ABCC9 encodes sulfonylurea receptor 2 (SUR2), a multipass ABC-family protein that regulates ATP-sensitive potassium (KATP) channels. Four SUR subunits associate with four pore-forming Kir6 subunits; potassium crosses Kir6, while SUR2 binds nucleotides and drugs and couples these signals to channel gating. Its nucleotide-binding domains bind ATP/ADP and possess ATPase activity, but SUR2 is not an ATP-driven ion pump. The major C-terminal splice isoforms SUR2A (O60706-1) and SUR2B (O60706-2) differ in their final 42 amino acids and in nucleotide/drug responses. SUR2A commonly partners with Kir6.2 in cardiac and skeletal muscle, whereas SUR2B commonly partners with Kir6.1 in vascular smooth muscle. At the plasma membrane these channels couple metabolic state to potassium conductance, membrane excitability and muscle/vascular responses. Activating ABCC9 variants cause dominant CantΓΊ syndrome; biallelic loss-of-function variants cause an intellectual disability and myopathy syndrome. Short intra-exonic splice products have also been reported in mitochondria, a distinct context from the canonical surface-channel isoforms.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005242 inward rectifier potassium channel activity | IEA GO_REF:0000107 | ACCEPT | Summary: SUR2 contributes to inwardly rectifying potassium conductance in the assembled KATP channel. Reason: The mouse orthology inference agrees with reconstitution of human SUR2A/Kir6.2 channels, including weak inward rectification (PMID:9831708). Preserve contributes_to: Kir6 supplies the ion-conducting pore, whereas SUR2 supplies nucleotide and drug regulation. The parent channel term accommodates different SUR2/Kir6 combinations. Supporting Evidence: PMID:9831708 The single-channel conductance of approximately 80 pS measured at -40 mV in quasi-symmetrical approximately 150 mmol/L K+ solutions, the intraburst kinetics that were dependent on K+ driving force, and the weak inward rectification were indistinguishable for both channels. PMID:34711681 They are uniquely evolved hetero-octameric complexes comprising four pore-forming inwardly rectifying potassium channel subunits, Kir6.x, and four regulatory sulfonylurea receptors, SURx |
| GO:0005267 potassium channel activity | IBA GO_REF:0000033 | ACCEPT | Summary: Inherited contribution to potassium channel activity is a core SUR2 function. Reason: The PTN002795677 IBA is consistent with human SUR2A functional reconstitution and mutation-dependent changes in channel currents (PMID:9831708; PMID:24439875). The contributes_to assertion describes a regulatory subunit of a channel complex, not an independent potassium pore. Human O60706 among the descendant evidence is legitimate grounding for the ancestral inference, not circular support. Supporting Evidence: PMID:9831708 ATP- and glibenclamide-sensitive K+ channels were produced when both subunits were coexpressed PMID:24439875 Functional expression of the V734I variant yielded a Mg-ATP ICβ
β that was 5-fold that of wild-type (WT). |
| GO:0005267 potassium channel activity | IEA GO_REF:0000107 | ACCEPT | Summary: The ortholog-inferred channel contribution is supported directly in human SUR2A. Reason: Human SUR2A and Kir6.2 coexpression produces functional potassium channels; either subunit alone did not produce the same channel phenotype (PMID:9831708). The contributes_to flag correctly limits this assertion to complex-level conductance. Supporting Evidence: PMID:9831708 ATP- and glibenclamide-sensitive K+ channels were produced when both subunits were coexpressed |
| GO:0005267 potassium channel activity | IMP PMID:24439875 ABCC9 is a novel Brugada and early repolarization syndrome s... | ACCEPT | Summary: Human ABCC9 variants alter the activity of reconstituted potassium channels. Reason: PMID:24439875 measures currents from wild-type and variant ABCC9-containing channels in TSA201 cells. These functional data support the contributes_to annotation independently of the strength of the proposed Brugada/early-repolarization disease association. SUR2 alters gating rather than forming the pore. Supporting Evidence: PMID:24439875 Functional expression of the V734I variant yielded a Mg-ATP ICβ
