Affinage

KCNJ8

ATP-sensitive inward rectifier potassium channel 8 · UniProt Q15842

Length
424 aa
Mass
48.0 kDa
Annotated
2026-04-28
100 papers in source corpus 36 papers cited in narrative 36 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KCNJ8 encodes Kir6.1, an inwardly rectifying potassium channel subunit that partners with sulfonylurea receptor subunits (SUR2B in vascular and visceral smooth muscle, SUR1 in astrocytes and hippocampal presynaptic terminals) to form nucleotide diphosphate-dependent KATP channels that couple cellular metabolic state to membrane potential across diverse tissues (PMID:9130167, PMID:8865068, PMID:11749042, PMID:17883401). Unlike Kir6.2-based channels, the Kir6.1/SUR2B channel is not directly inhibited by intracellular ATP at the pore but instead derives metabolic sensitivity from the nucleotide-binding domains of SUR2B; channel activity is inhibited by PKC phosphorylation at a cluster of C-terminal serines and by glibenclamide, and is activated by K+ channel openers such as pinacidil (PMID:18522960, PMID:18048350, PMID:10531400). In vascular smooth muscle, Kir6.1 is essential for coronary vasodilation and systemic blood pressure regulation, while gain-of-function mutations (S422L, C176S, V65M) that reduce ATP sensitivity cause Cantú syndrome, J-wave syndromes, and impaired lymphatic/intestinal contractility (PMID:11984590, PMID:24700710, PMID:20558321, PMID:32372450, PMID:33170808). Beyond vascular tone, Kir6.1 promotes astrocytic mitophagy, physically interacts with NLRP3 to suppress inflammasome assembly, modulates brain VSMC differentiation through Ca²⁺ oscillations, regulates NK cell maturation, and contributes to pancreatic insulin secretion (PMID:31288070, PMID:31387986, PMID:35588738, PMID:39687626, PMID:27956473).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1996 High

    Establishing that Kir6.1 requires a sulfonylurea receptor partner for pharmacological and ATP-gating properties resolved the question of whether Kir6.1 alone could form a functional KATP channel.

    Evidence Patch-clamp of HEK293 cells expressing Kir6.1 alone versus Kir6.1+SUR1 showed SUR1 confers diazoxide and ATP sensitivity

    PMID:8865068

    Open questions at the time
    • Tissue-specific SUR partner preferences not yet defined
    • Single-channel properties of Kir6.1/SUR1 not characterized
  2. 1997 High

    Reconstitution of Kir6.1/SUR2B revealed a channel gated by nucleotide diphosphates rather than inhibited by ATP, distinguishing it fundamentally from the Kir6.2-based pancreatic KATP channel.

    Evidence Inside-out and cell-attached patch-clamp of HEK293T cells coexpressing Kir6.1 and SUR2B

    PMID:9130167

    Open questions at the time
    • Structural basis for NDP activation at SUR2B unknown
    • In vivo identity of the Kir6.1/SUR2B channel not yet confirmed
  3. 1999 High

    Demonstration that Kir6.1 enhances SUR2B glibenclamide affinity ~5-fold established that the pore subunit allosterically modulates the pharmacology of its regulatory partner.

    Evidence Radioligand binding assays comparing SUR2B alone versus SUR2B+Kir6.1 in HEK cells

    PMID:10531400

    Open questions at the time
    • Structural interface between Kir6.1 and SUR2B mediating allosteric coupling unresolved
  4. 2000 High

    Dominant-negative experiments in ventricular myocytes showed Kir6.1 and Kir6.2 do not heteromultimerize in the heart, clarifying tissue-specific subunit composition.

    Evidence Adenoviral dominant-negative Kir6.1 and Kir6.2 constructs tested in native rabbit ventricular myocytes by patch-clamp

    PMID:10837494

    Open questions at the time
    • Endothelial cells later shown to contain Kir6.1/Kir6.2 heteromultimers, so exclusivity is tissue-dependent
    • Mechanism preventing heteromultimerization in cardiomyocytes unknown
  5. 2002 High

    Kir6.1 knockout mice established that Kir6.1 is the essential pore subunit for vascular smooth muscle KATP channels controlling coronary tone, answering whether Kir6.1 or Kir6.2 predominates in the vasculature.

    Evidence Kcnj8 KO mice; patch-clamp of VSMCs; loss of pinacidil-induced vasodilation and coronary vasospasm phenotype

    PMID:11984590

    Open questions at the time
    • Contribution of Kir6.1 to non-coronary vascular beds not fully mapped
    • Mechanism of spontaneous coronary vasospasm in KO not defined
  6. 2002 High

    Discovery that PKC directly inhibits Kir6.1/SUR2B but activates Kir6.2/SUR2B channels identified a kinase-mediated regulatory switch distinguishing the two KATP channel subtypes.

    Evidence Inside-out patch-clamp with purified PKC catalytic fragment applied to Kir6.1/SUR2B versus Kir6.2/SUR2B patches

    PMID:12015420

    Open questions at the time
    • Specific PKC isoform and phosphorylation sites on Kir6.1 not yet mapped
  7. 2004 High

    Co-immunoprecipitation from human coronary endothelial cells demonstrated that native endothelial KATP channels are Kir6.1/Kir6.2/SUR2B heteromultimers, revealing cell-type-specific heteromeric assembly.

    Evidence Reciprocal Co-IP, confocal co-localization, and RT-PCR in primary HCAECs

    PMID:15380676

    Open questions at the time
    • Stoichiometry of Kir6.1 versus Kir6.2 in heteromultimeric endothelial channels unknown
  8. 2007 High

    Mapping PKC phosphorylation to five C-terminal serines (354, 379, 385, 391, 397) in Kir6.1 and showing AVP inhibits the channel via Gq/PKC identified the molecular basis for receptor-mediated vasoconstrictive regulation of vascular KATP channels.

