; contractile measurements American journal of physiology. Heart and circulatory physiology High 12598229
2004 Heterozygous gain-of-function mutations in Kir6.2 (KCNJ11) cause permanent neonatal diabetes mellitus by reducing channel inhibition by ATP; mutations causing more severe reduction in ATP sensitivity (Q52R, V59G) cause additional neurological features (DEND syndrome), while milder mutations (R201C) cause diabetes alone, correlating disease severity with degree of K(ATP) current increase. Heterologous expression of wild-type and mutant Kir6.2/SUR1 in Xenopus oocytes; electrophysiology; simulated heterozygosity Proceedings of the National Academy of Sciences of the United States of America High 15583126
2005 KCNJ11 mutations causing neonatal diabetes (R201C, R201H, V59M, V59G) increase K(ATP) current in two ways: by decreasing ATP inhibition via Kir6.2 and by enhancing MgATP activation via SUR1 nucleotide-binding domains; the fraction of unblocked current at physiological MgATP correlates with clinical severity. Heterologous expression in Xenopus oocytes; electrophysiology with and without Mg2+; comparison of MgATP vs ATP effects Human molecular genetics High 16087682
2005 The I296L mutation at the internal mouth of the Kir6.2 pore (DEND syndrome) reduces ATP sensitivity indirectly by stabilizing the open state, implicating this region in Kir channel gating; the V59G mutation in the slide helix similarly acts by biasing toward open state rather than directly at the ATP binding site. Heterologous expression of mutant Kir6.2/SUR1 in Xenopus oocytes; single-channel and whole-cell electrophysiology; kinetic analysis EMBO reports High 15864298
2005 The F55L mutation in the Kir6.2 slide helix (congenital hyperinsulinism) reduces the intrinsic open probability of K(ATP) channels ~10-fold without affecting surface expression or nucleotide sensitivity; this low open probability can be reversed by PIP2 or oleoyl-CoA application, identifying reduced phospholipid/acyl-CoA responsiveness as the mechanism. Reconstitution of mutant channels in COS cells; patch-clamp electrophysiology; PIP2/oleoyl-CoA application The Journal of biological chemistry High 16332676
2005 Cardiac K(ATP) channels (Kir6.2/SUR2A) are less affected than pancreatic K(ATP) channels (Kir6.2/SUR1) by neonatal diabetes mutations (Q52R, R201H) because SUR2A-containing channels show much less Mg-nucleotide activation enhancement by the mutations; this explains why these gain-of-function mutations produce neurological and pancreatic but not cardiac phenotypes. Comparative electrophysiology of Kir6.2/SUR1 vs Kir6.2/SUR2A heterologously expressed in Xenopus oocytes with and without Mg2+ The Journal of physiology High 16339180
2005 3D structure of the purified Kir6.2-SUR1 K(ATP) channel complex at 18 Å resolution by single-particle electron microscopy reveals four SUR1 subunits embracing a central Kir6.2 tetramer in both transmembrane and cytosolic domains; ATP access cleft identified between adjacent SUR1 subunits; purified channel shows ATPase activity and supports Rb+ fluxes in liposomes. Heterologous expression and purification; single-particle electron microscopy; ATPase assay; liposome Rb+ flux assay The EMBO journal High 16308567
2007 The PIP2-binding site on Kir6.2 involves residues in the N-terminus (K39, N41, R54), transmembrane domain (K67), and C-terminus (R176, R177, E179, R301); PIP2 binding increases channel opening and decreases ATP binding/channel inhibition. Homology modeling, ligand docking, and site-directed mutagenesis of Kir6.2; electrophysiology The EMBO journal High 17673911
2002 A conserved alpha-helical region (residues ~306-315) in the Kir6.2 C-terminus, particularly E308, I309, W311, and F315, forms a critical phospholipid-interaction domain; GFP-tagged Kir6.2 C-terminus associates with isolated membranes in a PIP2-dependent manner that is reduced by m1 receptor-mediated phospholipid depletion. GFP-fusion membrane association assay; systematic mutagenesis of C-terminal helix; muscarinic receptor-mediated PIP2 depletion The Journal of general physiology High 12034765
2012 SUR1 residue E203 and Kir6.2 residue Q52 are in close proximity and interact to modulate ATP sensitivity; E203K/Q52E double mutant channels show ~100-fold higher ATP sensitivity; cross-linking of E203C/Q52C locks the channel in a closed state reversible by reducing agents, demonstrating this interaction dynamically regulates channel gating. Charge-swap mutagenesis; cysteine cross-linking with oxidizing/reducing agents; electrophysiology in Xenopus oocytes The Journal of general physiology High 22802363
