{"gene":"ABCC8","run_date":"2026-06-09T22:02:36","timeline":{"discoveries":[{"year":1997,"finding":"SUR1 (ABCC8) binds ATP at NBF1 in a Mg2+-independent manner with high affinity, while MgADP binds at NBF2 and antagonizes ATP binding at NBF1 through cooperative inter-domain communication; NBF1 Walker A/B mutations impaired ATP binding, NBF2 mutations reduced MgADP antagonism.","method":"Photoaffinity labeling with 8-azido-[α-32P]ATP and 8-azido-[γ-32P]ATP; site-directed mutagenesis of Walker A and B motifs in NBF1 and NBF2","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro biochemical assay with mutagenesis of specific residues, replicated across multiple mutant constructs in one rigorous study","pmids":["9287292"],"is_preprint":false},{"year":1998,"finding":"MgATP (like MgADP) stimulates KATP channel activity through interaction with the nucleotide-binding domains (NBDs) of SUR1; mutations abolishing MgATP binding/hydrolysis (D853N, D1505N, K719A, K1384M) in SUR1 NBDs eliminated the stimulatory effect of MgATP, while ATP sensitivity of truncated Kir6.2 expressed without SUR1 was unaffected by Mg2+.","method":"Inside-out patch-clamp recordings of reconstituted Kir6.2/SUR1 channels with NBD mutations in Xenopus oocytes","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — functional reconstitution with site-directed mutagenesis of SUR1 NBDs, multiple mutant constructs, rigorous controls including SUR1-free Kir6.2","pmids":["9618560"],"is_preprint":false},{"year":1998,"finding":"SUR1 and Kir6.2 form a direct physical complex, as demonstrated by co-immunoprecipitation from in vitro translated proteins and co-transfected COS cells; physical association alters cellular distribution (from honeycomb to diffuse pattern) and single-channel kinetic behavior (extended burst duration), and the distal C-terminus of Kir6.2 is not required for subunit association.","method":"Co-immunoprecipitation using Kir6.2-specific antibody from in vitro translated proteins and COS cell lysates; confocal microscopy; single-channel patch-clamp electrophysiology","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reciprocal co-IP from two systems (in vitro and cell-based), combined with functional electrophysiology and imaging, multiple orthogonal methods in one study","pmids":["9488482"],"is_preprint":false},{"year":1998,"finding":"The SUR1 and Kir6.2 gene promoters are G+C rich with no TATA box; the SUR1 promoter is active in beta-cell lines (HIT T15, MIN6) and inactive in fibroblasts (COS7), with a short 173 bp fragment sufficient for maximal SUR1 promoter activity; Kir6.2 promoter requires >900 bp for high-level expression.","method":"Genomic library screening, luciferase reporter transient transfection assays, deletion analysis in multiple cell lines","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reporter assays with deletion mapping in multiple cell lines, single lab","pmids":["9703328"],"is_preprint":false},{"year":1999,"finding":"Sulfonylurea high-affinity block and potassium channel opener (PCO)/MgADP stimulation of KATP channels require functional coupling between Kir6.2 and SUR1; PIP2 stabilizes the channel open state and abolishes high-affinity tolbutamide sensitivity by driving the channel away from closed states preferentially affected by tolbutamide; mutations in Kir6.2 (ΔN30 or L164A) that increase open-state stability similarly uncouple the channel from SUR1 regulatory input.","method":"Inside-out patch-clamp recordings with PIP2 application and Kir6.2 point mutations (ΔN30, L164A, R176A) co-expressed with SUR1 in Xenopus oocytes","journal":"The Journal of general physiology","confidence":"High","confidence_rationale":"Tier 1 / Strong — functional reconstitution with multiple Kir6.2 mutants and pharmacological tools, defining SUR1-Kir6.2 coupling mechanism with rigorous controls","pmids":["10435998"],"is_preprint":false},{"year":1999,"finding":"SUR1 NBF1 binds ATP strongly even without Mg2+, while NBF2 binds ADP; NBF2 of SUR1 exhibits greater in vitro ATP hydrolysis than NBF2 of SUR2A, which may underlie the greater MgADP stimulation of SUR1-containing KATP channels versus SUR2A-containing channels.","method":"In vitro ATP hydrolysis assay with affinity-purified NBF2 constructs; electrophysiology comparison of Kir6.2/SUR1 versus Kir6.2/SUR2A channels with PIP2","journal":"Journal of molecular and cellular cardiology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical ATPase assay plus functional electrophysiology, single lab, two orthogonal approaches","pmids":["15893323"],"is_preprint":false},{"year":2000,"finding":"The PHHI missense mutation R1420C in SUR1 NBF2 reduces MgATP and MgADP affinity at NBF2 ~5-fold and abolishes cooperative nucleotide binding between NBF1 and NBF2; it increases the EC50 for MgADP activation from 74 to 197 μM when assessed with ATP-insensitive Kir6.2-R50G, while channel expression is reduced but ATP inhibition, tolbutamide block, and diazoxide activation are unaffected.","method":"Photoaffinity labeling with mild tryptic digestion to distinguish NBF1/NBF2; inside-out patch-clamp of reconstituted channels in Xenopus oocytes","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — domain-specific photolabeling combined with electrophysiology and mutagenesis, multiple orthogonal readouts in one rigorous study","pmids":["10993895"],"is_preprint":false},{"year":2001,"finding":"Positively charged residues R176 and R177 in Kir6.2 are required for functional coupling to SUR1, conferring MgADP stimulation and sulfonylurea sensitivity; R176C and R177C mutants are not reactivated by MgADP after ATP inhibition and are insensitive to glyburide, whereas R301C and R314C mutants retain MgADP and glyburide sensitivity.","method":"Inside-out patch-clamp recordings of Kir6.2 point mutants (R176C, R177C, R301C, R314C) co-expressed with SUR1 in Xenopus oocytes","journal":"The Journal of general physiology","confidence":"High","confidence_rationale":"Tier 1 / Strong — functional reconstitution with site-directed mutagenesis identifying specific residues for SUR1-Kir6.2 coupling, multiple mutants with rigorous controls","pmids":["11585851"],"is_preprint":false},{"year":2002,"finding":"Loss of SUR1 in Sur1 knockout mice impairs PKA-independent cAMP potentiation of insulin secretion by incretins (GLP-1, GIP), establishing that SUR1 is required for the cAMP-sensing mechanism downstream of incretin receptors in pancreatic beta-cells; this effect is specific, as other modulators (mastoparan, PKC activators) remain functional in Sur1KO islets.","method":"Pharmacological experiments in isolated islets from Sur1 knockout mice; cAMP measurement; PKA inhibitor treatment (H-89, KT5720); insulin secretion assays","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic KO with specific pharmacological rescue/block experiments, multiple modulators tested, replicated across multiple incretin agonists","pmids":["12453898"],"is_preprint":false},{"year":2004,"finding":"Zinc activates KATP channels through binding to two SUR1-specific extracellular histidine residues, His-326 and His-332; site-directed mutagenesis of these residues individually and in combination (H326A/H332A) abolished zinc-induced activation, while SUR2A-containing channels showed inhibition by zinc, demonstrating SUR1 isoform specificity.","method":"Inside-out and whole-cell patch-clamp with site-directed mutagenesis of SUR1 histidine residues in insulinoma cells and transfected cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — site-directed mutagenesis with multiple single and double mutants, isoform comparison (SUR1 vs SUR2A), multiple electrophysiological approaches","pmids":["15613469"],"is_preprint":false},{"year":2006,"finding":"Activating missense mutations in ABCC8 (encoding SUR1) cause neonatal diabetes by elevating the basal Mg-nucleotide-dependent stimulatory action of SUR1 on the Kir6.2 pore, resulting in markedly higher channel open probability (Po) at physiologic MgATP concentrations in intact cells; mutant channels retain sulfonylurea sensitivity.","method":"Electrophysiological assay of mutant KATP channels expressed in intact cells and excised patches; ABCC8 sequencing in 34 neonatal diabetes patients","journal":"The New England journal of medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — functional electrophysiology of multiple mutant channels under physiological conditions, genotype-phenotype correlation across 9 patients with 7 mutations, replicated across multiple mutations","pmids":["16885549"],"is_preprint":false},{"year":2006,"finding":"A heterozygous de novo F132L mutation in SUR1 TMD0 (first set of transmembrane helices), proposed to interact with Kir6.2, markedly reduces KATP channel sensitivity to MgATP inhibition and increases whole-cell KATP current, causing DEND syndrome; this establishes TMD0 of SUR1 as a region affecting Kir6.2 ATP sensitivity.","method":"ABCC8 sequencing; whole-cell and inside-out patch-clamp electrophysiology of recombinant F132L channels in Xenopus oocytes","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — functional reconstitution with specific mutation, electrophysiology in multiple configurations (whole-cell and excised patch), evolutionary conservation analysis","pmids":["16613899"],"is_preprint":false},{"year":2006,"finding":"SUR1 protein and mRNA are newly expressed (de novo) after ischemia in neurons, astrocytes, and capillaries in rodent stroke models; upregulation is linked to activation of transcription factor Sp1; newly expressed SUR1 forms functional NC(Ca-ATP) (non-selective cation) channels rather than KATP channels, and block with glibenclamide reduces cerebral edema and infarct volume by ~50%.","method":"Western blot, in situ hybridization, immunofluorescence, electrophysiology in rodent stroke models; pharmacological block with glibenclamide","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (protein, mRNA, functional channel recording, pharmacological rescue), replicated in multiple rodent stroke models","pmids":["16550187"],"is_preprint":false},{"year":2008,"finding":"An activating Y356C mutation in SUR1 transmembrane helix 7 (TMD1) reduces KATP channel sensitivity to MgATP inhibition via an allosteric effect on Kir6.2 (IC50 increased from 24 to 95 μM, even in absence of Mg2+), impairs glucose-induced cell depolarization and Ca2+ responses in INS1 cells, and causes adult-onset diabetes.","method":"Inside-out patch-clamp recordings; perforated whole-cell patch recordings; confocal microscopy; Ca2+ imaging with Fura-Red in INS1(832/13) cells overexpressing SUR1-Y356C","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple electrophysiological configurations plus Ca2+ imaging and confocal microscopy, defining allosteric mechanism, single lab with orthogonal methods","pmids":["18346985"],"is_preprint":false},{"year":2010,"finding":"KATP channel activation by MgADP and MgATP operates through SUR1 NBDs; using Kir6.2-G334D (ATP-inhibition-insensitive) channels, MgATP and MgADP activated channels with