    Evidence Kir6.1-Kir6.2 chimeras, Ser→Ala mutagenesis, ³²P phosphorylation assay, and V1a receptor co-expression electrophysiology

    PMID:17428891 PMID:18048350

    Open questions at the time
    • Whether all five serines are phosphorylated simultaneously or sequentially is unclear
    • Crystal or cryo-EM structure of PKC-phosphorylated Kir6.1 unavailable
  9. 2007 High

    Kir6.1/SUR1 channels at hippocampal presynaptic terminals restrain glutamate release, establishing a neuronal (not only glial) role for Kir6.1 in brain excitability.

    Evidence Kir6.1 and SUR1 KO mice; hippocampal slice patch-clamp; seizure susceptibility testing

    PMID:17883401

    Open questions at the time
    • Whether Kir6.1-containing channels regulate inhibitory synapses similarly is untested
  10. 2008 High

    Demonstrating that metabolic sensitivity of Kir6.1/SUR2B resides in SUR2B's nucleotide-binding domains rather than the Kir6.1 pore clarified a fundamental mechanistic difference from Kir6.2-based channels.

    Evidence NBD mutagenesis of SUR2B combined with ⁸⁶Rb efflux assays and patch-clamp

    PMID:18522960

    Open questions at the time
    • Structural basis for NBD-to-pore coupling in Kir6.1/SUR2B not resolved
  11. 2010 High

    Identification of KCNJ8-S422L as a gain-of-function mutation with reduced ATP sensitivity linked Kir6.1 to J-wave syndromes, establishing a human cardiac disease mechanism.

    Evidence Patch-clamp of S422L mutant co-expressed with SUR2A in COS-1 and TSA201 cells; quantified IC50 shift from 38 to 786 µM ATP

    PMID:20558321 PMID:22056721

    Open questions at the time
    • Whether S422L affects SUR2B-containing vascular channels in patients not assessed
    • Structural basis for S422L-mediated ATP insensitivity unknown
  12. 2013 High

    Smooth muscle-specific conditional gain- and loss-of-function transgenic mice directly demonstrated that Kir6.1 activity level in vascular smooth muscle bidirectionally controls systemic blood pressure.

    Evidence Tamoxifen-inducible SM-Cre Kir6.1[G343D] GoF and dominant-negative mice; telemetric blood pressure; vessel contractility

    PMID:23974906

    Open questions at the time
    • Contribution of endothelial Kir6.1 to blood pressure not isolated in this model
  13. 2014 High

    Functional characterization of C176S established that KCNJ8 gain-of-function mutations cause Cantú syndrome, extending the genetic basis of this disorder beyond ABCC9.

    Evidence Patch-clamp of Kir6.1[C176S] with SUR1 and SUR2A in heterologous cells; patient with ABCC9-negative Cantú syndrome

    PMID:24700710

    Open questions at the time
    • Number of Cantú patients attributable to KCNJ8 versus ABCC9 mutations not determined
  14. 2017 High

    The V65M Cantú mutation in the Kir6.1 slide helix increased open-state stability and reduced both ATP and glibenclamide sensitivity, defining the slide helix as a critical structural element for channel gating.

    Evidence ⁸⁶Rb efflux, intact-cell and excised-patch electrophysiology with V65M versus V65L substitutions

    PMID:28842488

    Open questions at the time
    • High-resolution structure of human Kir6.1 pore with slide helix mutations not available
  15. 2019 High

    Discovery that astrocytic Kir6.1 promotes mitophagy and physically interacts with NLRP3 to suppress inflammasome assembly revealed non-canonical, ion-flux-independent functions of Kir6.1 in neuroinflammation.

    Evidence Astrocyte-specific Kir6.1 KO mice; Co-IP of Kir6.1 and NLRP3; mitophagy and ROS assays; MPTP PD model

    PMID:31288070 PMID:31387986

    Open questions at the time
    • Whether NLRP3 interaction is direct or scaffolded not resolved
    • Domain on Kir6.1 mediating NLRP3 binding not mapped
    • Whether channel conductance is required for mitophagy promotion is unclear
  16. 2020 High

    Cantú syndrome knockin mice demonstrated that Kir6.1/SUR2B gain-of-function impairs lymphatic and intestinal smooth muscle contractility, both rescuable by glibenclamide, explaining extra-cardiac features of the disease.

    Evidence Kir6.1 GoF knockin mice; pressure myography of lymphatic vessels; intestinal motility assays; glibenclamide rescue

    PMID:32372450 PMID:33170808

    Open questions at the time
    • Long-term efficacy and safety of glibenclamide for Cantú syndrome in humans not established
  17. 2022 High

    Kir6.1/ABCC9-containing KATP channels regulate brain VSMC differentiation through modulation of intracellular Ca²⁺ oscillations, linking channel activity to developmental vascular patterning and neurovascular coupling.

    Evidence Kcnj8 KO mice and zebrafish loss/gain-of-function; Ca²⁺ imaging; live vascular imaging

    PMID:35588738

    Open questions at the time
    • Downstream transcription factors connecting Ca²⁺ oscillations to VSMC differentiation not identified
  18. 2024 Medium

    NK cell-specific Kir6.1 deletion impaired NK cell maturation, extending the functional repertoire of Kir6.1 to immune cell development.