β that was 5-fold that of wild-type (WT). |
| GO:0005267 potassium channel activity | IMP PMID:26181369 Molecular determinants of ATP-sensitive potassium channel Mg... | ACCEPT | Summary: Human SUR2A contributes to potassium-channel gating in comparative SUR1/SUR2A experiments. Reason: The full Methods of PMID:26181369 explicitly uses human SUR1 and SUR2A constructs. Its patch-clamp experiments test SUR2A-dependent nucleotide and diazoxide responses. The paper is not restricted to the SUR1 diabetes variants foregrounded in its title. The contributes_to annotation is appropriate. Supporting Evidence: PMID:26181369 The presence of a positively charged lysine residue in the WT SUR2A Lys1337 and the mutant SUR1 Lys1369 KATP channels result in a significant decrease in their response to 0.1 mmol/l diazoxide in the absence of 0.1 mmol/l ADP. |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: ATP binding at SUR2 nucleotide-binding domains is integral to channel regulation. Reason: Domain-based ATP binding agrees with nucleotide-bound SUR2A/SUR2B structures and nucleotide-response experiments (PMID:35562524; PMID:37330603; PMID:26181369). ATP binding to SUR2 must be distinguished from the inhibitory ATP site on the Kir6 pore and from ATP-driven substrate translocation. Supporting Evidence: PMID:35562524 Mg-ATP was bound in the degenerate site and Mg-ADP was bound in the consensus site in all of the structures. PMID:34711681 SURx, through induced dimerization of the paired nucleotide binding domains (NBDs), requiring MgADP bound to NBD2 and MgATP bound to noncatalytic NBD1, activates the channel |
| GO:0005737 cytoplasm | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: An intracellular cytoplasmic pool of SUR2 has been reported in epididymal epithelial cells. Reason: The mouse P70170 source traces to IDA PMID:18434629. The accessible abstract explicitly describes cytoplasmic/Golgi immunostaining for SUR2 in rodent epididymal principal cells and expression in human epididymal epithelium. Retain this tissue-dependent pool without treating SUR2 as a soluble cytosolic protein or extrapolating a secretory function from expression alone. Supporting Evidence: PMID:18434629 A similar pattern was observed for SUR2 (ABCC9), although in the latter case, the Golgi labeling appeared to be region specific. |
| GO:0005739 mitochondrion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Mitochondrial localization has support for short SUR2 splice products, distinct from the canonical surface-channel context. Reason: The mouse donor has IDA/IMP evidence from PMID:19797704 and related mutant studies. Full PMID:19797704 identifies intra-exonic splice transcripts in mouse and human heart, then characterizes mouse SUR2A-55/SUR2B-55 mitochondrial targeting and function. Retain the localization with this variant scope; do not assign the short forms to O60706-1 or O60706-2, or infer that canonical full-length SUR2 is the universally established mitochondrial KATP pore. The later phenotype studies alone do not resolve mitochondrial complex composition. Supporting Evidence: PMID:19797704 Like the positive control mitoGFP, green signals in the SUR2 IES variant-GFP fusions overlapped with MitoTracker staining, suggesting that both variants were localized to mitochondria. PMID:19797704 mRNA isolated from human heart tissues |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Plasma-membrane localization is a conserved and experimentally supported location for SUR2 channels. Reason: PTN002795584 describes inherited membrane localization; human cardiac channel reconstitution and native sarcolemmal comparisons support this on the target itself (PMID:9831708). The phylogenetic annotation remains sound even though the larger ABC family contains proteins with different substrates and activities. Supporting Evidence: PMID:9831708 Recombinant channels activated by metabolic inhibition in cell-attached configuration or in inside-out patches with ATP-free internal solution were compared with sarcolemmal KATP channels in human ventricular cells. |