EC50 of 112 and 8 μM respectively; activation was suppressed by Walker A lysine mutations in either NBD of SUR1; MgATPγS activated channels; AMPPCP did not activate; both nucleotides produced identical single-channel kinetic effects (elevated Po>0.8, increased open time, reduced interburst closures).","method":"Inside-out patch-clamp of Kir6.2-G334D/SUR1 channels with NBD Walker A mutations in Xenopus oocytes","journal":"The Journal of general physiology","confidence":"High","confidence_rationale":"Tier 1 / Strong — functional reconstitution with inhibition-insensitive pore mutation to isolate SUR1 activation, multiple nucleotide analogues, NBD mutagenesis, single-channel kinetic analysis","pmids":["20876358"],"is_preprint":false},{"year":2011,"finding":"Hypoxia stimulates transcription of Abcc8 (SUR1) sequentially through HIF1α binding to HIF-binding sites on the Sp1 promoter, which then drives Sp1 expression; Sp1 in turn binds to the Abcc8 promoter to stimulate SUR1 transcription. HIF-binding sites on the Abcc8 promoter itself are not required; chromatin immunoprecipitation confirmed HIF binding to the Sp1 promoter after cerebral ischemia in vivo.","method":"Luciferase reporter assays with promoter deletions; chromatin immunoprecipitation (ChIP) in ischemic rat brain; co-expression of HIF1α; brain microvascular endothelial cell culture","journal":"Journal of cerebral blood flow and metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — reporter assays with deletion mapping, in vivo ChIP validation, multiple promoter species tested, consistent mechanism across in vitro and in vivo systems","pmids":["22086197"],"is_preprint":false},{"year":2011,"finding":"A conserved intramolecular disulfide bond formed between two N-terminal cysteines in SUR1 (ABCC8) is critical for ER exit and cell surface trafficking; a disease-causing mutation in a conserved N-terminal cysteine of SUR1 prevents the protein from reaching the cell surface, causing hyperinsulinemic hypoglycemia.","method":"Mutagenesis of conserved cysteines; glycosylation analysis; immunoblot; proteasome inhibitor MG132 rescue experiments in multiple cell types","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical reconstitution with mutagenesis, glycosylation analysis, proteasome inhibitor rescue, linking mechanism to human disease mutation","pmids":["21199866"],"is_preprint":false},{"year":2011,"finding":"Dominant loss-of-function ABCC8 mutations causing diazoxide-unresponsive diffuse hyperinsulinism produce SUR1 channels with normal plasma membrane trafficking but severely impaired responses to diazoxide or MgADP, contrasting with dominant mutations causing diazoxide-responsive disease; the degree of impairment of diazoxide/MgADP response distinguishes diazoxide-responsive from diazoxide-unresponsive dominant mutations.","method":"Expression in COSm6 cells; Rb+ efflux assay; ABCC8 sequencing in 15 families","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional expression with Rb+ flux assay across 13 different mutations in two phenotypic groups, defining mechanistic basis for differential drug response","pmids":["21536946"],"is_preprint":false},{"year":2012,"finding":"SUR1 co-assembles with TRPM4 (transient receptor potential melastatin 4) to form Sur1-TRPM4 heteromers that constitute the NC(Ca-ATP) non-selective cation channel in CNS injury; co-expression yields channels with biophysical properties of TRPM4 and pharmacological properties of SUR1; co-assembly with SUR1 doubles TRPM4 affinity for calmodulin and doubles its Ca2+ sensitivity; Sur1-TRPM4 heteromers appear de novo after spinal cord injury.","method":"FRET (Förster resonance energy transfer); co-immunoprecipitation; patch-clamp electrophysiology; calmodulin binding assay; rat spinal cord injury model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (FRET, co-IP, electrophysiology, calmodulin assay), functional characterization of heteromeric channel, replicated in vivo after SCI","pmids":["23255597"],"is_preprint":false},{"year":2012,"finding":"E203 in SUR1 and Q52 in Kir6.2 are in close proximity and their interaction dynamically regulates KATP channel ATP sensitivity; E203K/Q52E double mutant channels exhibit ~100-fold higher ATP sensitivity than wild-type; cross-linking of E203C and Q52C locks the channel in a closed state reversible by reducing agents.","method":"Site-directed mutagenesis (E203K in SUR1, Q52E in Kir6.2); cysteine cross-linking with oxidizing/reducing agents; inside-out patch-clamp in Xenopus oocytes","journal":"The Journal of general physiology","confidence":"High","confidence_rationale":"Tier 1 / Strong — charge-swap mutagenesis combined with cysteine cross-linking providing direct structural evidence for inter-subunit proximity, multiple orthogonal approaches","pmids":["22802363"],"is_preprint":false},{"year":2013,"finding":"EPAC (Exchange Protein Activated by cAMP) binds directly to an intracellular loop of SUR1 (amino acids 859-881); this binding closes KATP channels; ablation of EPAC or expression of the competing SUR1(859-881) peptide increases KATP channel open probability, inhibits glutamate release, and reduces seizure vulnerability in mice.","method":"Direct binding assay (EPAC to SUR1(859-881) peptide); patch-clamp electrophysiology; glutamate release assay; in vivo seizure model in adult mice with EPAC knockout","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay combined with electrophysiology and in vivo seizure model, single lab, two orthogonal functional readouts","pmids":["23678128"],"is_preprint":false},{"year":2017,"finding":"SUR1-TRPM4 co-assembles with AQP4 to form a heteromultimeric water/ion channel complex (SUR1-TRPM4-AQP4); the full tripartite complex is required for fast, high-capacity transmembrane water transport driving cell swelling; co-assembly confirmed by co-IP and FRET; genetic inactivation of the SUR1-TRPM4 solute pore blocked in vivo astrocyte swelling in a brain edema model.","method":"Co-immunoprecipitation; FRET; calcein fluorescence cell-swelling assay in COS-7 cells; diolistic labeling for in vivo astrocyte volume measurement; cold-injury mouse brain edema model","journal":"Glia","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (co-IP, FRET, functional swelling assay, in vivo genetic deletion), confirmed in both heterologous cells and primary astrocytes and in vivo","pmids":["28906027"],"is_preprint":false},{"year":2018,"finding":"Cryo-EM structures of pancreatic KATP channels reveal the glibenclamide binding site on SUR1, show how the Kir6.2 N-terminus couples the peripheral SUR1 subunit to the central Kir6.2 pore, reveal the binding mode of activating Mg-nucleotides at SUR1 NBDs, and suggest the mechanism by which Mg-ADP binding drives conformational change of SUR1.","method":"Cryo-electron microscopy at 4.1–4.5 Å resolution","journal":"Protein & cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structural determination with three distinct channel states, directly resolving drug binding site and subunit coupling mechanism","pmids":["29594720"],"is_preprint":false},{"year":2018,"finding":"NF-κB activation of brain endothelial cells (BEC) causes de novo expression of SUR1-TRPM4 channels; tPA induces PAR1-mediated opening of SUR1-TRPM4 channels in a plasmin-, TRPC3-, and Ca2+-dependent manner; functional SUR1-TRPM4 channels are required for tPA-induced phasic (but not tonic) secretion of MMP-9 from BEC; SUR1 inhibition decreases tPA-induced MMP-9 secretion.","method":"Patch-clamp electrophysiology; ELISA and zymography for MMP-9; calcium imaging; genetic and pharmacological manipulation of SUR1, TRPM4, PAR1, TRPC3; NF-κB activation in murine and human BEC","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (electrophysiology, secretion assay, Ca2+ imaging, genetic KO, pharmacology), defined signaling pathway with functional consequence in BEC","pmids":["29617457"],"is_preprint":false},{"year":2019,"finding":"SUR1-TRPM4 channels (not KATP channels) mediate post-ischemic brain swelling; antisense oligodeoxynucleotides against Abcc8/SUR1 or Trpm4/TRPM4 each reduced hemispheric swelling by ~50% in rat permanent MCA occlusion, whereas AS-ODNs against Kcnj8/KIR6.1 or Kcnj11/KIR6.2 had no significant effect on swelling; SUR1-TRPM4 heteromers were confirmed by immuno-FRET and co-IP in post-ischemic tissue.","method":"Antisense oligodeoxynucleotides (molecularly targeted knockdown); MRI-based hemispheric swelling measurement; immuno-FRET; co-immunoprecipitation in rat pMCAo model","journal":"Neuroscience letters","confidence":"High","confidence_rationale":"Tier 2 / Strong — molecularly specific ODN knockdown of four distinct channel subunits with direct comparison, FRET and co-IP for complex formation, clear epistatic dissection of SUR1-TRPM4 vs KATP","pmids":["31899311"],"is_preprint":false},{"year":2021,"finding":"Loss of SUR1 function in iPSC-derived islets (homozygous ABCC8-V187D) causes excess insulin secretion at low glucose, beta-cell proliferation, and nucleomegaly; pharmacological KATP channel inactivation in corrected cells recapitulates the proliferation phenotype, establishing that SUR1-mediated KATP channel activity regulates beta-cell proliferation during islet development.","method":"iPSC differentiation to SC-islets; CRISPR-Cas9 correction; static and dynamic insulin secretion assays; BrdU proliferation assay; pharmacological KATP inactivation; xenograft in NOD-SCID gamma mice","journal":"Diabetologia","confidence":"High","confidence_rationale":"Tier 2 / Strong — isogenic patient-derived iPSC model with CRISPR correction, multiple functional readouts in vitro and in vivo, pharmacological rescue confirming mechanism","pmids":["33404684"],"is_preprint":false},{"year":2023,"finding":"In ischemic stroke, SUR1-TRPM4 channels in perivascular astrocyte endfeet mediate Na+ influx that drives Ca2+ entry via NCX1 operating in reverse mode; elevated intra-endfoot Ca2+ triggers calmodulin-dependent AQP4 translocation to the plasma membrane, causing water influx and brain swelling; pharmacological inhibition or astrocyte-specific deletion of SUR1-TRPM4 or NCX1 reduced brain swelling and improved neurological function independently of infarct size.","method":"Mouse permanent MCA occlusion; astrocyte-specific Abcc8 conditional knockout (pGfap-cre); pharmacological inhibition; Ca2+ imaging; AQP4 surface localization assay; neurological function scoring","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional KO plus pharmacological inhibition, mechanistic pathway defined through Ca2+ imaging and AQP4 trafficking, multiple orthogonal interventions with consistent results","pmids":["37279286"],"is_preprint":false},{"year":2016,"finding":"Sur1-Trpm4 channels regulate NOS2 transcription in TLR4-activated microglia through a Ca2+-sensitive calcineurin/NFAT pathway; inhibition or gene silencing of Sur1 or Trpm4 paradoxically increases intracellular Ca2+ (by removing Na+ influx-driven Ca2+ suppression), yet decreases NFAT nuclear translocation via activation of CaMKII