    Evidence NK cell-specific Kcnj8 KO mice; flow cytometry; patch-clamp of NK cells confirming Kir6.1-dependent current

    PMID:39687626

    Open questions at the time
    • Mechanism by which Kir6.1 channel activity influences NK maturation signaling unknown
    • Single study; awaits independent replication

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution structure of the Kir6.1/SUR2B complex, the domain interface mediating the Kir6.1–NLRP3 interaction, and whether Kir6.1's non-canonical roles require ion conductance remain unresolved.
  • No cryo-EM or crystal structure of Kir6.1-containing channel complex published
  • Ion-flux dependence of mitophagy and inflammasome suppression functions not tested
  • Relative contribution of Kir6.1 versus Kir6.2 in pancreatic beta cells remains debated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 6 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 6 GO:0005739 mitochondrion 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-1643685 Disease 6 R-HSA-382551 Transport of small molecules 6 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 2 R-HSA-5357801 Programmed Cell Death 2
Partners
ABCC8ABCC9GJA1KCNJ11NLRP3
Complex memberships
Kir6.1/Kir6.2/SUR2B heteromultimeric KATP channelKir6.1/SUR1 KATP channelKir6.1/SUR2B KATP channel

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 Kir6.1 (KCNJ8) coexpressed with SUR2B forms a ~33 pS K+ channel that is activated by K+ channel openers (pinacidil, nicorandil) and nucleotide diphosphates (UDP, GDP), inhibited by glibenclamide, but not inhibited by intracellular ATP alone—defining it as an NDP-dependent rather than classical ATP-sensitive K+ channel. Patch-clamp electrophysiology (cell-attached and inside-out configurations) in HEK293T cells co-expressing SUR2B and Kir6.1 The Journal of physiology High 9130167
1996 SUR1 is required to confer diazoxide sensitivity and ATP sensitivity on Kir6.1; Kir6.1 alone expressed in HEK293 cells is unaffected by diazoxide or ATP dialysis, but Kir6.1+SUR1 co-expression restores both diazoxide activation and ATP inhibition. Whole-cell patch-clamp in HEK293 cells transiently transfected with Kir6.1 alone or Kir6.1+SUR1 The Journal of physiology High 8865068
2002 Genetic knockout of Kir6.1 (Kcnj8) in mice abolishes K+ channel opener (pinacidil)-induced currents in vascular smooth muscle cells and eliminates vasodilation responses to pinacidil, demonstrating that Kir6.1 is the pore-forming subunit of the vascular smooth muscle KATP channel required for normal coronary artery tone regulation. Kir6.1 knockout mouse model; patch-clamp of vascular smooth muscle cells; pharmacological challenge with pinacidil and methylergometrine Nature medicine High 11984590
1997 Kir6.1 protein localizes predominantly to mitochondria in rat skeletal muscle, cardiac muscle, liver, and pancreas, as demonstrated by immunoblot of mitochondrial fractions and electron-microscopic immunogold labeling of the inner mitochondrial membrane, suggesting a role as a subunit of mitochondrial KATP channels. Subcellular fractionation + immunoblot; immunofluorescence; immunoelectron microscopy with colloidal gold Biochemical and biophysical research communications Medium 9434770
2001 In the rat brain, Kir6.1 is the principal pore-forming subunit of plasma membrane KATP channels specifically in astrocytes (hippocampal, cortical, cerebellar), localized to perisynaptic and peridendritic astrocyte processes, with functional KATP channels confirmed in Bergmann glia by slice-patch-clamp. Immunohistochemistry with subunit-specific antibodies; ultrastructural immunolocalization; slice-patch-clamp electrophysiology Molecular and cellular neurosciences High 11749042
2004 Native KATP channels in primary human coronary artery endothelial cells (HCAEC) are heteromultimeric complexes of Kir6.1, Kir6.2, and SUR2B subunits, demonstrated by reciprocal co-immunoprecipitation and co-localization by confocal microscopy at the cell surface. Reciprocal co-immunoprecipitation; Western blotting; confocal microscopy; RT-PCR Journal of molecular and cellular cardiology High 15380676
2010 The KCNJ8-S422L missense mutation causes a marked gain-of-function in cardiac KATP current (Kir6.1/SUR2A), with significantly increased current over 0–40 mV range, identifying reduced ATP sensitivity as the mechanistic basis for J-wave syndrome susceptibility. Site-directed mutagenesis; whole-cell patch-clamp of COS-1 cells co-expressing Kir6.1-S422L and SUR2A Heart rhythm High 20558321
2011 The KCNJ8-S422L gain-of-function is mechanistically explained by reduced sensitivity to intracellular ATP inhibition (IC50 shifted from 38.4 μM for WT to 785.5 μM for mutant), leading to incomplete channel closure under normoxic conditions; whole-cell current is increased ~2-fold when co-expressed with SUR2A-WT. Whole-cell and inside-out patch-clamp in TSA201 cells; direct DNA sequencing of probands Heart rhythm High 22056721
2014 De novo Kir6.1[C176S] (KCNJ8) mutation causes Cantú syndrome through a gain-of-function mechanism: markedly higher channel activity due to reduced ATP sensitivity, whether co-expressed with SUR1 or SUR2A, establishing that Cantú syndrome results from gain of KATP channel function. Heterologous expression; patch-clamp electrophysiology; genetic sequencing of ABCC9-negative Cantú syndrome patient Human mutation High 24700710
2002 Protein kinase C (PKC) inhibits Kir6.1/SUR2B channel activity but enhances Kir6.2/SUR2B activity; purified PKC directly inhibits Kir6.1/SUR2B in inside-out patches with NDP, and this inhibition is blocked by a specific PKC inhibitor peptide, establishing PKC as a regulator that discriminates between the two Kir6.x channel types. Inside-out patch-clamp; application of purified PKC catalytic fragment; phorbol ester activation; specific PKC inhibitor peptide The Journal of physiology High 12015420