| GO:0005886 plasma membrane | IEA GO_REF:0000107 | ACCEPT | Summary: Mouse-to-human plasma-membrane localization is consistent with functional human surface channels. Reason: PMID:9831708 compares reconstituted human SUR2A/Kir6.2 channels with native human ventricular sarcolemmal channels. This directly corroborates the orthology-derived surface localization. Supporting Evidence: PMID:9831708 Recombinant channels activated by metabolic inhibition in cell-attached configuration or in inside-out patches with ATP-free internal solution were compared with sarcolemmal KATP channels in human ventricular cells. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-1369017 | ACCEPT | Summary: The Reactome record places SUR2-containing channels at the plasma membrane. Reason: Reactome:R-HSA-1369017 describes muscle KATP activation. This location is independently supported by human SUR2A/Kir6.2 functional expression and native sarcolemmal comparisons (PMID:9831708). Supporting Evidence: PMID:9831708 Recombinant channels activated by metabolic inhibition in cell-attached configuration or in inside-out patches with ATP-free internal solution were compared with sarcolemmal KATP channels in human ventricular cells. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-1454916 | ACCEPT | Summary: The Reactome record places SUR2-containing channels at the plasma membrane. Reason: Reactome:R-HSA-1454916 describes the ABCC-family pathway. This location is independently supported by human SUR2A/Kir6.2 functional expression and native sarcolemmal comparisons (PMID:9831708). Its family-level organic-anion-transport summary does not establish that SUR2 itself transports organic anions; that issue does not invalidate the location. Supporting Evidence: PMID:9831708 Recombinant channels activated by metabolic inhibition in cell-attached configuration or in inside-out patches with ATP-free internal solution were compared with sarcolemmal KATP channels in human ventricular cells. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5678261 | ACCEPT | Summary: The Reactome record places SUR2-containing channels at the plasma membrane. Reason: Reactome:R-HSA-5678261 describes KCNJ11:ABCC9-mediated potassium movement. This location is independently supported by human SUR2A/Kir6.2 functional expression and native sarcolemmal comparisons (PMID:9831708). Its inward-flux framing is conditional on the electrochemical gradient; physiological channel opening often produces outward potassium current. Supporting Evidence: PMID:9831708 Recombinant channels activated by metabolic inhibition in cell-attached configuration or in inside-out patches with ATP-free internal solution were compared with sarcolemmal KATP channels in human ventricular cells. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5678418 | ACCEPT | Summary: The Reactome record places SUR2-containing channels at the plasma membrane. Reason: Reactome:R-HSA-5678418 describes disease-associated KCNJ11:ABCC9 complexes. This location is independently supported by human SUR2A/Kir6.2 functional expression and native sarcolemmal comparisons (PMID:9831708). Its inward-flux framing is conditional on the electrochemical gradient; physiological channel opening often produces outward potassium current. Supporting Evidence: PMID:9831708 Recombinant channels activated by metabolic inhibition in cell-attached configuration or in inside-out patches with ATP-free internal solution were compared with sarcolemmal KATP channels in human ventricular cells. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9691566 | ACCEPT | Summary: The Reactome record places SUR2-containing channels at the plasma membrane. Reason: Reactome:R-HSA-9691566 describes nicorandil interaction with KCNJ11:ABCC9. This location is independently supported by human SUR2A/Kir6.2 functional expression and native sarcolemmal comparisons (PMID:9831708). Supporting Evidence: PMID:9831708 Recombinant channels activated by metabolic inhibition in cell-attached configuration or in inside-out patches with ATP-free internal solution were compared with sarcolemmal KATP channels in human ventricular cells. |