2005 High-affinity repaglinide binding (~150-fold increase vs SUR1 alone) requires both Kir6.2 co-expression with SUR1 and an intact Kir6.2 N-terminus; deletion of Kir6.2 N-terminal 14 residues abolishes high-affinity repaglinide binding, indicating that Kir6.2 causes a conformational change in SUR1 or contributes directly to the repaglinide binding site. Radioligand binding ([3H]-glibenclamide) with co-expressed Kir6.2/SUR1 in membranes; N-terminal deletion mutants; whole-cell patch-clamp British journal of pharmacology High 15678092
2011 Progressive N-terminal truncation of Kir6.2 impairs transduction of sulphonylurea (glibenclamide, repaglinide) binding into channel closure and accelerates glibenclamide dissociation, establishing that the Kir6.2 N-terminus is required for coupling drug binding at SUR1 to pore closure. Progressive N-terminal truncation of Kir6.2 (up to 20 amino acids); equilibrium [3H]-glibenclamide binding; inside-out patch-clamp in HEK cells Naunyn-Schmiedeberg's archives of pharmacology High 22083559
2013 βIV-spectrin directly associates with Kir6.2 in pancreatic islets and recruits CaMKII; CaMKII directly phosphorylates Kir6.2 at Thr224, and this phosphorylation inhibits K(ATP) channel function; βIV-spectrin mutant mice lacking CaMKII-binding motifs show aberrant Kir6.2 phosphorylation and altered insulin regulation. Co-immunoprecipitation; in vitro phosphorylation assay; mutagenesis of T224; electrophysiology; βIV-spectrin mutant mice Proceedings of the National Academy of Sciences of the United States of America High 24101510
2020 Kir6.2 is palmitoylated at Cys166; palmitoylation promotes channel opening by increasing open time and enhancing PIP2 sensitivity without affecting surface expression; mutagenesis of C166 prevents palmitoylation effects; clinical KCNJ11 variants affecting C166 show gain-of-function consistent with enhanced PIP2 interaction. Acyl-biotin exchange assay; patch-clamp electrophysiology in transfected cells, INS-1 cells, and cardiac myocytes; C166 mutagenesis; molecular modeling; palmitoylation inhibition/palmitate preincubation Proceedings of the National Academy of Sciences of the United States of America High 32332165
2006 Targeted expression of Kir6.2 in mitochondria of HEK293 and HL-1 cells increases mitochondrial K+ influx, substantially improves cell viability after hypoxic stress, and attenuates mitochondrial Ca2+ accumulation; an inactive Kir6.2 mutant abolishes these protective effects. Mitochondrial-targeted Kir6.2 expression via pCMV/mito/GFP vector; PBFI-AM K+ fluorescence; LDH release assay; rhod-2 mitochondrial Ca2+ measurement; inactive mutant control The Journal of physiology Medium 16959852
2004 Kir6.2 gene expression in intestinal progenitor cells is regulated by transcription factors Foxa2 (via a -1364/-1210 element) and Sp1/Sp3 (via a -1035/-939 element) in the Kir6.2 promoter; Isl-1 attenuates Foxa2 overexpression to enable Kir6.2 expression; knockdown of Isl-1 in beta-cells reduces Kir6.2 protein. Luciferase reporter assay; EMSA; Pdx-1/Isl-1 overexpression; Isl-1 siRNA knockdown in RIN-5F cells The Journal of biological chemistry Medium 15528203
2016 Memantine blocks Kir6.2-containing K(ATP) channels (inhibits Kir6.2 expressed in neuro2A cells, elevating intracellular Ca2+); Kir6.2 knockout mice exhibit severe memory deficits and impaired hippocampal LTP that cannot be rescued by memantine, establishing Kir6.2 as a target for memantine-mediated memory enhancement. Kir6.2 overexpression in neuro2A cells with Ca2+ measurement; Kir6.2 KO mice; hippocampal LTP recording; CaMKII activity assay; pinacidil rescue experiment Molecular psychiatry Medium 27777420
1999 Gene delivery of Kir6.2/SUR2A into cells lacking native K(ATP) channels confers resistance to metabolic (hypoxia-reoxygenation) stress by preventing intracellular Ca2+ loading; this effect is blocked by 5-hydroxydecanoate and requires the K+ channel activator pinacidil, establishing a direct causal link between Kir6.2/SUR2A channel activation and Ca2+ homeostasis under stress. Gene transfer of Kir6.2/SUR2A into somatic cells; fluorescent Ca2+ measurement; pharmacological inhibition with 5-HD FASEB journal Medium 10224235