2007 PKC inhibition of the vascular Kir6.1/SUR2B channel is mediated by a motif of four phosphorylation repeats (Ser-354, Ser-379, Ser-385, Ser-391, Ser-397) in the distal C-terminus of Kir6.1; combined mutation of these five serines to alanine almost completely abolishes PKC-dependent channel inhibition and reduces in vitro 32P incorporation. Kir6.1-Kir6.2 chimeras; site-directed mutagenesis; whole-cell patch-clamp in HEK293 cells; in vitro 32P phosphorylation assay The Journal of biological chemistry High 18048350
2007 Arginine vasopressin (AVP) inhibits Kir6.1/SUR2B channel activity via Gq-coupled V1a receptor and PKC signaling; AVP suppresses channel open-state probability without altering single-channel conductance, and the effect is blocked by selective PKC inhibitors. Whole-cell patch-clamp in HEK293 cells co-expressing Kir6.1/SUR2B with V1a receptor; isolated mesenteric artery ring tension studies American journal of physiology. Regulatory, integrative and comparative physiology High 17428891
1999 Co-expression of Kir6.1 with SUR2B increases the affinity of SUR2B for glibenclamide ~5-fold (Kd from 32 nM to 6 nM), establishing that the pore-forming Kir6.1 subunit modulates pharmacological properties of the SUR2B regulatory subunit. Radioligand binding assays; whole-cell voltage-clamp in transfected HEK cells Molecular pharmacology High 10531400
2006 KCNJ8 (Kir6.1) knockout mice show fatal susceptibility to endotoxemia linked to loss of coronary vasodilation capacity; K+ channel opener drug improved survival in WT but not Kir6.1 KO, placing Kir6.1 as the essential vascular sensor coupling metabolic demand to coronary vasoreactivity during septic shock. Kcnj8 KO mouse model; LPS-induced endotoxemia challenge; pharmacological rescue with K+ channel opener FASEB journal High 17077304
2013 Smooth muscle-specific expression of ATP-insensitive Kir6.1[G343D] gain-of-function transgene reduces systolic and diastolic blood pressure and blunts mesenteric artery contractile responses; dominant-negative Kir6.1 in smooth muscle elevates blood pressure, directly demonstrating that Kir6.1 overactivity in vascular smooth muscle causes chronic hypotension. Conditional transgenic mouse model (tamoxifen-inducible smooth muscle Cre); blood pressure telemetry; isolated vessel contractility; patch-clamp of mesenteric myocytes Journal of the American Heart Association High 23974906
2008 The metabolic sensitivity of Kir6.1/SUR2B channels is intrinsic and independent of PKA regulation; unlike Kir6.2-containing channels where ATP sensitivity resides in the pore subunit, metabolic sensitivity of Kir6.1/SUR2B is a property of the SUR2B subunit's nucleotide-binding domains (both NBDs required). 86Rb efflux assay; patch-clamp in HEK293 and CHO cells; site-directed mutagenesis of SUR2B NBDs Cardiovascular research High 18522960
2011 Loss-of-function KCNJ8 mutations (E332del and V346I) reduce pinacidil-activated KATP current by 40–68% when co-expressed with SUR2A, identifying reduced channel function as a novel pathogenic mechanism in SIDS. Whole-cell patch-clamp in COS-1 cells; site-directed mutagenesis; DNA sequencing of SIDS cohort Circulation. Cardiovascular genetics High 21836131
2017 Cantú syndrome-associated Kir6.1-V65M mutation in the slide helix increases open state stability and markedly reduces ATP sensitivity and high-affinity glibenclamide sensitivity in both intact cells and excised patches; this effect is subunit-specific (methionine but not leucine substitution causes the effect) and is conserved at the equivalent position in Kir6.2. Ion flux assay (86Rb efflux); patch-clamp in intact and excised configurations; site-directed mutagenesis of V65M and V65L in Kir6.1, V64M and V64L in Kir6.2 The Journal of biological chemistry High 28842488
2000 Dominant-negative Kir6.1 suppresses SUR2B+Kir6.1 currents but has no effect on native KATP currents in adult rabbit ventricular myocytes, while dominant-negative Kir6.2 does suppress ventricular KATP current, demonstrating that Kir6.1 and Kir6.2 do not functionally heteromultimerize and that Kir6.2 is the sole KATP pore-forming subunit in ventricular cardiomyocyte surface membranes. Adenoviral gene transfer of dominant-negative constructs; whole-cell patch-clamp in A549 cells and native rabbit ventricular myocytes The Journal of biological chemistry High 10837494
2010 Heterologously expressed Kir6.1-GFP and endogenous Kir6.1 localize predominantly to the endoplasmic reticulum rather than mitochondria or plasma membrane; dominant-negative Kir6.1 constructs significantly reduce ATP-stimulated Ca2+ transient amplitude in C2C12 muscle cells, suggesting Kir6.1 modifies Ca2+ release from the ER. Live cell imaging of Kir6.1-GFP; subcellular fractionation; siRNA knockdown and dominant-negative expression; Ca2+ imaging with fluorescent indicators The Journal of membrane biology Medium 20306027
2007 Functional Kir6.1/SUR1 channels are located at excitatory pre-synaptic terminals in the hippocampus; genetic deletion of Kir6.1 or SUR1 increases vulnerability to seizures and enhances glutamate release at CA3 synapses as measured by whole-cell patch-clamp recordings. Immunolocalization; Kir6.1/SUR1 knockout mice; whole-cell patch-clamp recordings from hippocampal slices; seizure susceptibility assay Journal of neurochemistry High 17883401
2012 Kir6.1 physically associates with Cx43 in a phospho-specific manner: Cx43 phosphorylated at serine 262 preferentially interacts with Kir6.1, and introduction of S262A phospho-deficient mutation completely abolishes the interaction. Pull-down assay; co-immunoprecipitation; co-localization studies; phospho-deficient mutagenesis Experimental cell research Medium 22960107
2014 PKC epsilon mediates the interaction between Cx43 (phosphorylated at S262) and Kir6.1 in cardiomyocyte mitochondria; this interaction prevents mitochondria-mediated hypoxia-induced cell apoptosis. Co-immunoprecipitation in H9C2 cardiomyocytes; hypoxia treatment; PKCε-specific pathway manipulation; apoptosis assays Cellular signalling Medium 24815185