| GO:0006813 potassium ion transport | IEA GO_REF:0000002 | MODIFY | Summary: SUR2 participates specifically in transmembrane potassium flux through KATP complexes. Reason: The broad InterPro potassium-transport inference is biologically sound but can be expressed more precisely as potassium ion transmembrane transport. The regulatory subunit directly participates in gating the transport complex; no ATP-driven ion pump is implied (PMID:9831708; PMID:34711681). Proposed replacements: potassium ion transmembrane transport Supporting Evidence: PMID:9831708 ATP- and glibenclamide-sensitive K+ channels were produced when both subunits were coexpressed PMID:34711681 SURx, through induced dimerization of the paired nucleotide binding domains (NBDs), requiring MgADP bound to NBD2 and MgATP bound to noncatalytic NBD1, activates the channel PMID:34711681 They are uniquely evolved hetero-octameric complexes comprising four pore-forming inwardly rectifying potassium channel subunits, Kir6.x, and four regulatory sulfonylurea receptors, SURx |
| GO:0008281 sulfonylurea receptor activity | IEA GO_REF:0000002 | ACCEPT | Summary: Sulfonylurea recognition is an established property of SUR2 that controls KATP-channel activity. Reason: The inference from InterPro is consistent with cloned rat SUR2 pharmacology (PMID:8630239) and human glibenclamide-sensitive SUR2A/Kir6.2 channels (PMID:9831708). SUR2 is the drug-binding regulatory component; the term does not make it a potassium pore. Rat SUR2B cryo-EM also directly resolves glibenclamide in its binding pocket (PMID:34711681). Supporting Evidence: PMID:9831708 ATP- and glibenclamide-sensitive K+ channels were produced when both subunits were coexpressed PMID:34711681 Glib cryoEM density was well resolved in both P1 and Q1 conformations of the vascular KATP structure, where it bound within the same pocket of SUR2B |
| GO:0008281 sulfonylurea receptor activity | ISS GO_REF:0000024 | ACCEPT | Summary: Sulfonylurea recognition is an established property of SUR2 that controls KATP-channel activity. Reason: The inference from the rat Q63563 ortholog is consistent with cloned rat SUR2 pharmacology (PMID:8630239) and human glibenclamide-sensitive SUR2A/Kir6.2 channels (PMID:9831708). SUR2 is the drug-binding regulatory component; the term does not make it a potassium pore. Rat SUR2B cryo-EM also directly resolves glibenclamide in its binding pocket (PMID:34711681). Supporting Evidence: PMID:9831708 ATP- and glibenclamide-sensitive K+ channels were produced when both subunits were coexpressed PMID:34711681 Glib cryoEM density was well resolved in both P1 and Q1 conformations of the vascular KATP structure, where it bound within the same pocket of SUR2B |
| GO:0008282 inward rectifying potassium channel | IDA PMID:20610380 Ankyrin-B regulates Kir6.2 membrane expression and function ... | ACCEPT | Summary: SUR2A is a component of the inwardly rectifying KATP channel complex. Reason: Full-text Results and Figure 3 of PMID:20610380 include cotransfection and coimmunoprecipitation of Kir6.2 with SUR2A, despite the title foregrounding ankyrin-B and Kir6.2. The complex term GO:0008282 explicitly encompasses four Kir6 and four SUR subunits. Retain the IDA assignment; no direct ankyrin-B/SUR2A binding is inferred. Supporting Evidence: PMID:9831708 ATP- and glibenclamide-sensitive K+ channels were produced when both subunits were coexpressed |
| GO:0008282 inward rectifying potassium channel | IEA GO_REF:0000120 | ACCEPT | Summary: The combined electronic inference correctly identifies SUR2 as a KATP complex subunit. Reason: The ARBA/orthology assignment agrees with human functional channel reconstitution and SUR2A/Kir6.2 coimmunoprecipitation (PMID:9831708; PMID:20610380). The ontology complex definition explicitly includes regulatory sulfonylurea receptor subunits. Supporting Evidence: PMID:9831708 ATP- and glibenclamide-sensitive K+ channels were produced when both subunits were coexpressed |
| GO:0008282 inward rectifying potassium channel | ISS GO_REF:0000024 | ACCEPT | Summary: The rat SUR2 complex assignment transfers appropriately to human SUR2. Reason: Q63563 is the rat ortholog with cloned channel-reconstitution evidence (PMID:8630239). Human SUR2A independently reconstitutes the same type of Kir6.2-containing inwardly rectifying channel (PMID:9831708). Supporting Evidence: PMID:9831708 ATP- and glibenclamide-sensitive K+ channels were produced when both subunits were coexpressed |
