Affinage

ABCC9

ATP-binding cassette sub-family C member 9 · UniProt O60706

Length
1549 aa
Mass
174.2 kDa
Annotated
2026-04-28
71 papers in source corpus 29 papers cited in narrative 29 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ABCC9 encodes the sulfonylurea receptor 2 (SUR2), the regulatory subunit of ATP-sensitive potassium (KATP) channels that couples cellular metabolic status to membrane excitability in cardiac, skeletal, and vascular smooth muscle (PMID:8826984). SUR2 assembles with Kir6.x pore-forming subunits into heterooctameric channels whose gating is controlled by asymmetric NBD1/NBD2 nucleotide-binding domains: Mg-ATP inhibits and Mg-ADP activates channel opening through a unique regulatory helix (R-helix) release mechanism, while the alternatively spliced C-terminal 42 residues allosterically tune NBD2 nucleotide sensing and drug selectivity (PMID:18311911, PMID:9692785, PMID:38227376). K-channel opener drugs bind a transmembrane pocket between TMD1 and TMD2 to stabilize the NBD-dimerized occluded activating state, and SUR2 also directs KATP channel trafficking between endosomal and sarcolemmal compartments and participates in neonatal cardiac metabolic maturation from glycolysis to fatty acid oxidation (PMID:35562524, PMID:20971764, PMID:24648545). Loss-of-function mutations cause AIMS (intellectual disability, myopathy, cardiac dysfunction), gain-of-function mutations cause Cantú syndrome and cardiac arrhythmias including Brugada and early repolarization syndromes, and vascular SUR2 loss produces coronary vasospasm and hypertension (PMID:31575858, PMID:22610116, PMID:24439875, PMID:12122112).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1996 High

    Identification of ABCC9 as encoding two alternatively spliced sulfonylurea receptor isoforms (SUR2A and SUR2B) that partner with Kir6.2 to form tissue-specific KATP channels established the molecular identity of cardiac, skeletal, and vascular smooth muscle KATP regulatory subunits.

    Evidence cDNA cloning, Northern blotting, RT-PCR, in situ hybridization, and FISH chromosomal localization

    PMID:8826984

    Open questions at the time
    • Stoichiometry of SUR2/Kir6.x assembly not yet defined
    • Structural basis of SUR2-Kir6.x coupling unknown
  2. 1998 High

    Demonstrating that the 42 C-terminal residues distinguishing SUR2A from SUR2B determine subtype-selective pharmacological activation (>100-fold difference in nicorandil EC50) established the molecular basis for isoform-specific drug selectivity.

    Evidence Heterologous expression in HEK293T cells with patch-clamp electrophysiology across SUR2 subtypes

    PMID:9692785

    Open questions at the time
    • How C-terminal residues structurally couple to the drug-binding site was unknown
    • Whether this selectivity extends to all K-channel openers was untested
  3. 2002 High

    Knockout mouse studies revealed that SUR2-containing KATP channels are essential regulators of vascular tone, insulin-stimulated glucose uptake, and survival: Sur2-null mice exhibit coronary vasospasm, hypertension, sudden death, and enhanced muscle glucose uptake, defining the in vivo physiological roles of these channels.

    Evidence Sur2 knockout mice with hemodynamic monitoring, coronary angiography, nifedipine rescue, hyperinsulinemic clamp, and isolated muscle glucose transport assays

    PMID:11562480 PMID:12122112

    Open questions at the time
    • Relative contributions of SUR2A vs SUR2B to each phenotype not dissected
    • Compensatory mechanisms in global knockout not excluded
  4. 2002 Medium

    Chimeric SUR2A/SUR2B analysis showed that the C-terminal 42 residues interact intramolecularly with Arg1344 at the Walker-A loop of NBD2, providing the first structural model for how isoform-specific C-termini differentially regulate ADP-induced channel activation.

    Evidence Chimeric SUR2A/SUR2B constructs with Kir6.2, patch-clamp electrophysiology, homology modeling

    PMID:11909819

    Open questions at the time
    • Based on homology modeling rather than direct structural data
    • Interaction not confirmed by direct binding assays with isolated domains
  5. 2004 High

    Discovery that ABCC9 mutations in dilated cardiomyopathy patients alter the intrinsic ATPase cycle of SUR2A established the first link between aberrant SUR2 catalytic activity and human cardiac disease, demonstrating that SUR2 functions as a metabolic signal decoder.

    Evidence Genomic DNA scanning of cardiomyopathy patients, functional expression of mutant SUR2A, inside-out patch-clamp, ATPase activity assays

    PMID:15034580

    Open questions at the time
    • Exact structural consequences of mutations on NBD conformation unknown
    • Whether these mutations also affect trafficking was not tested
  6. 2008 High

    Reconstitution of purified NBD1 and NBD2 domains demonstrated that SUR2A possesses intrinsically asymmetric NBDs whose heterodimeric assembly is required for optimal ATPase catalytic activity, revealing the enzymatic architecture underlying metabolic sensing.