2009 LPS up-regulates Kir6.1 and SUR2B mRNA expression in vascular smooth muscle via NF-κB-dependent signaling, leading to augmented KATP channel activity and cell hyperpolarization; this effect is abolished by NF-κB inhibitors and does not occur in heterologous cells lacking the LPS signaling pathway. Quantitative PCR; patch-clamp of aortic smooth muscle cells; pharmacological NF-κB inhibition; isolated mesenteric artery ring assays The Journal of biological chemistry High 19959479
2018 Kir6.1 deficiency in microglia enhances p38 MAPK-NF-κB pathway activation and shifts microglia toward the M1 (pro-inflammatory) phenotype; suppression of p38 MAPK in vivo partially rescues the effects of Kir6.1 ablation on microglia polarization and dopaminergic neuron death. Kir6.1 knockdown/overexpression in microglia; Kir6.1 KO mouse PD model; p38 MAPK inhibitor in vivo; M1/M2 marker analysis Cell death & disease High 29540778
2019 Astrocytic Kir6.1/KATP channel promotes mitophagy; its deletion inhibits mitophagy leading to accumulation of damaged mitochondria, increased ROS production, and neuroinflammation in astrocytes; restoration of mitophagy rescues the deleterious effects of astrocytic Kir6.1 KO on mitochondrial dysfunction and dopaminergic neuron death. Astrocyte-specific Kir6.1 KO mice; MPTP PD model; autophagy/mitophagy assays in vivo and in vitro; mitochondrial ROS measurements Brain, behavior, and immunity High 31288070
2019 Kir6.1 physically associates with NLRP3 and inhibits NLRP3 inflammasome assembly; Kir6.1 depletion activates the NLRP3 inflammasome and worsens insulin resistance, while Kir6.1 overexpression has the opposite effect both in vivo and in vitro. Co-immunoprecipitation; Kir6.1 knockdown/overexpression in mice and primary cells; NLRP3 inflammasome assembly assays; insulin resistance measurements Experimental & molecular medicine Medium 31387986
2022 Astrocytic Kir6.1 deletion promotes astroglial NF-κB activation and extracellular release of complement C3, which interacts with neuronal C3aR to induce neuron death; NF-κB inhibition or C3aR antagonism rescues neuron death caused by astrocytic Kir6.1 KO. Astrocyte-specific Kir6.1 KO mice; LPS-induced PD model; NF-κB inhibitor and C3aR antagonist rescue experiments; C3 expression and secretion assays Brain, behavior, and immunity High 33838249
2022 Kir6.1 physically interacts with NLRP3 and prevents NLRP3 inflammasome assembly in astrocytes; astrocyte-specific Kir6.1 KO increases NLRP3-mediated pyroptosis in response to chronic stress, and NLRP3 inhibitor VX-765 rescues depressive-like behaviors in astrocytic Kir6.1 KO mice. Astrocyte-specific Kir6.1 KO mice; chronic stress depression models; Co-immunoprecipitation of Kir6.1 and NLRP3; pharmacological NLRP3 inhibition rescue Theranostics Medium 36185602
2022 KCNJ8/ABCC9-containing KATP channel cell-autonomously regulates brain vascular smooth muscle cell (VSMC) differentiation through modulation of intracellular Ca2+ oscillations via voltage-dependent calcium channels; Kcnj8 KO mice show deficient VSMC differentiation and impaired neurovascular coupling. Kcnj8 KO mice; zebrafish KCNJ8/ABCC9 loss/gain-of-function; cell culture; Ca2+ imaging; live in vivo vascular imaging Developmental cell High 35588738
2020 Kir6.1/SUR2B subunits underlie KATP channels in lymphatic smooth muscle; smooth muscle-specific Kir6.1 gain-of-function profoundly impairs lymphatic contractility and hyperpolarizes lymphatic smooth muscle, partially rescued by glibenclamide, explaining lymphoedema in Cantú syndrome. Kir6.1 KO and SUR2 KO mice; smooth muscle-specific Kir6.1 GoF mice; pressure myography; patch-clamp; electrophysiology of human LSM The Journal of physiology High 32372450
2020 Kir6.1/SUR2 subunits underlie intestinal smooth muscle KATP channels; Cantú syndrome knockin mice carrying KCNJ8 and ABCC9 mutations show severely reduced intestinal contractility and GI insufficiency rescued by glibenclamide. Cantú syndrome knockin mice; intestinal motility assays; glibenclamide pharmacological rescue JCI insight High 33170808
2016 Gain-of-function Kir6.1 mutations expressed in pancreatic β cells under RIP control cause glucose intolerance and diabetes via reduced insulin secretion; BAC-Kir6.1[G343D] mice also show impaired glucose-stimulated insulin secretion, implicating native Kir6.1 in pancreatic KATP channel function. Transgenic mice (RIP-Cre and BAC-Kir6.1 GoF); glucose tolerance tests; insulin secretion assays; quantitative RT-PCR for native Kir6.1 in islets The Journal of general physiology High 27956473
2020 miR-223 is induced by methylglyoxal (MGO) in vascular smooth muscle cells and post-transcriptionally downregulates Kir6.1 mRNA via a 3'UTR binding site; miR-223 overexpression reduces Kir6.1 protein, inhibits KATP channel activity, and enhances vasoconstriction, while miR-223 knockdown attenuates MGO-induced Kir6.1 suppression. miR-223 overexpression/knockdown; luciferase reporter + 3'UTR mutagenesis; Western blot; patch-clamp; mesenteric artery ring assays Vascular pharmacology High 32151743
2017 FoxO1 directly regulates Kir6.1 expression by binding to a functional FoxO1-binding site in the Kir6.1 promoter; FoxO1 activation downregulates Kir6.1 expression and decreases mitochondrial membrane potential, while FoxO1 inactivation upregulates Kir6.1. Chromatin immunoprecipitation (ChIP); Kir6.1 overexpression and cardiac-specific KO in DCM mice; Western blot for AKT/FoxO1 phosphorylation Journal of cellular and molecular medicine Medium 33547878
2024 NK-cell specific Kcnj8 ablation results in fewer mature (CD27-CD11b+, KLRG1+) NK cells in bone marrow and spleen; patch-clamp shows a Kir6.1 blocker PNU-37883A-sensitive current in a subset of NK cells, establishing a role for Kir6.1-containing KATP channels in NK cell maturation. NK cell-specific Kir6.1 KO mice; patch-clamp of NK cells; flow cytometry; transcriptomics Frontiers in immunology Medium 39687626