| GO:0015272 ATP-activated inward rectifier potassium channel activity | NAS PMID:28842488 Conserved functional consequences of disease-associated muta... | ACCEPT | Summary: SUR2 contributes to the ATP-sensitive inward rectifier channel activity of KATP complexes. Reason: PMID:28842488 includes Kir6.2/SUR2A combinations, including wild-type control channels, rubidium efflux and nucleotide-dependent current measurements (Results/Figures 5β6). Preserve contributes_to. Live GO:0015272 has a misleading ATP-activated label but its definition describes ATP-sensitive inward rectification with pore block by ATP; the established KATP intent fits this channel. SUR2-mediated Mg-nucleotide activation and Kir6-mediated ATP inhibition are distinct. Supporting Evidence: PMID:9831708 ATP- and glibenclamide-sensitive K+ channels were produced when both subunits were coexpressed PMID:34711681 SURx, through induced dimerization of the paired nucleotide binding domains (NBDs), requiring MgADP bound to NBD2 and MgATP bound to noncatalytic NBD1, activates the channel |
| GO:0015459 potassium channel regulator activity | ISS GO_REF:0000024 | ACCEPT | Summary: Potassium channel regulation is the direct molecular function of SUR2. Reason: Rat SUR2 reconstitution (PMID:8630239), human SUR2A current assays (PMID:26181369), and SUR2A/SUR2B structural work establish allosteric control of Kir6 channels. This subunit-specific function is more accurate than describing SUR2 as an independent transporter or pore. Supporting Evidence: PMID:26181369 The presence of a positively charged lysine residue in the WT SUR2A Lys1337 and the mutant SUR1 Lys1369 KATP channels result in a significant decrease in their response to 0.1 mmol/l diazoxide in the absence of 0.1 mmol/l ADP. PMID:34711681 SURx, through induced dimerization of the paired nucleotide binding domains (NBDs), requiring MgADP bound to NBD2 and MgATP bound to noncatalytic NBD1, activates the channel |
| GO:0016020 membrane | IEA GO_REF:0000120 | MODIFY | Summary: SUR2 is a multipass membrane protein whose principal mature-channel location is the plasma membrane. Reason: The broad combined membrane inference is correct. Refine to plasma membrane, the directly supported functional location of the major SUR2A/SUR2B-containing KATP complexes. This refinement does not erase the separately retained mitochondrial short-variant evidence. Proposed replacements: plasma membrane Supporting Evidence: PMID:9831708 Recombinant channels activated by metabolic inhibition in cell-attached configuration or in inside-out patches with ATP-free internal solution were compared with sarcolemmal KATP channels in human ventricular cells. |
| GO:0016887 ATP hydrolysis activity | IEA GO_REF:0000002 | ACCEPT | Summary: SUR2 possesses nucleotide hydrolysis activity associated with channel regulation. Reason: PMID:26181369 directly measures MgATPase activity of recombinant human SUR2A NBD2 dimers and examines nucleotide-dependent gating of assembled channels. Retain ATP hydrolysis: the absence of ABC substrate transport does not imply loss of all ATPase activity. Domain-fragment activity and the intact channel gating cycle should not be conflated. Supporting Evidence: PMID:26181369 MgATPase activities of NBD2 dimers were determined by monitoring ADP formation PMID:26181369 the KM values are significantly lower in NBD2 dimers containing a lysine residue such as the WT SUR2A Lys1337 (38Β±6Β ΞΌmol/l) |