    Evidence Purified recombinant NBD1/NBD2, ATPase assays, dynamic light scattering, circular dichroism, AFM, TEM, site-directed mutagenesis of catalytic base D834E

    PMID:18311911

    Open questions at the time
    • Full-length SUR2 catalytic cycle not reconstituted
    • Coupling of NBD ATPase to channel gating not demonstrated biochemically
  7. 2010 High

    SUR2 was shown to direct KATP channels to intracellular endosomal/lysosomal compartments, with ischemia shifting channel distribution to the sarcolemma; separately, SUR2-null mitochondria showed altered membrane potential, Ca2+ tolerance, and ROS generation, expanding SUR2 function beyond sarcolemmal gating to subcellular trafficking and mitochondrial physiology.

    Evidence Immunofluorescence, surface HA-tag labeling, subcellular fractionation of rat hearts, fluorescence-based mitochondrial assays in SUR2-mutant mice

    PMID:20935152 PMID:20971764

    Open questions at the time
    • Molecular mechanism of ischemia-induced trafficking not defined
    • Whether SUR2 is physically present in mitochondrial membranes vs. indirectly affecting mitochondria was debated
  8. 2012 High

    Identification of dominant ABCC9 gain-of-function mutations as the cause of Cantú syndrome, with mutations clustering in transmembrane domains and reducing ATP-mediated inhibition of KATP channels, established a new Mendelian channelopathy paradigm for SUR2.

    Evidence Exome sequencing of multiple affected families, Sanger validation, electrophysiological measurements of mutant channel ATP sensitivity

    PMID:22608503 PMID:22610116

    Open questions at the time
    • How different Cantú mutations produce common phenotype despite distinct gating effects unknown
    • Tissue-specific pathophysiology (cardiac vs. vascular vs. skeletal) not dissected
  9. 2014 High

    Abcc9 exon 5 knockout mice revealed that SUR2 is required for the neonatal heart's metabolic transition from glycolysis to fatty acid oxidation, with loss causing mitochondrial immaturity and neonatal cardiomyopathy, establishing a developmental metabolic role for KATP channels.

    Evidence Exon 5 knockout mice, fatty acid oxidation assays, oxygen consumption measurements, electron microscopy of cardiac mitochondria

    PMID:24648545

    Open questions at the time
    • Whether sarcolemmal or mitochondrial KATP (or both) drive metabolic maturation not resolved
    • Upstream transcriptional regulators of neonatal ABCC9 expression unknown
  10. 2015 High

    Detailed electrophysiological dissection of multiple Cantú syndrome mutations revealed at least two distinct gain-of-function mechanisms: enhanced MgADP activation versus reduced ATP/glibenclamide sensitivity, showing that different mutations converge on channel overactivity through separate gating pathways.

    Evidence 86Rb efflux assays and inside-out patch-clamp of engineered mutant SUR2A/Kir6.2 channels

    PMID:26621776

    Open questions at the time
    • Whether mixed-mechanism mutations produce different disease severity not tested
    • Structural basis for mechanistic divergence unknown at the time
  11. 2019 High

    Discovery that homozygous ABCC9 loss-of-function causes AIMS (intellectual disability, myopathy, cardiac dysfunction) in humans, confirmed across mice and zebrafish, completed the allelic series from gain-of-function (Cantú) to loss-of-function and demonstrated SUR2 is essential for muscle and brain function.

    Evidence Patient exome sequencing, recombinant channel electrophysiology showing non-functional channels, SUR2 knockout mouse and zebrafish phenotyping

    PMID:31575858

    Open questions at the time
    • CNS pathophysiology mechanism not defined
    • Whether residual SUR2 splice variants modulate AIMS severity unknown
  12. 2021 High

    Cantú syndrome knockin mouse models revealed that the R1154Q mutation causes near-complete SUR2 protein loss through aberrant mRNA splicing rather than altered gating, and that SUR2[A478V] gain-of-function in skeletal muscle causes atrophy through upregulation of ubiquitin ligases, connecting KATP overactivity to muscle wasting pathways.

    Evidence CRISPR knockin mice, cDNA sequencing, recombinant channel expression, hiPSC-derived cardiomyocytes, skeletal muscle patch-clamp, histopathology, and qPCR of atrophy markers

    PMID:33529173 PMID:34359961

    Open questions at the time
    • Why R1154Q missense causes mis-splicing at the pre-mRNA level is mechanistically unexplained
    • Downstream signaling from KATP overactivity to atrogin-1/MuRF1 induction not mapped
  13. 2022 High

    Cryo-EM structures of SUR2A and SUR2B with KATP openers and Mg-nucleotides identified a common drug-binding pocket between TMD1 and TMD2 and showed that openers synergize with Mg-nucleotides to stabilize the NBD-dimerized occluded activating conformation, providing the first atomic-level mechanism of KATP opener action on SUR2.