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Sulphonylurea receptor 2B and Kir6.1 form a sulphonylurea-sensitive but ATP-insensitive K+ channel. The Journal of physiology 328 9130167
2002 Mouse model of Prinzmetal angina by disruption of the inward rectifier Kir6.1. Nature medicine 284 11984590
2009 Ventricular fibrillation with prominent early repolarization associated with a rare variant of KCNJ8/KATP channel. Journal of cardiovascular electrophysiology 201 19120683
2010 Gain-of-function mutation S422L in the KCNJ8-encoded cardiac K(ATP) channel Kir6.1 as a pathogenic substrate for J-wave syndromes. Heart rhythm 193 20558321
1997 Kir6.1: a possible subunit of ATP-sensitive K+ channels in mitochondria. Biochemical and biophysical research communications 135 9434770
2011 Molecular genetic and functional association of Brugada and early repolarization syndromes with S422L missense mutation in KCNJ8. Heart rhythm 121 22056721
2001 Kir6.1 is the principal pore-forming subunit of astrocyte but not neuronal plasma membrane K-ATP channels. Molecular and cellular neurosciences 105 11749042
2005 Pore-forming subunits of K-ATP channels, Kir6.1 and Kir6.2, display prominent differences in regional and cellular distribution in the rat brain. The Journal of comparative neurology 103 15739238
2012 A KCNJ8 mutation associated with early repolarization and atrial fibrillation. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology 94 22562657
2014 Cantú syndrome resulting from activating mutation in the KCNJ8 gene. Human mutation 92 24700710
2013 Mutation of KCNJ8 in a patient with Cantú syndrome with unique vascular abnormalities - support for the role of K(ATP) channels in this condition. European journal of medical genetics 83 24176758
1999 Glucose-receptive neurones in the rat ventromedial hypothalamus express KATP channels composed of Kir6.1 and SUR1 subunits. The Journal of physiology 82 10050011
2004 K ATP channels of primary human coronary artery endothelial cells consist of a heteromultimeric complex of Kir6.1, Kir6.2, and SUR2B subunits. Journal of molecular and cellular cardiology 78 15380676
2006 Gene knockout of the KCNJ8-encoded Kir6.1 K(ATP) channel imparts fatal susceptibility to endotoxemia. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 69 17077304
2018 Kir6.1/K-ATP channel modulates microglia phenotypes: implication in Parkinson's disease. Cell death & disease 68 29540778
1996 The sulphonylurea receptor confers diazoxide sensitivity on the inwardly rectifying K+ channel Kir6.1 expressed in human embryonic kidney cells. The Journal of physiology 68 8865068
2019 Kir6.1/K-ATP channel on astrocytes protects against dopaminergic neurodegeneration in the MPTP mouse model of Parkinson's disease via promoting mitophagy. Brain, behavior, and immunity 64 31288070
2013 Hypotension due to Kir6.1 gain-of-function in vascular smooth muscle. Journal of the American Heart Association 60 23974906
1995 cDNA sequence, gene structure, and chromosomal localization of the human ATP-sensitive potassium channel, uKATP-1, gene (KCNJ8). Genomics 60 8595887
2014 Protein kinase C (PKC) mediated interaction between conexin43 (Cx43) and K(+)(ATP) channel subunit (Kir6.1) in cardiomyocyte mitochondria: Implications in cytoprotection against hypoxia induced cell apoptosis. Cellular signalling 56 24815185
2007 Is Kir6.1 a subunit of mitoK(ATP)? Biochemical and biophysical research communications 56 18068667
2020 Kir6.1-dependent KATP channels in lymphatic smooth muscle and vessel dysfunction in mice with Kir6.1 gain-of-function. The Journal of physiology 51 32372450
2003 Differential expression of Kir6.1 and SUR2B mRNAs in the vasculature of various tissues in rats. The Journal of membrane biology 51 14724757
2002 Protein kinase C modulation of recombinant ATP-sensitive K(+) channels composed of Kir6.1 and/or Kir6.2 expressed with SUR2B. The Journal of physiology 48 12015420
2011 Loss-of-function mutations in the KCNJ8-encoded Kir6.1 K(ATP) channel and sudden infant death syndrome. Circulation. Cardiovascular genetics 47 21836131
1999 Coexpression with the inward rectifier K(+) channel Kir6.1 increases the affinity of the vascular sulfonylurea receptor SUR2B for glibenclamide. Molecular pharmacology 44 10531400
2000 Evidence against functional heteromultimerization of the KATP channel subunits Kir6.1 and Kir6.2. The Journal of biological chemistry 43 10837494
2000 The properties of the Kir6.1-6.2 tandem channel co-expressed with SUR2A. Pflugers Archiv : European journal of physiology 41 11007308
2009 Lipopolysaccharides up-regulate Kir6.1/SUR2B channel expression and enhance vascular KATP channel activity via NF-kappaB-dependent signaling. The Journal of biological chemistry 40 19959479
2007 Expression of functional Kir6.1 channels regulates glutamate release at CA3 synapses in generation of epileptic form of seizures. Journal of neurochemistry 38 17883401
2022 KCNJ8/ABCC9-containing K-ATP channel modulates brain vascular smooth muscle development and neurovascular coupling. Developmental cell 36 35588738
2016 Propofol Suppressed Hypoxia/Reoxygenation-Induced Apoptosis in HBVSMC by Regulation of the Expression of Bcl-2, Bax, Caspase3, Kir6.1, and p-JNK. Oxidative medicine and cellular longevity 34 27057270
2021 Astrocytic Kir6.1 deletion aggravates neurodegeneration in the lipopolysaccharide-induced mouse model of Parkinson's disease via astrocyte-neuron cross talk through complement C3-C3R signaling. Brain, behavior, and immunity 33 33838249