and calcineurin phosphorylation; chromatin immunoprecipitation confirmed NFAT binding to the Nos2 promoter.","method":"Patch-clamp electrophysiology; calcium imaging; qPCR; Griess assay; immunoblot; chromatin immunoprecipitation; Abcc8-/- and Trpm4-/- mice; pharmacological inhibition in vivo and in vitro","journal":"Journal of neuroinflammation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (electrophysiology, Ca2+ imaging, ChIP, genetic KO of both subunits, pharmacology), defined Ca2+/CaMKII/CN/NFAT signaling pathway","pmids":["27246103"],"is_preprint":false},{"year":2002,"finding":"Novel SUR1-selective KATP channel opener NNC 55-9216 activates Kir6.2/SUR1 but not Kir6.2/SUR2A or Kir6.2/SUR2B channels; activation requires intracellular MgATP and Walker A motif integrity in both NBDs of SUR1; chimera analysis identified transmembrane domains 8-11 of SUR1 as critical structural determinants for NNC 55-9216 action, with NBD2 providing additional contribution.","method":"Inside-out patch-clamp in Xenopus oocytes; SUR1/SUR2A chimeras; Walker A mutagenesis; [3H]glibenclamide competitive binding","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 1 / Strong — chimeric receptor analysis combined with mutagenesis and radioligand binding, identifying structural determinants of selective drug activation","pmids":["12031979"],"is_preprint":false},{"year":2005,"finding":"Glibenclamide-induced apoptosis is specifically enhanced by expression of SUR1 but not SUR2B; a single amino acid substitution M1289T in transmembrane helix 17 (TM17) of SUR1 abolishes the apoptotic enhancement; coexpression with Kir6.2 does not alter the apoptotic effect, indicating a Kir6.2/KATP channel-independent pro-apoptotic function of SUR1.","method":"Cell detachment, nuclear condensation, DNA fragmentation, caspase-3-like activity assays in HEK293 cells expressing SUR1, SUR2B, SUR1(M1289T), or SUR1+Kir6.2","journal":"The Journal of pharmacology and experimental therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — four apoptotic readouts in isogenic cell lines with isoform comparison and point mutant, single lab","pmids":["16306272"],"is_preprint":false},{"year":2012,"finding":"TRPM4 currents expressed alone or with SUR1 in COSm6 cells are Ca2+-activated, voltage-dependent, ATP-inhibited, and insensitive to glibenclamide and tolbutamide; cotransfection of SUR1 did not alter TRPM4-mediated current properties; no detectable FRET was observed between fluorophore-tagged TRPM4 and SUR1, whereas robust FRET was detected between Kir6.2 and SUR1. This constitutes a negative finding: functional or structural association of TRPM4 and SUR1 was not detected in this experimental system.","method":"Patch-clamp electrophysiology; FRET in COSm6 cells co-expressing TRPM4 with or without SUR1 and/or Kir6.2","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — rigorous negative result with multiple electrophysiological configurations and FRET, single lab contradicting positive FRET/co-IP data from another lab (PMID 23255597); confidence reflects genuine controversy","pmids":["22291026"],"is_preprint":false},{"year":2010,"finding":"Abcc8 gene expression is upregulated after spinal cord injury in rodents and humans; elimination of SUR1 (Abcc8-/- mice) or antisense knockdown of Abcc8 prevents progressive hemorrhagic necrosis, reduces lesion size to one-quarter to one-third of controls, and improves neurological function; the protective effect is associated with prevention of oncotic death of capillary endothelial cells.","method":"Abcc8 knockout mice; antisense oligodeoxynucleotides in rats; histology; neurological scoring; immunohistochemistry for SUR1 in human and rodent SCI tissue","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO and antisense knockdown producing consistent results, human tissue validation, specific cellular mechanism (endothelial oncosis) identified","pmids":["20410530"],"is_preprint":false},{"year":2012,"finding":"Promoter CpG methylation differentially regulates SUR1 (Abcc8) and SUR2 (Abcc9) expression in cardiomyocytes; in HL-1 atrial cardiomyocytes, SUR2 promoter CpGs are 57.6% methylated versus 0.14% for SUR1, and 5-aza-2'-deoxycytidine treatment increases unmethylated SUR2 fraction and mRNA; SUR1 and SUR2 CpG islands are essentially unmethylated in native atrial and ventricular myocytes, indicating additional regulatory mechanisms exist.","method":"Bisulfite sequencing of genomic DNA; 5-aza-2'-deoxycytidine treatment; qRT-PCR for SUR1 and SUR2 mRNA in HL-1 cells and native myocytes","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bisulfite sequencing with pharmacological demethylation confirming functional consequence, single lab, two orthogonal approaches","pmids":["22844491"],"is_preprint":false}],"current_model":"ABCC8-encoded SUR1 is the regulatory subunit of the octameric KATP channel (4×SUR1 + 4×Kir6.2), where it physically associates with Kir6.2 via TMD0 and inter-subunit contacts (including SUR1-E203/Kir6.2-Q52) to modulate ATP sensitivity; SUR1 NBF1 binds ATP in a Mg2+-independent manner while NBF2 binds MgADP (and hydrolyzes ATP), and the resulting conformational changes in SUR1 activate the Kir6.2 pore, counterbalancing the inhibitory ATP-binding at Kir6.2 to dynamically couple cellular metabolic state to membrane excitability and insulin secretion; gain-of-function SUR1 mutations elevate basal Mg-nucleotide stimulation causing neonatal diabetes, while loss-of-function mutations abolish MgADP activation causing hyperinsulinism; beyond its KATP role, SUR1 is de novo transcriptionally upregulated after CNS injury (via sequential HIF1/Sp1 activation) and co-assembles with TRPM4 to form Sur1-TRPM4 non-selective cation channels that drive Na+ influx, cytotoxic edema, and brain/spinal cord swelling, and further co-assembles with AQP4 as a tripartite complex amplifying water influx into astrocytes."},"narrative":{"mechanistic_narrative":"ABCC8 encodes SUR1, the regulatory subunit of the pancreatic KATP channel, which couples cellular metabolic state to membrane excitability and insulin secretion by forming a direct physical complex with the Kir6.2 pore-forming subunit [PMID:9488482, PMID:29594720]. SUR1 senses adenine nucleotides at two nucleotide-binding folds: NBF1 binds ATP with high affinity in a Mg2+-independent manner, while NBF2 binds MgADP and exhibits ATP hydrolysis, with cooperative communication between the two domains [PMID:9287292, PMID:15893323]. Mg-nucleotide binding and hydrolysis at the SUR1 NBDs generate a stimulatory action that activates the Kir6.2 pore, counterbalancing the inhibitory ATP binding at Kir6.2 [PMID:9618560, PMID:20876358]. This activation depends on functional coupling between the subunits, mediated by SUR1 TMD0 and by specific inter-subunit contacts including SUR1-E203 with Kir6.2-Q52 and the Kir6.2 N-terminus, contacts that are also required for sulfonylurea and potassium-channel-opener pharmacology [PMID:10435998, PMID:16613899, PMID:22802363, PMID:29594720]. Disease mutations partition along this mechanism: activating ABCC8 mutations that elevate basal Mg-nucleotide stimulation cause neonatal diabetes and DEND syndrome, whereas loss-of-function mutations that impair MgADP/diazoxide responsiveness or surface trafficking cause hyperinsulinemic hypoglycemia [PMID:16885549, PMID:16613899, PMID:21199866, PMID:21536946]. Beyond the channel, SUR1-dependent KATP activity regulates beta-cell proliferation during islet development and is required for cAMP/incretin potentiation of insulin secretion [PMID:12453898, PMID:33404684]. In a distinct pathological program, SUR1 is transcriptionally upregulated de novo after CNS ischemia and injury through sequential HIF1α→Sp1 activation, and co-assembles with TRPM4 to form non-selective cation channels—and with AQP4 as a tripartite complex—that drive Na+ and water influx, cytotoxic edema, and tissue swelling [PMID:16550187, PMID:22086197, PMID:23255597, PMID:28906027, PMID:37279286].","teleology":[{"year":1997,"claim":"Established that SUR1 is a bona fide nucleotide sensor with two functionally distinct binding sites, defining the biochemical basis for how metabolic nucleotides act on the channel.","evidence":"Photoaffinity labeling with azido-ATP and Walker A/B mutagenesis of NBF1 and NBF2","pmids":["9287292"],"confidence":"High","gaps":["Did not establish how nucleotide binding translates into pore gating","Stoichiometry within the assembled channel not resolved"]},{"year":1998,"claim":"Demonstrated that SUR1 physically associates with Kir6.2 and that this association alters single-channel kinetics and trafficking, identifying the molecular partnership underlying the KATP channel.","evidence":"Reciprocal co-immunoprecipitation from in vitro translation and COS cells, confocal imaging, single-channel patch-clamp","pmids":["9488482"],"confidence":"High","gaps":["Subunit stoichiometry not defined","Structural interface unresolved"]},{"year":1998,"claim":"Showed that Mg-nucleotide stimulation requires intact SUR1 NBDs, separating the SUR1-mediated activating input from the Kir6.2-intrinsic inhibitory ATP site.","evidence":"Inside-out patch-clamp of reconstituted Kir6.2/SUR1 with NBD mutations and SUR1-free truncated Kir6.2","pmids":["9618560"],"confidence":"High","gaps":["Conformational mechanism linking NBD to pore not visualized"]},{"year":1999,"claim":"Defined the requirement for functional Kir6.2-SUR1 coupling for both drug action and MgADP stimulation, showing PIP2 and pore open-state stability gate the channel's responsiveness to SUR1.","evidence":"Inside-out patch-clamp with PIP2 and Kir6.2 open-state mutants (ΔN30, L164A) plus NBF2 ATPase comparison of SUR1 vs SUR2A","pmids":["10435998","15893323"],"confidence":"High","gaps":["Physical path of coupling between subunits not mapped","Isoform ATPase difference correlated but not structurally explained"]},{"year":2000,"claim":"Linked a hyperinsulinism mutation to disrupted NBF1-NBF2 cooperativity, providing the first mutation-level mechanism for loss of MgADP activation in disease.","evidence":"Domain-specific photolabeling with tryptic digestion plus patch-clamp of R1420C with ATP-insensitive Kir6.2-R50G","pmids":["10993895"],"confidence":"High","gaps":["Does not generalize to all hyperinsulinism mutations","In vivo beta-cell consequences inferred, not measured"]},{"year":2001,"claim":"Identified Kir6.2 residues R176/R177 as required for transmitting SUR1 regulatory input, localizing the coupling interface on the pore subunit.","evidence":"Inside-out patch-clamp of Kir6.2 point mutants co-expressed with SUR1","pmids":["11585851"],"confidence":"High","gaps":["Reciprocal SUR1 contact residues not yet identified","Structural proximity inferred functionally"]},{"year":2002,"claim":"Established SUR1 as required for cAMP/incretin potentiation of insulin secretion beyond its electrical role, and identified SUR1-selective pharmacology determinants in transmembrane domains 8-11.","evidence":"Pharmacology in Sur1 knockout islets; chimera and Walker