    Evidence Cryo-EM structure determination of SUR2A and SUR2B with bound P1075 or levcromakalim

    PMID:35562524

    Open questions at the time
    • Transition-state intermediates between inward-facing and occluded conformations not captured
    • Structures of disease-mutant SUR2 not yet determined
  14. 2022 High

    KCNJ8/ABCC9-containing KATP channels were shown to cell-autonomously regulate brain vascular smooth muscle cell differentiation through modulation of Ca2+ oscillations via voltage-dependent calcium channels, extending SUR2 function to developmental vascular biology.

    Evidence Kcnj8 KO mice, zebrafish models, chemical KATP modulation, live Ca2+ imaging, VSMC differentiation assays

    PMID:35588738

    Open questions at the time
    • Transcriptional targets downstream of Ca2+ oscillation changes not identified
    • Relative contribution of SUR2 vs. Kir6.1 to differentiation signal not separated
  15. 2024 Medium

    Synthesis of structural data revealed a unique SUR2-specific regulatory helix (R-helix) absent in SUR1 that mediates Mg-ADP-induced channel activation, and confirmed that the C-terminal 42 residues allosterically regulate Mg-nucleotide binding kinetics on NBD2, unifying decades of pharmacological and mutagenesis data into a coherent conformational gating model.

    Evidence Review and synthesis of cryo-EM structural studies with functional validation

    PMID:38227376

    Open questions at the time
    • R-helix deletion/mutation experiments in full-length SUR2 not reported
    • Dynamic conformational pathway from R-helix release to pore opening not resolved
  16. 2025 High

    The H60Y Cantú syndrome mutation was shown to cause gain-of-function selectively in Kir6.1-SUR2B but not Kir6.2-SUR2B channels, with valine 334 in the Kir6.1 C-terminus identified as the determinant, establishing that ABCC9 disease mutations can exploit pore-subunit isoform differences to produce tissue-selective pathophysiology.

    Evidence Membrane potential assays with chimeric Kir6.1/Kir6.2-SUR2 channels, site-directed mutagenesis

    PMID:41448431

    Open questions at the time
    • In vivo tissue-selective phenotype of H60Y not yet characterized
    • Structural basis of Val334-mediated isoform selectivity not determined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the identity and physiological role of a bona fide mitochondrial KATP channel containing SUR2 splice variants; the structural basis of disease-mutant SUR2 conformations; the signaling pathways linking KATP overactivity to skeletal muscle atrophy; and the mechanism by which SUR2 contributes to brain function as revealed by AIMS intellectual disability.
  • Mitochondrial KATP molecular composition remains unresolved
  • No structural data for disease-mutant SUR2
  • CNS mechanism of AIMS intellectual disability undefined
  • Signaling cascade from KATP to atrogin-1/MuRF1 not mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 7 GO:0140657 ATP-dependent activity 4 GO:0005215 transporter activity 3
Localization
GO:0005886 plasma membrane 3 GO:0005739 mitochondrion 2 GO:0005768 endosome 1
Pathway
R-HSA-1643685 Disease 4 R-HSA-382551 Transport of small molecules 4 R-HSA-162582 Signal Transduction 3 R-HSA-1430728 Metabolism 2
Partners
KCNJ11KCNJ8
Complex memberships
KATP channel (SUR2A/Kir6.2)KATP channel (SUR2B/Kir6.1)KATP channel (SUR2B/Kir6.2)