1998 Cystic fibrosis transmembrane conductance regulator mediates sulphonylurea block of the inwardly rectifying K+ channel Kir6.1. The Journal of physiology 33 9490811
2013 The antiepileptic effect of the glycolytic inhibitor 2-deoxy-D-glucose is mediated by upregulation of K(ATP) channel subunits Kir6.1 and Kir6.2. Neurochemical research 31 23475455
2013 Kir6.1 knockdown aggravates cerebral ischemia/reperfusion-induced neural injury in mice. CNS neuroscience & therapeutics 30 23663330
2002 ATP-sensitive K(+) channels composed of Kir6.1 and SUR2B subunits in guinea pig gastric myocytes. American journal of physiology. Gastrointestinal and liver physiology 30 11751167
2022 Kir6.1/K-ATP channel in astrocytes is an essential negative modulator of astrocytic pyroptosis in mouse model of depression. Theranostics 29 36185602
2017 Conserved functional consequences of disease-associated mutations in the slide helix of Kir6.1 and Kir6.2 subunits of the ATP-sensitive potassium channel. The Journal of biological chemistry 29 28842488
2007 A short motif in Kir6.1 consisting of four phosphorylation repeats underlies the vascular KATP channel inhibition by protein kinase C. The Journal of biological chemistry 28 18048350
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
2007 Arginine vasopressin inhibits Kir6.1/SUR2B channel and constricts the mesenteric artery via V1a receptor and protein kinase C. American journal of physiology. Regulatory, integrative and comparative physiology 26 17428891
2020 Kir6.1- and SUR2-dependent KATP overactivity disrupts intestinal motility in murine models of Cantú syndrome. JCI insight 25 33170808
2018 Astrocyte-specific deletion of Kir6.1/K-ATP channel aggravates cerebral ischemia/reperfusion injury through endoplasmic reticulum stress in mice. Experimental neurology 25 30315808
2004 Selective expression of Kir6.1 protein in different vascular and non-vascular tissues. Biochemical pharmacology 25 14667937
2002 Cloning of rabbit Kir6.1, SUR2A, and SUR2B: possible candidates for a renal K(ATP) channel. American journal of physiology. Renal physiology 25 11788443
1999 Block of human aorta Kir6.1 by the vascular KATP channel inhibitor U37883A. British journal of pharmacology 25 10516647
1997 Channel activators regulate ATP-sensitive potassium channel (KIR6.1) expression in chick cardiomyocytes. FEBS letters 23 9257703
2008 Differences in the mechanism of metabolic regulation of ATP-sensitive K+ channels containing Kir6.1 and Kir6.2 subunits. Cardiovascular research 21 18522960
2012 Adenosine-triphosphate-sensitive K+ channel (Kir6.1): a novel phosphospecific interaction partner of connexin 43 (Cx43). Experimental cell research 20 22960107
2003 The Kir6.1-protein, a pore-forming subunit of ATP-sensitive potassium channels, is prominently expressed by giant cholinergic interneurons in the striatum of the rat brain. Brain research 20 12965237
2002 SURI and Kir6.1 subunits of K(ATP)-channels are co-localized in retinal glial (Müller) cells. Neuroreport 20 11924895
1998 Genomic organization and expression of KCNJ8/Kir6.1, a gene encoding a subunit of an ATP-sensitive potassium channel. Gene 20 9573340
2010 The intracellular localization and function of the ATP-sensitive K+ channel subunit Kir6.1. The Journal of membrane biology 19 20306027
2008 Decreased expression of aortic KIR6.1 and SUR2B in hypertension does not correlate with changes in the functional role of K(ATP) channels. European journal of pharmacology 19 18471810
2019 The pore-forming subunit Kir6.1 of the K-ATP channel negatively regulates the NLRP3 inflammasome to control insulin resistance by interacting with NLRP3. Experimental & molecular medicine 18 31387986
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
2007 Expression of ATP sensitive K+ channel subunit Kir6.1 in rat kidney. European journal of histochemistry : EJH 18 17548268
2010 Activation of SUR2B/Kir6.1 subtype of adenosine triphosphate-sensitive potassium channel improves pressure overload-induced cardiac remodeling via protecting endothelial function. Journal of cardiovascular pharmacology 17 20505525
2014 Total flavonoids from Ganshanbian (Herba Hyperici Attenuati) effect the expression of CaL-alpha1C and K(ATP)-Kir6.1 mRNA of the myocardial cell membrane in myocardial ischemia-reperfusion arrhythmia rats. Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan 16 24992765
2013 The KCNJ8-S422L variant previously associated with J-wave syndromes is found at an increased frequency in Ashkenazi Jews. European journal of human genetics : EJHG 14 23632791
2021 Zoledronic Acid as a Novel Dual Blocker of KIR6.1/2-SUR2 Subunits of ATP-Sensitive K+ Channels: Role in the Adverse Drug Reactions. Pharmaceutics 13 34575427
2009 Analysis of two KCNJ11 neonatal diabetes mutations, V59G and V59A, and the analogous KCNJ8 I60G substitution: differences between the channel subtypes formed with SUR1. The Journal of biological chemistry 13 19139106
2003 Iptkalim inhibits cocaine challenge-induced enhancement of dopamine levels in nucleus accumbens and striatum of rats by up-regulating Kir6.1 and Kir6.2 mRNA expression. Acta pharmacologica Sinica 13 12791178
2021 KATP Opener Attenuates Diabetic-Induced Müller Gliosis and Inflammation by Modulating Kir6.1 in Microglia. Investigative ophthalmology & visual science 12 33523201
2018 SUR2B/Kir6.1 channel openers correct endothelial dysfunction in chronic heart failure via the miR-1-3p/ET-1 pathway. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 12 30530045
2020 Memantine Improves Depressive-like Behaviors via Kir6.1 Channel Inhibition in Olfactory Bulbectomized Mice. Neuroscience 11 32531473