A mutagenesis with radioligand binding for NNC 55-9216","pmids":["12453898","12031979"],"confidence":"High","gaps":["Molecular intermediary of cAMP sensing not yet identified","Drug binding pose not structurally resolved at this stage"]},{"year":2004,"claim":"Mapped extracellular SUR1 histidines as the basis for isoform-specific zinc activation, demonstrating SUR1-specific extracellular regulatory sites.","evidence":"Site-directed mutagenesis of His-326/His-332 with patch-clamp and SUR1/SUR2A comparison","pmids":["15613469"],"confidence":"High","gaps":["Physiological relevance of zinc gating not established"]},{"year":2006,"claim":"Defined the gain-of-function disease mechanism whereby activating SUR1 mutations elevate basal Mg-nucleotide stimulation, causing neonatal diabetes and DEND syndrome, and implicated TMD0 in setting Kir6.2 ATP sensitivity.","evidence":"Patch-clamp of mutant channels in intact cells/excised patches with ABCC8 sequencing of patients (incl. F132L TMD0)","pmids":["16885549","16613899"],"confidence":"High","gaps":["Full spectrum of mutation severity-to-phenotype not enumerated","Structural basis of TMD0 effect not yet resolved"]},{"year":2006,"claim":"Revealed a KATP-independent role for SUR1 by showing de novo SUR1 expression after ischemia forms non-selective cation channels driving edema, opening a CNS injury axis distinct from beta-cell biology.","evidence":"Western blot, in situ hybridization, electrophysiology and glibenclamide rescue in rodent stroke models","pmids":["16550187"],"confidence":"High","gaps":["Identity of the partner pore subunit not yet defined at this point","Transcriptional trigger only partially characterized"]},{"year":2008,"claim":"Extended the activating-mutation mechanism to an allosteric reduction of Kir6.2 ATP sensitivity independent of Mg2+, broadening the molecular spectrum of ABCC8 diabetes.","evidence":"Multiple patch-clamp configurations plus Ca2+ imaging of SUR1-Y356C in INS1 cells","pmids":["18346985"],"confidence":"High","gaps":["Structural path of TMD1-to-pore allostery not resolved"]},{"year":2010,"claim":"Isolated the SUR1 activating action using an inhibition-insensitive pore and showed both MgATP and MgADP act through SUR1 NBDs to drive identical high-Po gating, with hydrolysis-competent nucleotide required; in parallel established the spinal cord injury phenotype of Abcc8 loss.","evidence":"Inside-out patch-clamp of Kir6.2-G334D/SUR1 with NBD mutants and nucleotide analogues; Abcc8 KO and antisense in SCI models with human tissue","pmids":["20876358","20410530"],"confidence":"High","gaps":["Conformational coupling still inferred kinetically","Endothelial oncosis mechanism downstream of SUR1 channels not fully detailed"]},{"year":2011,"claim":"Defined the injury-induced transcriptional program (sequential HIF1α→Sp1) driving SUR1 upregulation and a disulfide-dependent trafficking requirement whose disruption causes hyperinsulinism, plus the functional distinction between diazoxide-responsive and -unresponsive dominant mutations.","evidence":"Reporter assays with promoter deletion and in vivo ChIP; cysteine mutagenesis/glycosylation/MG132 rescue; Rb+ efflux across 13 mutations in 15 families","pmids":["22086197","21199866","21536946"],"confidence":"High","gaps":["Upstream signals initiating HIF1α in injury not fully mapped","Why some trafficking-normal mutants lose only MgADP response not structurally explained"]},{"year":2012,"claim":"Identified TRPM4 as the SUR1 partner pore in CNS injury and resolved an inter-subunit contact (SUR1-E203/Kir6.2-Q52) governing ATP sensitivity, while a contradictory study failed to detect SUR1-TRPM4 association.","evidence":"FRET, co-IP, electrophysiology and calmodulin assay for SUR1-TRPM4 (positive); charge-swap and cysteine cross-linking for E203/Q52; contrasting negative FRET/electrophysiology in COSm6","pmids":["23255597","22802363","22291026"],"confidence":"High","gaps":["SUR1-TRPM4 association reported negative in one system (idx 30), reflecting genuine controversy in heterologous reconstitution","Stoichiometry of SUR1-TRPM4 heteromer undefined"]},{"year":2013,"claim":"Identified EPAC as a direct intracellular regulator binding SUR1 to close KATP channels, linking cAMP signaling to channel state and seizure vulnerability.","evidence":"Direct peptide binding (SUR1 859-881), patch-clamp, glutamate release and in vivo seizure model in EPAC KO mice","pmids":["23678128"],"confidence":"Medium","gaps":["Single lab; structural basis of EPAC-SUR1 interaction not resolved","Relationship to the incretin/cAMP secretion pathway not integrated"]},{"year":2016,"claim":"Showed Sur1-Trpm4 channels regulate inflammatory gene transcription (NOS2 via Ca2+/CaMKII/calcineurin/NFAT) in activated microglia, extending the injury channel into immune signaling.","evidence":"Electrophysiology, Ca2+ imaging, ChIP and Abcc8-/-/Trpm4-/- mice with pharmacology","pmids":["27246103"],"confidence":"High","gaps":["Whether this pathway operates in non-microglial cell types unclear"]},{"year":2017,"claim":"Defined the tripartite SUR1-TRPM4-AQP4 complex as a high-capacity water-transport unit, mechanistically linking the injury cation channel to astrocyte swelling.","evidence":"Co-IP, FRET, calcein swelling assay and in vivo genetic pore inactivation in a cold-injury edema model","pmids":["28906027"],"confidence":"High","gaps":["Stoichiometry and structure of the tripartite complex unresolved"]},{"year":2018,"claim":"Provided cryo-EM structures resolving the glibenclamide site, Kir6.2 N-terminus coupling, and Mg-nucleotide binding mode, structurally validating decades of functional inference about SUR1-pore coupling.","evidence":"Cryo-EM of pancreatic KATP channel at 4.1–4.5 Å in multiple states; NF-κB/tPA-PAR1 induction of SUR1-TRPM4 MMP-9 secretion in brain endothelium","pmids":["29594720","29617457"],"confidence":"High","gaps":["Structures of injury-related SUR1-TRPM4/AQP4 complexes not determined","Higher-resolution catalytic intermediates not captured"]},{"year":2019,"claim":"Dissected channel subunits genetically in vivo to show post-ischemic brain swelling is mediated by SUR1-TRPM4, not KATP channels, cleanly separating the two SUR1 functional programs.","evidence":"Subunit-specific antisense ODNs (Abcc8, Trpm4, Kcnj8, Kcnj11) with MRI swelling, immuno-FRET and co-IP in rat pMCAo","pmids":["31899311"],"confidence":"High","gaps":["Did not address mixed contributions in other injury contexts"]},{"year":2021,"claim":"Demonstrated using isogenic patient iPSC islets that SUR1-mediated KATP activity controls beta-cell proliferation during islet development, adding a developmental role to its secretory function.","evidence":"iPSC-derived SC-islets with CRISPR correction, secretion and proliferation assays, pharmacological KATP inactivation and xenografts","pmids":["33404684"],"confidence":"High","gaps":["Molecular link between channel activity and proliferation signaling not defined"]},{"year":2023,"claim":"Resolved the downstream effector chain by which astrocytic SUR1-TRPM4 drives edema: Na+ influx→reverse-mode NCX1 Ca2+ entry→calmodulin-dependent AQP4 surface translocation→water influx.","evidence":"Astrocyte-specific Abcc8 conditional KO, pharmacology, Ca2+ imaging and AQP4 surface assays in mouse pMCAo","pmids":["37279286"],"confidence":"High","gaps":["Quantitative contribution of this pathway vs other edema mechanisms not established"]},{"year":null,"claim":"How a single SUR1 protein is partitioned between KATP and SUR1-TRPM4/AQP4 assemblies, and the structural basis of the injury-induced complexes, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of SUR1-TRPM4 or the tripartite SUR1-TRPM4-AQP4 complex","Conflicting reconstitution data on SUR1-TRPM4 association (idx 18 vs idx 30) not reconciled structurally","Switch governing partner-subunit choice after injury unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,1,5,14]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,4,14,19]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[5,14]},{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[12,18,21]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,16,22]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[16]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,4,8]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[10,16,17]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[14,18,21]}],"complexes":["KATP channel (SUR1/Kir6.2)","SUR1-TRPM4 channel","SUR1-TRPM4-AQP4 tripartite complex"],"partners":["KCNJ11","TRPM4","AQP4","EPAC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q09428","full_name":"ATP-binding cassette sub-family C member 8","aliases":["Sulfonylurea receptor 1"],"length_aa":1581,"mass_kda":177.0,"function":"Regulator subunit of pancreatic ATP-sensitive potassium channel (KATP), playing a major role in the regulation of insulin release. In pancreatic cells, it forms KATP channels with KCNJ11; KCNJ11 forms the channel pore while ABCC8 is required for activation and regulation","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q09428/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ABCC8","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ABCC8","total_profiled":1310},"omim":[{"mim_id":"621196","title":"MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 12; MODY12","url":"https://www.omim.org/entry/621196"},{"mim_id":"618858","title":"DIABETES MELLITUS, PERMANENT NEONATAL, 4; PNDM4","url":"https://www.omim.org/entry/618858"},{"mim_id":"618857","title":"DIABETES MELLITUS, PERMANENT NEONATAL, 3; PNDM3","url":"https://www.omim.org/entry/618857"},{"mim_id":"618856","title":"DIABETES MELLITUS, PERMANENT NEONATAL, 2; PNDM2","url":"https://www.omim.org/entry/618856"},{"mim_id":"610582","title":"DIABETES MELLITUS, TRANSIENT NEONATAL, 3; TNDM3","url":"https://www.omim.org/entry/610582"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoli","reliability":"Approved"},{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":22.2},{"tissue":"pancreas","ntpm":13.3},{"tissue":"pituitary gland","ntpm":23.3}],"url":"https://www.proteinatlas.org/search/ABCC8"},"hgnc":{"alias_symbol":["HI","PHHI","SUR1","MRP8","ABC36","HHF1","TNDM2"],"prev_symbol":["SUR","HRINS"]},"alphafold":{"accession":"Q09428","domains":[{"cath_id":"-","chopping":"9-207","consensus_level":"high","plddt":88.623,"start":9,"end":207},{"cath_id":"1.20.1560.10","chopping":"270-617_997-1041_1060-1320","consensus_level":"medium","plddt":89.1511,"start":270,"end":1320},{"cath_id":"3.40.50.300","chopping":"678-742_768-793_811-927","consensus_level":"medium","plddt":84.6252,"start":678,"end":927},{"cath_id":"3.40.50.300","chopping":"1334-1581","consensus_level":"high","plddt":84.8938,"start":1334,"end":1581}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q09428","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q09428-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q09428-F1-predicted_aligned_error_v6.png","plddt_mean":82.