| GO:0019829 ATPase-coupled monoatomic cation transmembrane transporter activity | ISS GO_REF:0000024 | MODIFY | Summary: The source supports an ATP-regulated channel, not an ATP-driven cation pump. Reason: The rat Q63563 donor carries GO:0019829 with IGI PMID:28842488. That study examines Kir6/SUR channel gating and rubidium efflux, including SUR2A controls; it does not demonstrate stoichiometric ATP hydrolysis driving ions against a gradient. GO:0019829 explicitly describes such a coupled transport reaction. Preserve the biological essence with the SUR2-specific potassium channel regulator term, supported by independent human and structural studies. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:Q63563 SOURCE BAD Live donor record carries IGI GO:0019829 from PMID:28842488; the accessible Results/Figure5 support SUR2A/Kir6 channel gating and flux, not an ATP-driven cation pump. Proposed replacements: potassium channel regulator activity Supporting Evidence: PMID:34711681 nontransporting members of the ABCC subfamily of ABC transporters PMID:34711681 SURx, through induced dimerization of the paired nucleotide binding domains (NBDs), requiring MgADP bound to NBD2 and MgATP bound to noncatalytic NBD1, activates the channel |
| GO:0022857 transmembrane transporter activity | IEA GO_REF:0000117 | MODIFY | Summary: A broad transporter prediction conflates the SUR2 regulatory component with the conducting pore. Reason: ARBA00028127 predicts transmembrane transporter activity from the ABC-family context. SUR2 binds and regulates Kir6 channels; Kir6 provides the ion-permeation pathway. Replace the independently enabled transporter function with potassium channel regulator activity, while retaining the separate contributes_to channel annotations and transport-process participation. Proposed replacements: potassium channel regulator activity Supporting Evidence: PMID:34711681 nontransporting members of the ABCC subfamily of ABC transporters PMID:34711681 SURx, through induced dimerization of the paired nucleotide binding domains (NBDs), requiring MgADP bound to NBD2 and MgATP bound to noncatalytic NBD1, activates the channel |
| GO:0030017 sarcomere | IEA GO_REF:0000107 | UNDECIDED | Summary: The mouse donor has sarcomere immunolocalization evidence whose precise subcellular interpretation remains unresolved. Reason: P70170 carries IDA GO:0030017 from PMID:16085792. Its accessible abstract establishes developmental expression and a mature-like subcellular pattern but does not resolve contractile sarcomeres versus associated transverse-tubular/sarcolemmal membranes. The full donor study remains inaccessible after publisher/PDF searches. GO:0030017 denotes the contractile thick/thin-filament unit; a striated staining pattern alone is insufficient for this review to confirm or reject that location. |
| GO:0031004 potassium ion-transporting ATPase complex | ISS GO_REF:0000024 | MODIFY | Summary: SUR2 belongs to an inwardly rectifying potassium-channel complex, not a potassium-pumping ATPase complex. Reason: Q63563 carries RCA GO:0031004 from PMID:28842488. Live GO:0031004 describes an ATP-hydrolysis-coupled potassium importer, exemplified by Kdp-type machinery. KATP channels conduct potassium through Kir6 and are regulated by SUR nucleotide binding; their name does not mean potassium-transporting ATPase. Replace with the explicitly Kir6/SUR-containing complex GO:0008282. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: COMPARTMENT OR COMPLEX MISMATCH Sources checked: UniProtKB:Q63563 SOURCE BAD Live donor record carries RCA GO:0031004 from PMID:28842488. Kir6/SUR KATP channels do not meet the GO definition of potassium-transporting ATPase complex. Proposed replacements: inward rectifying potassium channel Supporting Evidence: PMID:34711681 nontransporting members of the ABCC subfamily of ABC transporters PMID:34711681 They are uniquely evolved hetero-octameric complexes comprising four pore-forming inwardly rectifying potassium channel subunits, Kir6.x, and four regulatory sulfonylurea receptors, SURx |
| GO:0033198 response to ATP | IEA GO_REF:0000117 | ACCEPT | Summary: Changes in ATP availability regulate SUR2-containing potassium-channel activity. Reason: The response-to-ATP assertion from ARBA00092810 is consistent with the core coupling between cellular nucleotide state and channel gating. ATP inhibition at Kir6 and Mg-nucleotide stimulation through SUR2 must be distinguished; the annotation does not mean ATP simply activates every SUR2 channel under all conditions. Human reconstitution and mechanistic studies corroborate this response (PMID:9831708; PMID:26181369). Supporting Evidence: PMID:9831708 They were "refreshed" by MgATP and stimulated by ADP in the presence of Mg2+ when inhibited by ATP. PMID:34711681 SURx, through induced dimerization of the paired nucleotide binding domains (NBDs), requiring MgADP bound to NBD2 and MgATP bound to noncatalytic NBD1, activates the channel |