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 ABCC9 encodes SUR2A and SUR2B, alternatively spliced isoforms of the sulfonylurea receptor that form the regulatory subunit of cardiac, skeletal muscle, and vascular KATP channels by partnering with the inwardly rectifying K+ channel subunit KIR6.2; SUR2A is expressed exclusively in heart while SUR2B is ubiquitous. cDNA cloning, Northern blotting, RT-PCR, in situ hybridization, FISH chromosomal localization Diabetes High 8826984
1998 The C-terminal 42 amino acid residues that differ between SUR2A and SUR2B determine subtype-selective pharmacological activation of KATP channels; nicorandil preferentially activates SUR2B/Kir6.2 channels (>100-fold lower EC50) over SUR2A/Kir6.2 channels, implicating the C-terminal tail in drug selectivity. Heterologous expression in HEK293T cells, patch-clamp electrophysiology (cell-attached and whole-cell configurations) British journal of pharmacology High 9692785
2001 Disruption of SUR2-containing KATP channels in skeletal muscle enhances insulin-stimulated glucose uptake, demonstrating that SUR2-dependent membrane excitability is a component of the insulin-stimulated glucose uptake mechanism. Gene-targeted Sur2 knockout mice, glucose tolerance tests, hyperinsulinemic euglycemic clamp, in vitro insulin-stimulated glucose transport assay in isolated muscle Proceedings of the National Academy of Sciences of the United States of America High 11562480
2002 Sur2-containing KATP channels in vascular smooth muscle are critical regulators of episodic vasomotor activity; Sur2 null mice develop elevated resting blood pressure, sudden death, and episodic coronary artery vasospasm that is reversible by calcium channel antagonist treatment. Gene-targeted Sur2 knockout mice, in vivo hemodynamic monitoring, coronary angiography, pharmacological rescue with nifedipine The Journal of clinical investigation High 12122112
2002 The C-terminal 42 amino acid residues of SUR2 subtypes mediate intramolecular interaction with the second nucleotide-binding domain (NBD2), specifically a 7-residue segment that electrostatically interacts with Arg1344 at the Walker-A loop of NBD2, determining ADP-induced differential activation of KATP channels in SUR2A vs SUR2B. Chimeric SUR2A/SUR2B constructs expressed with Kir6.2, patch-clamp electrophysiology, 3D structural modeling based on HisP crystal structure Circulation research Medium 11909819
2004 Two ABCC9 missense and frameshift mutations identified in dilated cardiomyopathy patients map to conserved domains adjacent to the catalytic ATPase pocket within SUR2A, causing aberrant redistribution of conformations in the intrinsic ATP hydrolytic cycle that translates into abnormal KATP channel phenotypes with compromised metabolic signal decoding. Genomic DNA scanning, functional expression of mutant SUR2A, electrophysiology (inside-out patch-clamp), ATPase activity assays Nature genetics High 15034580
2007 Conventional sarcolemmal cardiomyocyte KATP channels containing full-length SUR2 are not required for mediating cardioprotection against acute ischemia-reperfusion injury; SUR2 null mice show reduced infarct size, and nifedipine treatment to block baseline vasospasm reveals that the protection is partly vasospasm-dependent. SUR2 null mice, Langendorff-perfused heart ischemia model, infarct size measurement, nifedipine pharmacological dissection Journal of molecular and cellular cardiology Medium 17765261
2008 SUR2A contains asymmetric NBD1 and NBD2 domains; heterodomain NBD1/NBD2 interaction produces conformational rearrangements and enhances intrinsic ATPase activity. Mutation of the predicted catalytic base residue D834E in NBD1 alters NBD1 ATPase activity and disrupts potentiation of catalytic behavior, establishing NBD1/NBD2 assembly as the molecular basis for optimal SUR2A catalytic activity. Purified recombinant NBD1/NBD2 domains, dynamic light scattering, circular dichroism, atomic force microscopy, transmission electron microscopy, ATPase activity assays, site-directed mutagenesis Journal of proteome research High 18311911
2010 SUR2 subunits are essential for trafficking KATP channels to an intracellular endosomal/lysosomal compartment; SUR2-containing channels dynamically cycle between endosomal and plasmalemmal compartments, and ischemia shifts this balance toward the sarcolemmal fraction, increasing surface KATP channel density without changing mRNA levels. Immunofluorescence microscopy, surface HA-tag labeling, subcellular fractionation of rat hearts, patch-clamp recording from ischemic ventricular myocytes American journal of physiology. Heart and circulatory physiology High 20971764