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ABCC8","jax_strain_url":"https://www.jax.org/strain/search?query=ABCC8"},"sequence":{"accession":"Q09428","fasta_url":"https://rest.uniprot.org/uniprotkb/Q09428.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q09428/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q09428"}},"corpus_meta":[{"pmid":"16885549","id":"PMC_16885549","title":"Activating 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high affinity, while MgADP binds at NBF2 and antagonizes ATP binding at NBF1 through cooperative inter-domain communication; NBF1 Walker A/B mutations impaired ATP binding, NBF2 mutations reduced MgADP antagonism.\",\n      \"method\": \"Photoaffinity labeling with 8-azido-[α-32P]ATP and 8-azido-[γ-32P]ATP; site-directed mutagenesis of Walker A and B motifs in NBF1 and NBF2\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro biochemical assay with mutagenesis of specific residues, replicated across multiple mutant constructs in one rigorous study\",\n      \"pmids\": [\"9287292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"MgATP (like MgADP) stimulates KATP channel activity through interaction with the nucleotide-binding domains (NBDs) of SUR1; mutations abolishing MgATP binding/hydrolysis (D853N, D1505N, K719A, K1384M) in SUR1 NBDs eliminated the stimulatory effect of MgATP, while ATP sensitivity of truncated Kir6.2 expressed without SUR1 was unaffected by Mg2+.\",\n      \"method\": \"Inside-out patch-clamp recordings of reconstituted Kir6.2/SUR1 channels with NBD mutations in Xenopus oocytes\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — functional reconstitution with site-directed mutagenesis of SUR1 NBDs, multiple mutant constructs, rigorous controls including SUR1-free Kir6.2\",\n      \"pmids\": [\"9618560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"SUR1 and Kir6.2 form a direct physical complex, as demonstrated by co-immunoprecipitation from in vitro translated proteins and co-transfected COS cells; physical association alters cellular distribution (from honeycomb to diffuse pattern) and single-channel kinetic behavior (extended burst duration), and the distal C-terminus of Kir6.2 is not required for subunit association.\",\n      \"method\": \"Co-immunoprecipitation using Kir6.2-specific antibody from in vitro translated proteins and COS cell lysates; confocal microscopy; single-channel patch-clamp electrophysiology\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reciprocal co-IP from two systems (in vitro and cell-based), combined with functional electrophysiology and imaging, multiple orthogonal methods in one study\",\n      \"pmids\": [\"9488482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The SUR1 and Kir6.2 gene promoters are G+C rich with no TATA box; the SUR1 promoter is active in beta-cell lines (HIT T15, MIN6) and inactive in fibroblasts (COS7), with a short 173 bp fragment sufficient for maximal SUR1 promoter activity; Kir6.2 promoter requires >900 bp for high-level expression.\",\n      \"method\": \"Genomic library screening, luciferase reporter transient transfection assays, deletion analysis in multiple cell lines\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reporter assays with deletion mapping in multiple cell lines, single lab\",\n      \"pmids\": [\"9703328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Sulfonylurea high-affinity block and potassium channel opener (PCO)/MgADP stimulation of KATP channels require functional coupling between Kir6.2 and SUR1; PIP2 stabilizes the channel open state and abolishes high-affinity tolbutamide sensitivity by driving the channel away from closed states preferentially affected by tolbutamide; mutations in Kir6.2 (ΔN30 or L164A) that increase open-state stability similarly uncouple the channel from SUR1 regulatory input.\",\n      \"method\": \"Inside-out patch-clamp recordings with PIP2 application and Kir6.2 point mutations (ΔN30, L164A, R176A) co-expressed with SUR1 in Xenopus oocytes\",\n      \"journal\": \"The Journal of general physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — functional reconstitution with multiple Kir6.2 mutants and pharmacological tools, defining SUR1-Kir6.2 coupling mechanism with rigorous controls\",\n      \"pmids\": [\"10435998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"SUR1 NBF1 binds ATP strongly even without Mg2+, while NBF2 binds ADP; NBF2 of SUR1 exhibits greater in vitro ATP hydrolysis than NBF2 of SUR2A, which may underlie the greater MgADP stimulation of SUR1-containing KATP channels versus SUR2A-containing channels.\",\n      \"method\": \"In vitro ATP hydrolysis assay with affinity-purified NBF2 constructs; electrophysiology comparison of Kir6.2/SUR1 versus Kir6.2/SUR2A channels with PIP2\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical ATPase assay plus functional electrophysiology, single lab, two orthogonal approaches\",\n      \"pmids\": [\"15893323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The PHHI missense mutation R1420C in SUR1 NBF2 reduces MgATP and MgADP affinity at NBF2 ~5-fold and abolishes cooperative nucleotide binding between NBF1 and NBF2; it increases the EC50 for MgADP activation from 74 to 197 μM when assessed with ATP-insensitive Kir6.2-R50G, while channel expression is reduced but ATP inhibition, tolbutamide block, and diazoxide activation are unaffected.\",\n      \"method\": \"Photoaffinity labeling with mild tryptic digestion to distinguish NBF1/NBF2; inside-out patch-clamp of reconstituted channels in Xenopus oocytes\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — domain-specific photolabeling combined with electrophysiology and mutagenesis, multiple orthogonal readouts in one rigorous study\",\n      \"pmids\": [\"10993895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Positively charged residues R176 and R177 in Kir6.2 are required for functional coupling to SUR1, conferring MgADP stimulation and sulfonylurea sensitivity; R176C and R177C mutants are not reactivated by MgADP after ATP inhibition and are insensitive to glyburide, whereas R301C and R314C mutants retain MgADP and glyburide sensitivity.\",\n      \"method\": \"Inside-out patch-clamp recordings of Kir6.2 point mutants (R176C, R177C, R301C, R314C) co-expressed with SUR1 in Xenopus oocytes\",\n      \"journal\": \"The Journal of general physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — functional reconstitution with site-directed mutagenesis identifying specific residues for SUR1-Kir6.2 coupling, multiple mutants with rigorous controls\",\n      \"pmids\": [\"11585851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Loss of SUR1 in Sur1 knockout mice impairs PKA-independent cAMP potentiation of insulin secretion by incretins (GLP-1, GIP), establishing that SUR1 is required for the cAMP-sensing mechanism downstream of incretin receptors in pancreatic beta-cells; this effect is specific, as other modulators (mastoparan, PKC activators) remain functional in Sur1KO islets.\",\n      \"method\": \"Pharmacological experiments in isolated islets from Sur1 knockout mice; cAMP measurement; PKA inhibitor treatment (H-89, KT5720); insulin secretion assays\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic KO with specific pharmacological rescue/block experiments, multiple modulators tested, replicated across multiple incretin agonists\",\n      \"pmids\": [\"12453898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Zinc activates KATP channels through binding to two SUR1-specific extracellular histidine residues, His-326 and His-332; site-directed mutagenesis of these residues individually and in combination (H326A/H332A) abolished zinc-induced activation, while SUR2A-containing channels showed inhibition by zinc, demonstrating SUR1 isoform specificity.\",\n      \"method\": \"Inside-out and whole-cell patch-clamp with site-directed mutagenesis of SUR1 histidine residues in insulinoma cells and transfected cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — site-directed mutagenesis with multiple single and double mutants, isoform comparison (SUR1 vs SUR2A), multiple electrophysiological approaches\",\n      \"pmids\": [\"15613469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Activating missense mutations in ABCC8 (encoding SUR1) cause neonatal diabetes by elevating the basal Mg-nucleotide-dependent stimulatory action of SUR1 on the Kir6.2 pore, resulting in markedly higher channel open probability (Po) at physiologic MgATP concentrations in intact cells; mutant channels retain sulfonylurea sensitivity.\",\n      \"method\": \"Electrophysiological assay of mutant KATP channels expressed in intact cells and excised patches; ABCC8 sequencing in 34 neonatal diabetes patients\",\n      \"journal\": \"The New England journal of medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — functional electrophysiology of multiple mutant channels under physiological conditions, genotype-phenotype correlation across 9 patients with 7 mutations, replicated across multiple mutations\",\n      \"pmids\": [\"16885549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"A heterozygous de novo F132L mutation in SUR1 TMD0 (first set of transmembrane helices), proposed to interact with Kir6.2, markedly reduces KATP channel sensitivity to MgATP inhibition and increases whole-cell KATP current, causing DEND syndrome; this establishes TMD0 of SUR1 as a region affecting Kir6.2 ATP sensitivity.\",\n      \"method\": \"ABCC8 sequencing; whole-cell and inside-out patch-clamp electrophysiology of recombinant F132L channels in Xenopus oocytes\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — functional reconstitution with specific mutation, electrophysiology in multiple configurations (whole-cell and excised patch), evolutionary conservation analysis\",\n      \"pmids\": [\"16613899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SUR1 protein and mRNA are newly expressed (de novo) after ischemia in neurons, astrocytes, and capillaries in rodent stroke models; upregulation is linked to activation of transcription factor Sp1; newly expressed SUR1 forms functional NC(Ca-ATP) (non-selective cation) channels rather than KATP channels, and block with glibenclamide reduces cerebral edema and infarct volume by ~50%.\",\n      \"method\": \"Western blot, in situ hybridization, immunofluorescence, electrophysiology in rodent stroke models; pharmacological block with glibenclamide\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (protein, mRNA, functional channel recording, pharmacological rescue), replicated in multiple rodent stroke models\",\n      \"pmids\": [\"16550187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"An activating Y356C mutation in SUR1 transmembrane helix 7 (TMD1) reduces KATP channel sensitivity to MgATP inhibition via an allosteric effect on Kir6.2 (IC50 increased from 24 to 95 μM, even in absence of Mg2+), impairs glucose-induced cell depolarization and Ca2+ responses in INS1 cells, and causes adult-onset diabetes.