2018 From in silico to in vitro: a trip to reveal flavonoid binding on the Rattus norvegicus Kir6.1 ATP-sensitive inward rectifier potassium channel. PeerJ 11 29736333
2005 Mediation of the effect of nicotine on Kir6.1 channels by superoxide anion production. Journal of cardiovascular pharmacology 11 15821440
2016 Diabetes induced by gain-of-function mutations in the Kir6.1 subunit of the KATP channel. The Journal of general physiology 10 27956473
2003 Absence of Kir6.1/KCNJ8 mutations in Italian patients with abnormal coronary vasomotion. International journal of molecular medicine 9 12964027
2009 Genes controlling postural changes in blood pressure: comprehensive association analysis of ATP-sensitive potassium channel genes KCNJ8 and ABCC9. Physiological genomics 8 19952277
2021 Kir6.1 improves cardiac dysfunction in diabetic cardiomyopathy via the AKT-FoxO1 signalling pathway. Journal of cellular and molecular medicine 7 33547878
2012 Association of muscarinic M₃ receptors and Kir6.1 with caveolae in human detrusor muscle. European journal of pharmacology 7 22410194
2023 Involvement of SUR2/Kir6.1 channel in the physiopathology of pulmonary arterial hypertension. Frontiers in cardiovascular medicine 6 36704469
2022 Cantù syndrome: Report of a patient with a novel variant in KCNJ8 and revision of literature. American journal of medical genetics. Part A 6 35243770
2017 Electrophysiological analyses of transgenic mice overexpressing KCNJ8 with S422L mutation in cardiomyocytes. Journal of pharmacological sciences 6 28928055
2016 Pharmacological evidence: a new therapeutic approach to the treatment of chronic heart failure through SUR2B/Kir6.1 channel in endothelial cells. Acta pharmacologica Sinica 6 27890915
2015 Diazoxide Cardioprotection Is Independent of Adenosine Triphosphate-Sensitive Potassium Channel Kir6.1 Subunit in Response to Stress. Journal of the American College of Surgeons 6 25872691
2006 Mutational analysis of Kir6.1 in Japanese patients with coronary spastic angina. International journal of molecular medicine 6 16964409
2017 MiR-20 regulates myocardiac ischemia by targeting KATP subunit Kir6.1. Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban 5 28786072
2013 Oleic acid inhibits the K(ATP) channel subunit Kir6.1 and the K(ATP) current in human umbilical artery smooth muscle cells. The American journal of the medical sciences 5 23114200
2023 Zoledronic Acid Blocks Overactive Kir6.1/SUR2-Dependent KATP Channels in Skeletal Muscle and Osteoblasts in a Murine Model of Cantú Syndrome. Cells 4 36980269
2016 Increased tolerance to stress in cardiac expressed gain-of-function of adenosine triphosphate-sensitive potassium channel subunit Kir6.1. The Journal of surgical research 4 27884343
2010 [Effects of Guanxinkang on expressions of ATP-sensitive potassium channel subunits Kir6.1, Kir6.2, SUR2A and SUR2B in ischemic myocytes of rats]. Zhong xi yi jie he xue bao = Journal of Chinese integrative medicine 4 20456845
2019 Kir6.1 Heterozygous Mice Exhibit Aberrant Amygdala-Dependent Cued Fear Memory. Molecular neurobiology 3 31808063
2011 Mutational analysis of the Kir6.1 gene in Chinese hypertensive patients treated with the novel ATP-sensitive potassium channel opener iptakalim. Experimental and therapeutic medicine 3 22977571
2020 Methylglyoxal-induced miR-223 suppresses rat vascular KATP channel activity by downregulating Kir6.1 mRNA in carbonyl stress. Vascular pharmacology 2 32151743
2018 Ectopic overexpression of Kir6.1 in the mouse heart impacts on the life expectancy. Scientific reports 2 30082733
2016 ATP-sensitive K(+) channels (Kir6.1/SUR1) regulate gap junctional coupling in cochlear-supporting cells. Pflugers Archiv : European journal of physiology 2 27030354
2025 Automated patch clamp analysis of heterologously expressed Kir6.2/SUR1 and Kir6.1/SUR2B KATP currents. American journal of physiology. Cell physiology 1 40465479
2024 Kir6.1, a component of an ATP-sensitive potassium channel, regulates natural killer cell development. bioRxiv : the preprint server for biology 1 39211194
2018 ATP sensitive K+ channel subunits (Kir6.1, Kir6.2) are the candidate mediators regulating ameliorating effects of pulsed magnetic field on aortic contractility in diabetic rats. Bioelectromagnetics 1 29446477
2017 Effects of corticotropin-releasing hormone on the expression of adenosine triphosphate-sensitive potassium channels (Kir6.1/SUR2B) in human term pregnant myometrium. Obstetrics & gynecology science 1 29372145
2012 [Protective effects of SUR2B/Kir6.1 potassium channel opener natakalim against RAVECs injuries induced by hypoxia]. Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology 1 22860425
2026 Biophysical Characterization of a Novel KCNJ8 Rare Variant Linked With Inherited and Acquired J Wave Syndrome. JACC. Clinical electrophysiology 0 41995661
2024 Kir6.1, a component of an ATP-sensitive potassium channel, regulates natural killer cell development. Frontiers in immunology 0 39687626
2022 [Interventional effects of activating SUR2B/Kir6.1-type KATP channels on renal cells injury and its mechanisms]. Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology 0 37308403
2020 BPI and KIR6.1 as significant hub genes for vein graft restenosis. The Journal of international medical research 0 33259239
2012 Activation of SUR2B/Kir6.1-type K(ATP) channels protects glomerular endothelial, mesangial and tubular epithelial cells against oleic acid renal damage. Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology 0 23581188