2010 SUR2 mutant mice have an altered mitochondrial phenotype including less polarized mitochondrial membrane potential, increased Ca2+ tolerance, enhanced ROS generation, and greater K+ influx compared to wild-type, consistent with SUR2 participation in mitochondrial KATP channel function and providing a basis for ischemic cardioprotection. Fluorescence-based assays of mitochondrial membrane potential, Ca2+ loading, ROS; light scattering volumetric assays; isolated mitochondria and intact myocyte experiments American journal of physiology. Heart and circulatory physiology Medium 20935152
2011 SUR2B is the sole SUR isoform expressed in murine cerebral artery smooth muscle cells, and SUR2-containing KATP channels mediate vasodilation induced by oxygen/glucose deprivation (OGD) and metabolic inhibition but not by hypoxia alone; loss of SUR2 impairs postischemic loss of myogenic tone. SUR2 null mice, pressurized cerebral artery myography, pinacidil pharmacology, hypoxia/OGD/metabolic inhibitor protocols, RT-PCR isoform identification American journal of physiology. Heart and circulatory physiology High 21784985
2012 Dominant missense mutations in ABCC9 cause Cantú syndrome by reducing ATP-mediated inhibition of KATP channels, resulting in gain-of-function channel opening; all mutations alter amino acids in or near the transmembrane domains of SUR2. Exome sequencing of affected families, Sanger sequencing, electrophysiological measurements of mutant channel ATP sensitivity Nature genetics High 22610116
2012 Cantú syndrome ABCC9 mutations are heterozygous missense variants with a hotspot at Arg1154 within the second type 1 transmembrane region, consistent with an activating (gain-of-function) mechanism for KATP channels. Exome sequencing of proband-parent trios and unrelated cases, Sanger sequencing American journal of human genetics Medium 22608503
2012 CpG methylation of the ABCC9/SUR2 promoter region regulates SUR2 expression in HL-1 cardiomyocytes; 57.6% of CpGs in the SUR2 promoter are methylated versus 0.14% for SUR1, and demethylation with 5-aza-2'-deoxycytidine increases SUR2 mRNA expression. Bisulfite sequencing of genomic DNA, 5-aza-dC treatment, quantitative RT-PCR PloS one Medium 22844491
2013 The ABCC9 V734I mutation (in NBD1) selectively reduces MgATP inhibition and MgNDP activation of Kir6.2/SUR2B vascular channels but not Kir6.2/SUR2A cardiac or Kir6.1/SUR2B channels, linking impaired nucleotide sensing in vascular KATP channels to susceptibility to coronary vasospasm and myocardial infarction. Patch-clamp electrophysiology of recombinant channels in heterologous expression system, inside-out and whole-cell configurations International journal of cardiology High 23739550
2013 A SUR2A splice variant (SUR2A-55) lacking NBD1 and two transmembrane domains can co-assemble with Kir6.1 and Kir6.2 to form functional KATP channels with 70-fold reduced ATP sensitivity and markedly reduced drug sensitivity, suggesting it as a candidate mitoKATP regulatory subunit. Heterologous expression in COS cells, patch-clamp electrophysiology, pharmacological profiling with pinacidil/diazoxide/glibenclamide Channels (Austin, Tex.) Medium 24037327
2014 Abcc9 is required for the neonatal heart's transition from glycolytic to oxidative metabolism; deletion of exon 5 ablates both plasma membrane and mitochondria-associated Abcc9 proteins, causing neonatal cardiomyopathy with reduced fatty acid oxidation, reduced oxygen consumption, and mitochondrial immaturity. Exon 5 knockout mice, mitochondrial membrane potential assays, fatty acid oxidation assays, oxygen consumption measurements, electron microscopy of cardiac mitochondria, diazoxide KATP agonist testing FASEB journal High 24648545
2014 ABCC9 gain-of-function mutations cause early repolarization and Brugada syndromes by increasing KATP channel activity; V734I-ABCC9 increases Mg-ATP IC50 5-fold and S1402C-ABCC9 shifts ATP IC50, both producing gain-of-function IK-ATP. Direct sequencing of susceptibility genes, whole-cell and inside-out patch-clamp in TSA201 cells expressing mutant SUR2A with Kir6.2 International journal of cardiology High 24439875
2015 Three Cantú syndrome ABCC9 mutations (P432L, A478V, C1043Y) all produce gain-of-function KATP channels but through at least two distinct mechanisms: P429L and A475V enhance MgADP activation with normal ATP sensitivity, while C1039Y reduces sensitivity to both ATP inhibition and glibenclamide block without affecting MgADP activation. Rubidium efflux assays, inside-out patch-clamp electrophysiology; engineered mutations in rat SUR2A expressed with mouse Kir6.2 The Journal of general physiology High 26621776
2015 ABCC9 rs704180 risk allele functions as an expression quantitative trait locus (eQTL) in brain, associated with increased ABCC9 transcript levels and enrichment for a shorter 3' UTR; miR-30c down-regulates SUR2 transcripts with the longer 3' UTR. 3' RACE of human brain cDNA, eQTL analysis across multiple brain expression databases, microRNA transfection experiments Journal of neurochemistry Medium 26115089