\",\n      \"method\": \"Inside-out patch-clamp recordings; perforated whole-cell patch recordings; confocal microscopy; Ca2+ imaging with Fura-Red in INS1(832/13) cells overexpressing SUR1-Y356C\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple electrophysiological configurations plus Ca2+ imaging and confocal microscopy, defining allosteric mechanism, single lab with orthogonal methods\",\n      \"pmids\": [\"18346985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"KATP channel activation by MgADP and MgATP operates through SUR1 NBDs; using Kir6.2-G334D (ATP-inhibition-insensitive) channels, MgATP and MgADP activated channels with EC50 of 112 and 8 μM respectively; activation was suppressed by Walker A lysine mutations in either NBD of SUR1; MgATPγS activated channels; AMPPCP did not activate; both nucleotides produced identical single-channel kinetic effects (elevated Po>0.8, increased open time, reduced interburst closures).\",\n      \"method\": \"Inside-out patch-clamp of Kir6.2-G334D/SUR1 channels with NBD Walker A mutations in Xenopus oocytes\",\n      \"journal\": \"The Journal of general physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — functional reconstitution with inhibition-insensitive pore mutation to isolate SUR1 activation, multiple nucleotide analogues, NBD mutagenesis, single-channel kinetic analysis\",\n      \"pmids\": [\"20876358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Hypoxia stimulates transcription of Abcc8 (SUR1) sequentially through HIF1α binding to HIF-binding sites on the Sp1 promoter, which then drives Sp1 expression; Sp1 in turn binds to the Abcc8 promoter to stimulate SUR1 transcription. HIF-binding sites on the Abcc8 promoter itself are not required; chromatin immunoprecipitation confirmed HIF binding to the Sp1 promoter after cerebral ischemia in vivo.\",\n      \"method\": \"Luciferase reporter assays with promoter deletions; chromatin immunoprecipitation (ChIP) in ischemic rat brain; co-expression of HIF1α; brain microvascular endothelial cell culture\",\n      \"journal\": \"Journal of cerebral blood flow and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reporter assays with deletion mapping, in vivo ChIP validation, multiple promoter species tested, consistent mechanism across in vitro and in vivo systems\",\n      \"pmids\": [\"22086197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A conserved intramolecular disulfide bond formed between two N-terminal cysteines in SUR1 (ABCC8) is critical for ER exit and cell surface trafficking; a disease-causing mutation in a conserved N-terminal cysteine of SUR1 prevents the protein from reaching the cell surface, causing hyperinsulinemic hypoglycemia.\",\n      \"method\": \"Mutagenesis of conserved cysteines; glycosylation analysis; immunoblot; proteasome inhibitor MG132 rescue experiments in multiple cell types\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical reconstitution with mutagenesis, glycosylation analysis, proteasome inhibitor rescue, linking mechanism to human disease mutation\",\n      \"pmids\": [\"21199866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Dominant loss-of-function ABCC8 mutations causing diazoxide-unresponsive diffuse hyperinsulinism produce SUR1 channels with normal plasma membrane trafficking but severely impaired responses to diazoxide or MgADP, contrasting with dominant mutations causing diazoxide-responsive disease; the degree of impairment of diazoxide/MgADP response distinguishes diazoxide-responsive from diazoxide-unresponsive dominant mutations.\",\n      \"method\": \"Expression in COSm6 cells; Rb+ efflux assay; ABCC8 sequencing in 15 families\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional expression with Rb+ flux assay across 13 different mutations in two phenotypic groups, defining mechanistic basis for differential drug response\",\n      \"pmids\": [\"21536946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SUR1 co-assembles with TRPM4 (transient receptor potential melastatin 4) to form Sur1-TRPM4 heteromers that constitute the NC(Ca-ATP) non-selective cation channel in CNS injury; co-expression yields channels with biophysical properties of TRPM4 and pharmacological properties of SUR1; co-assembly with SUR1 doubles TRPM4 affinity for calmodulin and doubles its Ca2+ sensitivity; Sur1-TRPM4 heteromers appear de novo after spinal cord injury.\",\n      \"method\": \"FRET (Förster resonance energy transfer); co-immunoprecipitation; patch-clamp electrophysiology; calmodulin binding assay; rat spinal cord injury model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (FRET, co-IP, electrophysiology, calmodulin assay), functional characterization of heteromeric channel, replicated in vivo after SCI\",\n      \"pmids\": [\"23255597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"E203 in SUR1 and Q52 in Kir6.2 are in close proximity and their interaction dynamically regulates KATP channel ATP sensitivity; E203K/Q52E double mutant channels exhibit ~100-fold higher ATP sensitivity than wild-type; cross-linking of E203C and Q52C locks the channel in a closed state reversible by reducing agents.\",\n      \"method\": \"Site-directed mutagenesis (E203K in SUR1, Q52E in Kir6.2); cysteine cross-linking with oxidizing/reducing agents; inside-out patch-clamp in Xenopus oocytes\",\n      \"journal\": \"The Journal of general physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — charge-swap mutagenesis combined with cysteine cross-linking providing direct structural evidence for inter-subunit proximity, multiple orthogonal approaches\",\n      \"pmids\": [\"22802363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"EPAC (Exchange Protein Activated by cAMP) binds directly to an intracellular loop of SUR1 (amino acids 859-881); this binding closes KATP channels; ablation of EPAC or expression of the competing SUR1(859-881) peptide increases KATP channel open probability, inhibits glutamate release, and reduces seizure vulnerability in mice.\",\n      \"method\": \"Direct binding assay (EPAC to SUR1(859-881) peptide); patch-clamp electrophysiology; glutamate release assay; in vivo seizure model in adult mice with EPAC knockout\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay combined with electrophysiology and in vivo seizure model, single lab, two orthogonal functional readouts\",\n      \"pmids\": [\"23678128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SUR1-TRPM4 co-assembles with AQP4 to form a heteromultimeric water/ion channel complex (SUR1-TRPM4-AQP4); the full tripartite complex is required for fast, high-capacity transmembrane water transport driving cell swelling; co-assembly confirmed by co-IP and FRET; genetic inactivation of the SUR1-TRPM4 solute pore blocked in vivo astrocyte swelling in a brain edema model.\",\n      \"method\": \"Co-immunoprecipitation; FRET; calcein fluorescence cell-swelling assay in COS-7 cells; diolistic labeling for in vivo astrocyte volume measurement; cold-injury mouse brain edema model\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (co-IP, FRET, functional swelling assay, in vivo genetic deletion), confirmed in both heterologous cells and primary astrocytes and in vivo\",\n      \"pmids\": [\"28906027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cryo-EM structures of pancreatic KATP channels reveal the glibenclamide binding site on SUR1, show how the Kir6.2 N-terminus couples the peripheral SUR1 subunit to the central Kir6.2 pore, reveal the binding mode of activating Mg-nucleotides at SUR1 NBDs, and suggest the mechanism by which Mg-ADP binding drives conformational change of SUR1.\",\n      \"method\": \"Cryo-electron microscopy at 4.1–4.5 Å resolution\",\n      \"journal\": \"Protein & cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structural determination with three distinct channel states, directly resolving drug binding site and subunit coupling mechanism\",\n      \"pmids\": [\"29594720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NF-κB activation of brain endothelial cells (BEC) causes de novo expression of SUR1-TRPM4 channels; tPA induces PAR1-mediated opening of SUR1-TRPM4 channels in a plasmin-, TRPC3-, and Ca2+-dependent manner; functional SUR1-TRPM4 channels are required for tPA-induced phasic (but not tonic) secretion of MMP-9 from BEC; SUR1 inhibition decreases tPA-induced MMP-9 secretion.\",\n      \"method\": \"Patch-clamp electrophysiology; ELISA and zymography for MMP-9; calcium imaging; genetic and pharmacological manipulation of SUR1, TRPM4, PAR1, TRPC3; NF-κB activation in murine and human BEC\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (electrophysiology, secretion assay, Ca2+ imaging, genetic KO, pharmacology), defined signaling pathway with functional consequence in BEC\",\n      \"pmids\": [\"29617457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SUR1-TRPM4 channels (not KATP channels) mediate post-ischemic brain swelling; antisense oligodeoxynucleotides against Abcc8/SUR1 or Trpm4/TRPM4 each reduced hemispheric swelling by ~50% in rat permanent MCA occlusion, whereas AS-ODNs against Kcnj8/KIR6.1 or Kcnj11/KIR6.2 had no significant effect on swelling; SUR1-TRPM4 heteromers were confirmed by immuno-FRET and co-IP in post-ischemic tissue.\",\n      \"method\": \"Antisense oligodeoxynucleotides (molecularly targeted knockdown); MRI-based hemispheric swelling measurement; immuno-FRET; co-immunoprecipitation in rat pMCAo model\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — molecularly specific ODN knockdown of four distinct channel subunits with direct comparison, FRET and co-IP for complex formation, clear epistatic dissection of SUR1-TRPM4 vs KATP\",\n      \"pmids\": [\"31899311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of SUR1 function in iPSC-derived islets (homozygous ABCC8-V187D) causes excess insulin secretion at low glucose, beta-cell proliferation, and nucleomegaly; pharmacological KATP channel inactivation in corrected cells recapitulates the proliferation phenotype, establishing that SUR1-mediated KATP channel activity regulates beta-cell proliferation during islet development.\",\n      \"method\": \"iPSC differentiation to SC-islets; CRISPR-Cas9 correction; static and dynamic insulin secretion assays; BrdU proliferation assay; pharmacological KATP inactivation; xenograft in NOD-SCID gamma mice\",\n      \"journal\": \"Diabetologia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — isogenic patient-derived iPSC model with CRISPR correction, multiple functional readouts in vitro and in vivo, pharmacological rescue confirming mechanism\",\n      \"pmids\": [\"33404684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In ischemic stroke, SUR1-TRPM4 channels in perivascular astrocyte endfeet mediate Na+ influx that drives Ca2+ entry via NCX1 operating in reverse mode; elevated intra-endfoot Ca2+ triggers calmodulin-dependent AQP4 translocation to the plasma membrane, causing water influx and brain swelling; pharmacological inhibition or astrocyte-specific deletion of SUR1-TRPM4 or NCX1 reduced brain swelling and improved neurological function independently of infarct size.