| GO:0033198 response to ATP | IMP PMID:24439875 ABCC9 is a novel Brugada and early repolarization syndrome s... | ACCEPT | Summary: Changes in ATP availability regulate SUR2-containing potassium-channel activity. Reason: The response-to-ATP assertion from human ABCC9 variant experiments in PMID:24439875 is consistent with the core coupling between cellular nucleotide state and channel gating. ATP inhibition at Kir6 and Mg-nucleotide stimulation through SUR2 must be distinguished; the annotation does not mean ATP simply activates every SUR2 channel under all conditions. Human reconstitution and mechanistic studies corroborate this response (PMID:9831708; PMID:26181369). Supporting Evidence: PMID:24439875 Functional expression of the V734I variant yielded a Mg-ATP ICβ
β that was 5-fold that of wild-type (WT). |
| GO:0033198 response to ATP | ISS GO_REF:0000024 | ACCEPT | Summary: Changes in ATP availability regulate SUR2-containing potassium-channel activity. Reason: The response-to-ATP assertion from rat SUR2 orthology is consistent with the core coupling between cellular nucleotide state and channel gating. ATP inhibition at Kir6 and Mg-nucleotide stimulation through SUR2 must be distinguished; the annotation does not mean ATP simply activates every SUR2 channel under all conditions. Human reconstitution and mechanistic studies corroborate this response (PMID:9831708; PMID:26181369). Supporting Evidence: PMID:9831708 They were "refreshed" by MgATP and stimulated by ADP in the presence of Mg2+ when inhibited by ATP. PMID:34711681 SURx, through induced dimerization of the paired nucleotide binding domains (NBDs), requiring MgADP bound to NBD2 and MgATP bound to noncatalytic NBD1, activates the channel |
| GO:0033198 response to ATP | ISS PMID:26621776 Differential mechanisms of CantΓΊ syndrome-associated gain of... | ACCEPT | Summary: Changes in ATP availability regulate SUR2-containing potassium-channel activity. Reason: The response-to-ATP assertion from rat SUR2A variant assays in PMID:26621776 is consistent with the core coupling between cellular nucleotide state and channel gating. ATP inhibition at Kir6 and Mg-nucleotide stimulation through SUR2 must be distinguished; the annotation does not mean ATP simply activates every SUR2 channel under all conditions. PMID:26621776 assays rat SUR2A/mouse Kir6.2 equivalents of human CantΓΊ variants, matching the ISS evidence scope. Supporting Evidence: PMID:26621776 C1039Y-dependent channels were significantly less sensitive to inhibition by ATP or by glibenclamide, but MgADP activation was comparable to WT. PMID:34711681 SURx, through induced dimerization of the paired nucleotide binding domains (NBDs), requiring MgADP bound to NBD2 and MgATP bound to noncatalytic NBD1, activates the channel |
| GO:0042383 sarcolemma | IEA GO_REF:0000107 | ACCEPT | Summary: Sarcolemmal localization is a central location for SUR2A-containing muscle KATP channels. Reason: The mouse donor traces to IDA PMID:18001767. Independent human data compare reconstituted SUR2A/Kir6.2 channels with native ventricular sarcolemmal channels (PMID:9831708). Retain this specific membrane location without asserting that every SUR2 isoform is restricted to cardiomyocytes. Supporting Evidence: PMID:9831708 Recombinant channels activated by metabolic inhibition in cell-attached configuration or in inside-out patches with ATP-free internal solution were compared with sarcolemmal KATP channels in human ventricular cells. |