2019 Homozygous loss-of-function splice-site mutation in ABCC9 (c.1320+1 G>A) causing in-frame deletion of exon 8 results in non-functional SUR2-containing KATP channels and produces a syndrome (AIMS) of intellectual disability, myopathy, and cardiac dysfunction; SUR2 loss-of-function causes fatigability and cardiac dysfunction in mice and zebrafish. Patient exome sequencing, recombinant channel expression with electrophysiology, SUR2 knockout mouse and zebrafish models with functional phenotyping Nature communications High 31575858
2020 Kir6.1/SUR2-containing KATP channels underlie smooth muscle KATP throughout the intestine; gain-of-function mutations in Kir6.1/SUR2 (Cantú syndrome knockin mice) reduce intestinal contractility and cause GI dysmotility reversible by glibenclamide, a KATP inhibitor. Kir6.1/SUR2 knockin mice carrying human CS mutations, intestinal contractility assays, glibenclamide pharmacological rescue, subunit identification by genetic ablation JCI insight High 33170808
2021 SUR2[A478V] gain-of-function knockin mutation reduces MgATP sensitivity of KATP currents in skeletal muscle fibers and causes muscle atrophy with up-regulation of atrogin-1 and MuRF1 mRNA, linking KATP overactivity to skeletal muscle atrophy in Cantú syndrome. Heterozygous and homozygous SUR2[A478V] knockin mice, patch-clamp of Flexor digitorum brevis fibers, muscle histopathology, qPCR of atrophy markers Cells High 34359961
2021 SUR2[R1154Q] Cantú syndrome mutation causes near-complete loss of SUR2 protein and KATP channel activity in homozygous ventricular tissue due to aberrant splicing (in-frame deletion of exon 28 in ~90% of transcripts from homozygous tissue), revealing that ABCC9 mutations can act through mRNA mis-splicing rather than purely by altered channel gating. CRISPR/Cas9 knockin mice, cDNA sequencing, recombinant expression of SUR2A lacking exon 28, patch-clamp electrophysiology, hiPSC-derived cardiomyocyte analysis JCI insight High 33529173
2022 Cryo-EM structures of SUR2A and SUR2B in complex with Mg-nucleotides and KATP openers P1075 or levcromakalim reveal that both vasodilators bind a common site in the transmembrane domain between TMD1 and TMD2 (embraced by TM10, TM11, TM12, TM14, and TM17), and synergize with Mg-nucleotides to stabilize SUR2 in the NBD-dimerized occluded state to activate the channel. Cryo-EM structure determination of SUR2A and SUR2B with bound ligands Nature communications High 35562524
2022 KCNJ8/ABCC9-containing KATP channels cell-autonomously regulate brain vascular smooth muscle cell (VSMC) differentiation through modulation of intracellular Ca2+ oscillation via voltage-dependent calcium channels; loss or gain of KATP function suppresses or promotes arterial VSMC differentiation, and Kcnj8 KO mice show deficient vasoconstrictive capacity and impaired neurovascular coupling. Kcnj8 KO mice, zebrafish genetic models, chemical KATP inhibition/activation, live imaging of Ca2+ oscillations, VSMC differentiation assays in cell culture Developmental cell High 35588738
2023 Loss of SUR2 in skeletal muscle specifically underlies myopathy in AIMS; ABCC9 loss-of-function results in abnormal generation of unstimulated forces in isolated muscle, and CaV1.1 channel blockade by verapamil causes premature death in AIMS mice, indicating Ca2+ influx through CaV1.1 is not the primary pathological mechanism. Tissue-selective KATP suppression with premature stop codon mouse models, isolated muscle force measurements, verapamil pharmacological intervention, CaV1.1 non-permeable mutant genetic rescue EMBO molecular medicine High 37154692
2024 SUR2 undergoes ligand-dependent dynamic conformational changes between an inhibitory inward-facing conformation and an activating occluded conformation; Mg-ADP binding to NBD2 competes with inhibitory Mg-ATP to promote release of a unique inhibitory Regulatory helix (R helix) absent in SUR1, initiating channel activation; the C-terminal 42 residues (C42) allosterically regulate Mg-nucleotide binding kinetics on NBD2. Structural studies (cryo-EM) with functional validation (referenced as 'recent structural studies') BioEssays : news and reviews in molecular, cellular and developmental biology Medium 38227376
2025 SUR2[H60Y] Cantú syndrome mutation causes gain-of-function selectively in Kir6.1-SUR2B channels but not Kir6.2-SUR2B channels; chimeric and mutagenesis analysis identifies the N and C termini of Kir6.1 and specifically valine 334 in Kir6.1 as necessary for this isoform-specific GOF effect. DiBAC4(3) membrane potential measurements in intact cells expressing Kir6.1/Kir6.2-SUR2 combinations, chimeric channel approach, site-directed mutagenesis of Kir6.1 The Journal of biological chemistry High 41448431