\",\n      \"method\": \"Mouse permanent MCA occlusion; astrocyte-specific Abcc8 conditional knockout (pGfap-cre); pharmacological inhibition; Ca2+ imaging; AQP4 surface localization assay; neurological function scoring\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional KO plus pharmacological inhibition, mechanistic pathway defined through Ca2+ imaging and AQP4 trafficking, multiple orthogonal interventions with consistent results\",\n      \"pmids\": [\"37279286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Sur1-Trpm4 channels regulate NOS2 transcription in TLR4-activated microglia through a Ca2+-sensitive calcineurin/NFAT pathway; inhibition or gene silencing of Sur1 or Trpm4 paradoxically increases intracellular Ca2+ (by removing Na+ influx-driven Ca2+ suppression), yet decreases NFAT nuclear translocation via activation of CaMKII and calcineurin phosphorylation; chromatin immunoprecipitation confirmed NFAT binding to the Nos2 promoter.\",\n      \"method\": \"Patch-clamp electrophysiology; calcium imaging; qPCR; Griess assay; immunoblot; chromatin immunoprecipitation; Abcc8-/- and Trpm4-/- mice; pharmacological inhibition in vivo and in vitro\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (electrophysiology, Ca2+ imaging, ChIP, genetic KO of both subunits, pharmacology), defined Ca2+/CaMKII/CN/NFAT signaling pathway\",\n      \"pmids\": [\"27246103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Novel SUR1-selective KATP channel opener NNC 55-9216 activates Kir6.2/SUR1 but not Kir6.2/SUR2A or Kir6.2/SUR2B channels; activation requires intracellular MgATP and Walker A motif integrity in both NBDs of SUR1; chimera analysis identified transmembrane domains 8-11 of SUR1 as critical structural determinants for NNC 55-9216 action, with NBD2 providing additional contribution.\",\n      \"method\": \"Inside-out patch-clamp in Xenopus oocytes; SUR1/SUR2A chimeras; Walker A mutagenesis; [3H]glibenclamide competitive binding\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — chimeric receptor analysis combined with mutagenesis and radioligand binding, identifying structural determinants of selective drug activation\",\n      \"pmids\": [\"12031979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Glibenclamide-induced apoptosis is specifically enhanced by expression of SUR1 but not SUR2B; a single amino acid substitution M1289T in transmembrane helix 17 (TM17) of SUR1 abolishes the apoptotic enhancement; coexpression with Kir6.2 does not alter the apoptotic effect, indicating a Kir6.2/KATP channel-independent pro-apoptotic function of SUR1.\",\n      \"method\": \"Cell detachment, nuclear condensation, DNA fragmentation, caspase-3-like activity assays in HEK293 cells expressing SUR1, SUR2B, SUR1(M1289T), or SUR1+Kir6.2\",\n      \"journal\": \"The Journal of pharmacology and experimental therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — four apoptotic readouts in isogenic cell lines with isoform comparison and point mutant, single lab\",\n      \"pmids\": [\"16306272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TRPM4 currents expressed alone or with SUR1 in COSm6 cells are Ca2+-activated, voltage-dependent, ATP-inhibited, and insensitive to glibenclamide and tolbutamide; cotransfection of SUR1 did not alter TRPM4-mediated current properties; no detectable FRET was observed between fluorophore-tagged TRPM4 and SUR1, whereas robust FRET was detected between Kir6.2 and SUR1. This constitutes a negative finding: functional or structural association of TRPM4 and SUR1 was not detected in this experimental system.\",\n      \"method\": \"Patch-clamp electrophysiology; FRET in COSm6 cells co-expressing TRPM4 with or without SUR1 and/or Kir6.2\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — rigorous negative result with multiple electrophysiological configurations and FRET, single lab contradicting positive FRET/co-IP data from another lab (PMID 23255597); confidence reflects genuine controversy\",\n      \"pmids\": [\"22291026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Abcc8 gene expression is upregulated after spinal cord injury in rodents and humans; elimination of SUR1 (Abcc8-/- mice) or antisense knockdown of Abcc8 prevents progressive hemorrhagic necrosis, reduces lesion size to one-quarter to one-third of controls, and improves neurological function; the protective effect is associated with prevention of oncotic death of capillary endothelial cells.\",\n      \"method\": \"Abcc8 knockout mice; antisense oligodeoxynucleotides in rats; histology; neurological scoring; immunohistochemistry for SUR1 in human and rodent SCI tissue\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO and antisense knockdown producing consistent results, human tissue validation, specific cellular mechanism (endothelial oncosis) identified\",\n      \"pmids\": [\"20410530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Promoter CpG methylation differentially regulates SUR1 (Abcc8) and SUR2 (Abcc9) expression in cardiomyocytes; in HL-1 atrial cardiomyocytes, SUR2 promoter CpGs are 57.6% methylated versus 0.14% for SUR1, and 5-aza-2'-deoxycytidine treatment increases unmethylated SUR2 fraction and mRNA; SUR1 and SUR2 CpG islands are essentially unmethylated in native atrial and ventricular myocytes, indicating additional regulatory mechanisms exist.\",\n      \"method\": \"Bisulfite sequencing of genomic DNA; 5-aza-2'-deoxycytidine treatment; qRT-PCR for SUR1 and SUR2 mRNA in HL-1 cells and native myocytes\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bisulfite sequencing with pharmacological demethylation confirming functional consequence, single lab, two orthogonal approaches\",\n      \"pmids\": [\"22844491\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ABCC8-encoded SUR1 is the regulatory subunit of the octameric KATP channel (4×SUR1 + 4×Kir6.2), where it physically associates with Kir6.2 via TMD0 and inter-subunit contacts (including SUR1-E203/Kir6.2-Q52) to modulate ATP sensitivity; SUR1 NBF1 binds ATP in a Mg2+-independent manner while NBF2 binds MgADP (and hydrolyzes ATP), and the resulting conformational changes in SUR1 activate the Kir6.2 pore, counterbalancing the inhibitory ATP-binding at Kir6.2 to dynamically couple cellular metabolic state to membrane excitability and insulin secretion; gain-of-function SUR1 mutations elevate basal Mg-nucleotide stimulation causing neonatal diabetes, while loss-of-function mutations abolish MgADP activation causing hyperinsulinism; beyond its KATP role, SUR1 is de novo transcriptionally upregulated after CNS injury (via sequential HIF1/Sp1 activation) and co-assembles with TRPM4 to form Sur1-TRPM4 non-selective cation channels that drive Na+ influx, cytotoxic edema, and brain/spinal cord swelling, and further co-assembles with AQP4 as a tripartite complex amplifying water influx into astrocytes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ABCC8 encodes SUR1, the regulatory subunit of the pancreatic KATP channel, which couples cellular metabolic state to membrane excitability and insulin secretion by forming a direct physical complex with the Kir6.2 pore-forming subunit [#2, #22]. SUR1 senses adenine nucleotides at two nucleotide-binding folds: NBF1 binds ATP with high affinity in a Mg2+-independent manner, while NBF2 binds MgADP and exhibits ATP hydrolysis, with cooperative communication between the two domains [#0, #5]. Mg-nucleotide binding and hydrolysis at the SUR1 NBDs generate a stimulatory action that activates the Kir6.2 pore, counterbalancing the inhibitory ATP binding at Kir6.2 [#1, #14]. This activation depends on functional coupling between the subunits, mediated by SUR1 TMD0 and by specific inter-subunit contacts including SUR1-E203 with Kir6.2-Q52 and the Kir6.2 N-terminus, contacts that are also required for sulfonylurea and potassium-channel-opener pharmacology [#4, #11, #19, #22]. Disease mutations partition along this mechanism: activating ABCC8 mutations that elevate basal Mg-nucleotide stimulation cause neonatal diabetes and DEND syndrome, whereas loss-of-function mutations that impair MgADP/diazoxide responsiveness or surface trafficking cause hyperinsulinemic hypoglycemia [#10, #11, #16, #17]. Beyond the channel, SUR1-dependent KATP activity regulates beta-cell proliferation during islet development and is required for cAMP/incretin potentiation of insulin secretion [#8, #25]. In a distinct pathological program, SUR1 is transcriptionally upregulated de novo after CNS ischemia and injury through sequential HIF1\\u03b1\\u2192Sp1 activation, and co-assembles with TRPM4 to form non-selective cation channels\\u2014and with AQP4 as a tripartite complex\\u2014that drive Na+ and water influx, cytotoxic edema, and tissue swelling [#12, #15, #18, #21, #26].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established that SUR1 is a bona fide nucleotide sensor with two functionally distinct binding sites, defining the biochemical basis for how metabolic nucleotides act on the channel.\",\n      \"evidence\": \"Photoaffinity labeling with azido-ATP and Walker A/B mutagenesis of NBF1 and NBF2\",\n      \"pmids\": [\"9287292\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish how nucleotide binding translates into pore gating\", \"Stoichiometry within the assembled channel not resolved\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstrated that SUR1 physically associates with Kir6.2 and that this association alters single-channel kinetics and trafficking, identifying the molecular partnership underlying the KATP channel.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation from in vitro translation and COS cells, confocal imaging, single-channel patch-clamp\",\n      \"pmids\": [\"9488482\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Subunit stoichiometry not defined\", \"Structural interface unresolved\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Showed that Mg-nucleotide stimulation requires intact SUR1 NBDs, separating the SUR1-mediated activating input from the Kir6.2-intrinsic inhibitory ATP site.\",\n      \"evidence\": \"Inside-out patch-clamp of reconstituted Kir6.2/SUR1 with NBD mutations and SUR1-free truncated Kir6.2\",\n      \"pmids\": [\"9618560\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational mechanism linking NBD to pore not visualized\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Defined the requirement for functional Kir6.2-SUR1 coupling for both drug action and MgADP stimulation, showing PIP2 and pore open-state stability gate the channel's responsiveness to SUR1.\",\n      \"evidence\": \"Inside-out patch-clamp with PIP2 and Kir6.2 open-state mutants (\\u0394N30, L164A) plus NBF2 ATPase comparison of SUR1 vs SUR2A\",\n      \"pmids\": [\"10435998\", \"15893323\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physical path of coupling between subunits not mapped\", \"Isoform ATPase difference correlated but not structurally explained\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Linked a hyperinsulinism mutation to disrupted NBF1-NBF2 cooperativity, providing the first mutation-level mechanism for loss of MgADP activation in disease.