2017 NFκB signaling elevates KCNJ11 expression in hepatocellular carcinoma; KCNJ11 protein interacts with lactate dehydrogenase A (LDHA) and enhances its enzymatic activity, promoting tumor cell proliferation, reducing apoptosis, and increasing invasion; pharmacological inhibition of LDHA compromises these KCNJ11-dependent oncogenic functions. NFκB inhibition; KCNJ11 knockdown; co-immunoprecipitation of KCNJ11-LDHA complex; LDHA enzymatic activity assay; cell proliferation/apoptosis/invasion assays; pharmacological LDHA inhibition Biochemical and biophysical research communications Medium 29108994

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Truncation of Kir6.2 produces ATP-sensitive K+ channels in the absence of the sulphonylurea receptor. Nature 669 9144288
1998 A single BIR domain of XIAP sufficient for inhibiting caspases. The Journal of biological chemistry 507 9525868
1996 Mutation of the pancreatic islet inward rectifier Kir6.2 also leads to familial persistent hyperinsulinemic hypoglycemia of infancy. Human molecular genetics 343 8923010
1999 An exegesis of IAPs: salvation and surprises from BIR motifs. Trends in cell biology 290 10407412
2007 Association of CDKAL1, IGF2BP2, CDKN2A/B, HHEX, SLC30A8, and KCNJ11 with susceptibility to type 2 diabetes in a Japanese population. Diabetes 225 18162508
2000 NMR structure and mutagenesis of the third Bir domain of the inhibitor of apoptosis protein XIAP. The Journal of biological chemistry 212 10934209
1999 Caenorhabditis elegans inhibitor of apoptosis protein (IAP) homologue BIR-1 plays a conserved role in cytokinesis. Current biology : CB 204 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 193 15583126
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
2010 Impact of common variants of PPARG, KCNJ11, TCF7L2, SLC30A8, HHEX, CDKN2A, IGF2BP2, and CDKAL1 on the risk of type 2 diabetes in 5,164 Indians. Diabetes 141 20424228
2005 3-D structural and functional characterization of the purified KATP channel complex Kir6.2-SUR1. The EMBO journal 138 16308567
2005 Relapsing diabetes can result from moderately activating mutations in KCNJ11. Human molecular genetics 136 15718250
2000 Diverse roles of K(ATP) channels learned from Kir6.2 genetically engineered mice. Diabetes 128 10868950
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 126 32027066
2003 Requirement of both the second and third BIR domains for the relief of X-linked inhibitor of apoptosis protein (XIAP)-mediated caspase inhibition by Smac. The Journal of biological chemistry 126 14512414
1997 Control of rectification and gating of cloned KATP channels by the Kir6.2 subunit. The Journal of general physiology 119 9236207
2003 Knockout of Kir6.2 negates ischemic preconditioning-induced protection of myocardial energetics. American journal of physiology. Heart and circulatory physiology 113 12598229
2006 KCNJ11 activating mutations are associated with developmental delay, epilepsy and neonatal diabetes syndrome and other neurological features. European journal of human genetics : EJHG 111 16670688
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 91 20685672
2005 A gating mutation at the internal mouth of the Kir6.2 pore is associated with DEND syndrome. EMBO reports 85 15864298
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
2011 Hyperinsulinaemic hypoglycaemia and diabetes mellitus due to dominant ABCC8/KCNJ11 mutations. Diabetologia 73 21674179
2019 Targeting the BIR Domains of Inhibitor of Apoptosis (IAP) Proteins in Cancer Treatment. Computational and structural biotechnology journal 71 30766663
2003 Identification of residues contributing to the ATP binding site of Kir6.2. The EMBO journal 69 12805206
1999 Physical association between recombinant cardiac ATP-sensitive K+ channel subunits Kir6.2 and SUR2A. Journal of molecular and cellular cardiology 69 10093054
1999 The N-terminus of KIR6.2 limits spontaneous bursting and modulates the ATP-inhibition of KATP channels. Biochemical and biophysical research communications 68 10049691
1997 Localization of the ATP-sensitive K+ channel subunit Kir6.2 in mouse pancreas. Diabetes 68 9287044
2011 KCNJ11 gene E23K variant and therapeutic response to sulfonylureas. European journal of internal medicine 67 22385882
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