Source papers

Stage 0 corpus · 71 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating. Nature genetics 286 15034580
1996 Cloning, tissue expression, and chromosomal localization of SUR2, the putative drug-binding subunit of cardiac, skeletal muscle, and vascular KATP channels. Diabetes 224 8826984
2002 Transcription control by E1A and MAP kinase pathway via Sur2 mediator subunit. Science (New York, N.Y.) 211 11934987
2000 The SUR2 gene of Arabidopsis thaliana encodes the cytochrome P450 CYP83B1, a modulator of auxin homeostasis. Proceedings of the National Academy of Sciences of the United States of America 207 11114200
2002 Episodic coronary artery vasospasm and hypertension develop in the absence of Sur2 K(ATP) channels. The Journal of clinical investigation 198 12122112
1998 Sur2 mutations of Arabidopsis thaliana define a new locus involved in the control of auxin homeostasis. The Plant journal : for cell and molecular biology 192 9675903
2012 Dominant missense mutations in ABCC9 cause Cantú syndrome. Nature genetics 160 22610116
2012 Cantú syndrome is caused by mutations in ABCC9. American journal of human genetics 132 22608503
1995 sur-2, a novel gene, functions late in the let-60 ras-mediated signaling pathway during Caenorhabditis elegans vulval induction. Genes & development 107 7557379
2014 ABCC9 is a novel Brugada and early repolarization syndrome susceptibility gene. International journal of cardiology 104 24439875
2001 Disruption of Sur2-containing K(ATP) channels enhances insulin-stimulated glucose uptake in skeletal muscle. Proceedings of the National Academy of Sciences of the United States of America 96 11562480
2014 ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology. Acta neuropathologica 76 24770881
2020 TRIM11 facilitates chemoresistance in nasopharyngeal carcinoma by activating the β-catenin/ABCC9 axis via p62-selective autophagic degradation of Daple. Oncogenesis 73 32382014
1998 SUR2 subtype (A and B)-dependent differential activation of the cloned ATP-sensitive K+ channels by pinacidil and nicorandil. British journal of pharmacology 73 9692785
2002 C. elegans EOR-1/PLZF and EOR-2 positively regulate Ras and Wnt signaling and function redundantly with LIN-25 and the SUR-2 Mediator component. Genes & development 72 12130541
2015 Reassessment of risk genotypes (GRN, TMEM106B, and ABCC9 variants) associated with hippocampal sclerosis of aging pathology. Journal of neuropathology and experimental neurology 66 25470345
2015 ABCC9/SUR2 in the brain: Implications for hippocampal sclerosis of aging and a potential therapeutic target. Ageing research reviews 62 26226329
2021 Analysis of genes (TMEM106B, GRN, ABCC9, KCNMB2, and APOE) implicated in risk for LATE-NC and hippocampal sclerosis provides pathogenetic insights: a retrospective genetic association study. Acta neuropathologica communications 47 34526147
2010 Endosomal KATP channels as a reservoir after myocardial ischemia: a role for SUR2 subunits. American journal of physiology. Heart and circulatory physiology 39 20971764
2007 Mice lacking sulfonylurea receptor 2 (SUR2) ATP-sensitive potassium channels are resistant to acute cardiovascular stress. Journal of molecular and cellular cardiology 39 17765261
2022 KCNJ8/ABCC9-containing K-ATP channel modulates brain vascular smooth muscle development and neurovascular coupling. Developmental cell 36 35588738
2019 ABCC9-related Intellectual disability Myopathy Syndrome is a KATP channelopathy with loss-of-function mutations in ABCC9. Nature communications 36 31575858
2002 Intramolecular interaction of SUR2 subtypes for intracellular ADP-Induced differential control of K(ATP) channels. Circulation research 34 11909819
2015 Differential mechanisms of Cantú syndrome-associated gain of function mutations in the ABCC9 (SUR2) subunit of the KATP channel. The Journal of general physiology 33 26621776
2000 Molecular characterization of human SUR2-containing K(ATP) channels. Gene 29 11054556
2020 Repurposing Kir6/SUR2 Channel Activator Minoxidil to Arrests Growth of Gynecologic Cancers. Frontiers in pharmacology 28 32457608
2017 Gene-based association study of genes linked to hippocampal sclerosis of aging neuropathology: GRN, TMEM106B, ABCC9, and KCNMB2. Neurobiology of aging 27 28131462
2013 Coronary spasm and acute myocardial infarction due to a mutation (V734I) in the nucleotide binding domain 1 of ABCC9. International journal of cardiology 26 23739550
2020 Kir6.1- and SUR2-dependent KATP overactivity disrupts intestinal motility in murine models of Cantú syndrome. JCI insight 25 33170808
2006 A novel Val734Ile variant in the ABCC9 gene associated with myocardial infarction. Clinica chimica acta; international journal of clinical chemistry 25 16563363
2008 Interaction of asymmetric ABCC9-encoded nucleotide binding domains determines KATP channel SUR2A catalytic activity. Journal of proteome research 24 18311911
2013 Wide clinical variability in conditions with coarse facial features and hypertrichosis caused by mutations in ABCC9. American journal of medical genetics. Part A 23 23307537
2012 Promoter DNA methylation regulates murine SUR1 (Abcc8) and SUR2 (Abcc9) expression in HL-1 cardiomyocytes. PloS one 22 22844491
2015 Novel human ABCC9/SUR2 brain-expressed transcripts and an eQTL relevant to hippocampal sclerosis of aging. Journal of neurochemistry 18 26115089
2014 Abcc9 is required for the transition to oxidative metabolism in the newborn heart. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 18 24648545