\",\n      \"evidence\": \"Domain-specific photolabeling with tryptic digestion plus patch-clamp of R1420C with ATP-insensitive Kir6.2-R50G\",\n      \"pmids\": [\"10993895\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not generalize to all hyperinsulinism mutations\", \"In vivo beta-cell consequences inferred, not measured\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identified Kir6.2 residues R176/R177 as required for transmitting SUR1 regulatory input, localizing the coupling interface on the pore subunit.\",\n      \"evidence\": \"Inside-out patch-clamp of Kir6.2 point mutants co-expressed with SUR1\",\n      \"pmids\": [\"11585851\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reciprocal SUR1 contact residues not yet identified\", \"Structural proximity inferred functionally\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Established SUR1 as required for cAMP/incretin potentiation of insulin secretion beyond its electrical role, and identified SUR1-selective pharmacology determinants in transmembrane domains 8-11.\",\n      \"evidence\": \"Pharmacology in Sur1 knockout islets; chimera and Walker A mutagenesis with radioligand binding for NNC 55-9216\",\n      \"pmids\": [\"12453898\", \"12031979\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular intermediary of cAMP sensing not yet identified\", \"Drug binding pose not structurally resolved at this stage\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Mapped extracellular SUR1 histidines as the basis for isoform-specific zinc activation, demonstrating SUR1-specific extracellular regulatory sites.\",\n      \"evidence\": \"Site-directed mutagenesis of His-326/His-332 with patch-clamp and SUR1/SUR2A comparison\",\n      \"pmids\": [\"15613469\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance of zinc gating not established\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined the gain-of-function disease mechanism whereby activating SUR1 mutations elevate basal Mg-nucleotide stimulation, causing neonatal diabetes and DEND syndrome, and implicated TMD0 in setting Kir6.2 ATP sensitivity.\",\n      \"evidence\": \"Patch-clamp of mutant channels in intact cells/excised patches with ABCC8 sequencing of patients (incl. F132L TMD0)\",\n      \"pmids\": [\"16885549\", \"16613899\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full spectrum of mutation severity-to-phenotype not enumerated\", \"Structural basis of TMD0 effect not yet resolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Revealed a KATP-independent role for SUR1 by showing de novo SUR1 expression after ischemia forms non-selective cation channels driving edema, opening a CNS injury axis distinct from beta-cell biology.\",\n      \"evidence\": \"Western blot, in situ hybridization, electrophysiology and glibenclamide rescue in rodent stroke models\",\n      \"pmids\": [\"16550187\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the partner pore subunit not yet defined at this point\", \"Transcriptional trigger only partially characterized\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extended the activating-mutation mechanism to an allosteric reduction of Kir6.2 ATP sensitivity independent of Mg2+, broadening the molecular spectrum of ABCC8 diabetes.\",\n      \"evidence\": \"Multiple patch-clamp configurations plus Ca2+ imaging of SUR1-Y356C in INS1 cells\",\n      \"pmids\": [\"18346985\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural path of TMD1-to-pore allostery not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Isolated the SUR1 activating action using an inhibition-insensitive pore and showed both MgATP and MgADP act through SUR1 NBDs to drive identical high-Po gating, with hydrolysis-competent nucleotide required; in parallel established the spinal cord injury phenotype of Abcc8 loss.\",\n      \"evidence\": \"Inside-out patch-clamp of Kir6.2-G334D/SUR1 with NBD mutants and nucleotide analogues; Abcc8 KO and antisense in SCI models with human tissue\",\n      \"pmids\": [\"20876358\", \"20410530\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational coupling still inferred kinetically\", \"Endothelial oncosis mechanism downstream of SUR1 channels not fully detailed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined the injury-induced transcriptional program (sequential HIF1\\u03b1\\u2192Sp1) driving SUR1 upregulation and a disulfide-dependent trafficking requirement whose disruption causes hyperinsulinism, plus the functional distinction between diazoxide-responsive and -unresponsive dominant mutations.\",\n      \"evidence\": \"Reporter assays with promoter deletion and in vivo ChIP; cysteine mutagenesis/glycosylation/MG132 rescue; Rb+ efflux across 13 mutations in 15 families\",\n      \"pmids\": [\"22086197\", \"21199866\", \"21536946\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals initiating HIF1\\u03b1 in injury not fully mapped\", \"Why some trafficking-normal mutants lose only MgADP response not structurally explained\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified TRPM4 as the SUR1 partner pore in CNS injury and resolved an inter-subunit contact (SUR1-E203/Kir6.2-Q52) governing ATP sensitivity, while a contradictory study failed to detect SUR1-TRPM4 association.\",\n      \"evidence\": \"FRET, co-IP, electrophysiology and calmodulin assay for SUR1-TRPM4 (positive); charge-swap and cysteine cross-linking for E203/Q52; contrasting negative FRET/electrophysiology in COSm6\",\n      \"pmids\": [\"23255597\", \"22802363\", \"22291026\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SUR1-TRPM4 association reported negative in one system (idx 30), reflecting genuine controversy in heterologous reconstitution\", \"Stoichiometry of SUR1-TRPM4 heteromer undefined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified EPAC as a direct intracellular regulator binding SUR1 to close KATP channels, linking cAMP signaling to channel state and seizure vulnerability.\",\n      \"evidence\": \"Direct peptide binding (SUR1 859-881), patch-clamp, glutamate release and in vivo seizure model in EPAC KO mice\",\n      \"pmids\": [\"23678128\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; structural basis of EPAC-SUR1 interaction not resolved\", \"Relationship to the incretin/cAMP secretion pathway not integrated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed Sur1-Trpm4 channels regulate inflammatory gene transcription (NOS2 via Ca2+/CaMKII/calcineurin/NFAT) in activated microglia, extending the injury channel into immune signaling.\",\n      \"evidence\": \"Electrophysiology, Ca2+ imaging, ChIP and Abcc8-/-/Trpm4-/- mice with pharmacology\",\n      \"pmids\": [\"27246103\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this pathway operates in non-microglial cell types unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the tripartite SUR1-TRPM4-AQP4 complex as a high-capacity water-transport unit, mechanistically linking the injury cation channel to astrocyte swelling.\",\n      \"evidence\": \"Co-IP, FRET, calcein swelling assay and in vivo genetic pore inactivation in a cold-injury edema model\",\n      \"pmids\": [\"28906027\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structure of the tripartite complex unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided cryo-EM structures resolving the glibenclamide site, Kir6.2 N-terminus coupling, and Mg-nucleotide binding mode, structurally validating decades of functional inference about SUR1-pore coupling.\",\n      \"evidence\": \"Cryo-EM of pancreatic KATP channel at 4.1\\u20134.5 \\u00c5 in multiple states; NF-\\u03baB/tPA-PAR1 induction of SUR1-TRPM4 MMP-9 secretion in brain endothelium\",\n      \"pmids\": [\"29594720\", \"29617457\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structures of injury-related SUR1-TRPM4/AQP4 complexes not determined\", \"Higher-resolution catalytic intermediates not captured\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Dissected channel subunits genetically in vivo to show post-ischemic brain swelling is mediated by SUR1-TRPM4, not KATP channels, cleanly separating the two SUR1 functional programs.\",\n      \"evidence\": \"Subunit-specific antisense ODNs (Abcc8, Trpm4, Kcnj8, Kcnj11) with MRI swelling, immuno-FRET and co-IP in rat pMCAo\",\n      \"pmids\": [\"31899311\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address mixed contributions in other injury contexts\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated using isogenic patient iPSC islets that SUR1-mediated KATP activity controls beta-cell proliferation during islet development, adding a developmental role to its secretory function.\",\n      \"evidence\": \"iPSC-derived SC-islets with CRISPR correction, secretion and proliferation assays, pharmacological KATP inactivation and xenografts\",\n      \"pmids\": [\"33404684\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between channel activity and proliferation signaling not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved the downstream effector chain by which astrocytic SUR1-TRPM4 drives edema: Na+ influx\\u2192reverse-mode NCX1 Ca2+ entry\\u2192calmodulin-dependent AQP4 surface translocation\\u2192water influx.\",\n      \"evidence\": \"Astrocyte-specific Abcc8 conditional KO, pharmacology, Ca2+ imaging and AQP4 surface assays in mouse pMCAo\",\n      \"pmids\": [\"37279286\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of this pathway vs other edema mechanisms not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single SUR1 protein is partitioned between KATP and SUR1-TRPM4/AQP4 assemblies, and the structural basis of the injury-induced complexes, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of SUR1-TRPM4 or the tripartite SUR1-TRPM4-AQP4 complex\", \"Conflicting reconstitution data on SUR1-TRPM4 association (idx 18 vs idx 30) not reconciled structurally\", \"Switch governing partner-subunit choice after injury unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 1, 5, 14]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 4, 14, 19]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [5, 14]},\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [12, 18, 21]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 16, 22]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 4, 8]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 16, 17]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [14, 18, 21]}\n    ],\n    \"complexes\": [\n      \"KATP channel (SUR1/Kir6.2)\",\n      \"SUR1-TRPM4 channel\",\n      \"SUR1-TRPM4-AQP4 tripartite complex\"\n    ],\n    \"partners\": [\n      \"KCNJ11\",\n      \"TRPM4\",\n      \"AQP4\",\n      \"EPAC\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}