2016 De Novo Mutation in ABCC9 Causes Hypertrichosis Acromegaloid Facial Features Disorder. Pediatric dermatology 17 26871653
2004 Requirement of Sur2 for efficient replication of mouse adenovirus type 1. Journal of virology 17 15542641
2021 Complex consequences of Cantu syndrome SUR2 variant R1154Q in genetically modified mice. JCI insight 15 33529173
2021 Consequences of SUR2[A478V] Mutation in Skeletal Muscle of Murine Model of Cantu Syndrome. Cells 15 34359961
2022 Structural identification of vasodilator binding sites on the SUR2 subunit. Nature communications 13 35562524
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
2011 Vasodilation induced by oxygen/glucose deprivation is attenuated in cerebral arteries of SUR2 null mice. American journal of physiology. Heart and circulatory physiology 12 21784985
2010 The mitochondrial bioenergetic phenotype for protection from cardiac ischemia in SUR2 mutant mice. American journal of physiology. Heart and circulatory physiology 12 20935152
2004 Cloning and functional characterization of the SUR2/SYR2 gene encoding sphinganine hydroxylase in Pichia ciferrii. Yeast (Chichester, England) 12 15116344
2024 Novel loss-of-function variants expand ABCC9-related intellectual disability and myopathy syndrome. Brain : a journal of neurology 9 38217872
2019 A rare case of familial restrictive cardiomyopathy, with mutations in MYH7 and ABCC9 genes. Discoveries (Craiova, Romania) 9 32309617
2013 ATP-sensitive potassium currents from channels formed by Kir6 and a modified cardiac mitochondrial SUR2 variant. Channels (Austin, Tex.) 9 24037327
2021 Identification of sur2 mutation affecting the lifespan of fission yeast. FEMS microbiology letters 8 34114004
2020 Cantú syndrome versus Zimmermann-Laband syndrome: Report of nine individuals with ABCC9 variants. European journal of medical genetics 8 32622958
2009 Genes controlling postural changes in blood pressure: comprehensive association analysis of ATP-sensitive potassium channel genes KCNJ8 and ABCC9. Physiological genomics 8 19952277
2023 Genetic Interaction between Arabidopsis SUR2/CYP83B1 and GNOM Indicates the Importance of Stabilizing Local Auxin Accumulation in Lateral Root Initiation. Plant & cell physiology 7 37522618
2007 The Kir6.2-F333I mutation differentially modulates KATP channels composed of SUR1 or SUR2 subunits. The Journal of physiology 7 17395632
2023 Involvement of SUR2/Kir6.1 channel in the physiopathology of pulmonary arterial hypertension. Frontiers in cardiovascular medicine 6 36704469
2023 Skeletal muscle delimited myopathy and verapamil toxicity in SUR2 mutant mouse models of AIMS. EMBO molecular medicine 6 37154692
2022 Lymphedema as first clinical presentation of Cantu Syndrome: reversed phenotyping after identification of gain-of-function variant in ABCC9. European journal of human genetics : EJHG 6 36336713
2019 Functional characterization of ABCC9 variants identified in sudden unexpected natural death. Forensic science international 6 30878466
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
2024 Loss of SUR2 alters the composition of ceramides and shortens chronological lifespan of Saccharomyces cerevisiae. Biochimica et biophysica acta. Molecular and cell biology of lipids 2 39719180
2022 Case Report: Loss-of-Function ABCC9 Genetic Variant Associated With Ventricular Fibrillation. Frontiers in genetics 2 35495129
2021 Cardiac dysfunction in spontaneously hypertensive old rats is associated with a significant decrease of SUR2 expression. Molecular and cellular biochemistry 2 34455535
2017 Clinical and Molecular Delineation of a Novel Cys1050Phe Missense Mutation in the ABCC9 Gene in a Korean Patient with Cantú Syndrome. Clinical laboratory 2 28627835
2024 Sulfonylurea receptor 2 (SUR2), intricate sensors for intracellular Mg-nucleotides. BioEssays : news and reviews in molecular, cellular and developmental biology 1 38227376
2013 Expression and purification of a soluble ESX-binding core domain of SUR2. Preparative biochemistry & biotechnology 1 23464919
2025 Beyond Tachycardia-Induced Cardiomyopathy: ABCC9-Related Dilated Cardiomyopathy and Familial Atrial Fibrillation. JACC. Case reports 0 40923965
2025 ABCC9 knockdown attenuates isoproterenol‑induced myocardial hypertrophy by inhibiting the PI3K/AKT signaling pathway. Molecular medicine reports 0 41347799
2025 Cantu syndrome-associated SUR2[H60Y] mutation confers selective gain of function on Kir6.1 ATP-sensitive potassium channels. The Journal of biological chemistry 0 41448431
2024 A novel ABCC9 variant in a Greek family with Cantu syndrome affecting multiple generations highlights the functional role of the SUR2B NBD1. American journal of medical genetics. Part A 0 39031464
2024 [Clinical characteristics and genetic analysis of a child with Cantú syndrome due to variant of ABCC9 gene]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 0 39344622
2023 An ABCC9 Missense Variant Is Associated with Sudden Cardiac Death and Dilated Cardiomyopathy in Juvenile Dogs. Genes 0 37239348
2022 ABCC9 Is Downregulated and Prone to Microsatellite Instability on ABCC9tetra in Canine Breast Cancer. Frontiers in veterinary science 0 35071399
2017 Draft genome sequence of Chryseobacterium limigenitum SUR2T (LMG 28734T) isolated from dehydrated sludge. Brazilian journal of microbiology : [publication of the Brazilian Society for Microbiology] 0 28774639