| GO:0042626 ATPase-coupled transmembrane transporter activity | IDA PMID:26181369 Molecular determinants of ATP-sensitive potassium channel Mg... | MODIFY | Summary: The direct biochemical assay establishes ATP hydrolysis, not ATPase-coupled ion pumping. Reason: Full PMID:26181369 measures ADP production by GST-NBD2 dimers made from human SUR1/SUR2A sequences. Separate assembled-channel assays test GTP/nucleotide-dependent gating. Neither readout establishes ATP-driven transmembrane substrate transport by SUR2. Refine the experimentally grounded enzymatic activity to ATP hydrolysis, preserving the original IDA source assertion outside this review. Proposed replacements: ATP hydrolysis activity Supporting Evidence: PMID:26181369 MgATPase activities of NBD2 dimers were determined by monitoring ADP formation PMID:26181369 the KM values are significantly lower in NBD2 dimers containing a lysine residue such as the WT SUR2A Lys1337 (38Β±6Β ΞΌmol/l) |
| GO:0042626 ATPase-coupled transmembrane transporter activity | TAS Reactome:R-HSA-1454916 | MODIFY | Summary: The family-level Reactome mapping assigns active transport too broadly to a nontransporting channel regulator. Reason: Reactome:R-HSA-1454916 summarizes organic-anion transport by MRPs. ABCC9/SUR2 is an atypical ABCC regulatory protein; its established activity is allosteric control of Kir6 potassium channels, not the active organic-anion transport described in that pathway summary. Replace the ATPase-coupled transmembrane transporter term with potassium channel regulator activity. Proposed replacements: potassium channel regulator activity Supporting Evidence: PMID:34711681 nontransporting members of the ABCC subfamily of ABC transporters PMID:34711681 SURx, through induced dimerization of the paired nucleotide binding domains (NBDs), requiring MgADP bound to NBD2 and MgATP bound to noncatalytic NBD1, activates the channel |
| GO:0044325 transmembrane transporter binding | IPI PMID:20610380 Ankyrin-B regulates Kir6.2 membrane expression and function ... | ACCEPT | Summary: SUR2A binds the pore-forming Kir6.2 transmembrane channel subunit. Reason: PMID:20610380 Results/Figure 3 directly coimmunoprecipitates SUR2A with Kir6.2 in cotransfected cells. The supporting entity Q14654 is the Kir6.2 partner, and this specific channel-subunit interaction underlies regulatory coupling. Unlike generic protein binding, this transporter-binding term identifies a mechanistically relevant interaction. It does not demonstrate direct SUR2A binding to ankyrin-B. Supporting Evidence: |
| GO:0044877 protein-containing complex binding | IEA GO_REF:0000107 | UNDECIDED | Summary: The donor protein-complex-binding assertion needs source verification before transfer can be adjudicated. Reason: Mouse P70170 carries IDA GO:0044877 from PMID:11934987. The cached abstract concerns a metazoan Mediator component named Sur2 in embryonic stem cells. Because the complete original study was not accessible, this review cannot establish whether any ABCC9 experiment occurs elsewhere in the paper or confidently declare a naming/misattribution error. Retain the source row unresolved and request full-text donor audit. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:P70170 UNRESOLVED Current donor IDA points to PMID:11934987. Its abstract concerns Mediator Sur2, but complete source verification is unavailable; no naming-error verdict is assigned. |
| GO:0051607 defense response to virus | IMP PMID:18026101 ATP-sensitive potassium channels mediate survival during inf... | UNDECIDED | Summary: KATP channels support survival during infection, but the human ABCC9-specific experimental assertion cannot be verified from the available text. Reason: PMID:18026101 reports mouse Kcnj8-null susceptibility and Drosophila dSUR RNAi phenotypes, and links the mammalian response to coronary vascular homeostasis. The full study remains inaccessible. The abstract alone cannot establish which ABCC9-specific experiments the curator used or whether defense response to virus is the appropriate direct process for human SUR2. Do not infer a wrong-gene error or manufacture an antiviral mechanism. Supporting Evidence: PMID:18026101 In Drosophila melanogaster, suppression of dSUR by RNA interference similarly causes hypersensitivity to infection by flock house virus. |
| GO:0055085 transmembrane transport | IEA GO_REF:0000002 | MODIFY | Summary: SUR2 contributes specifically to potassium movement across the plasma membrane as a channel regulator. Reason: The broad transmembrane-transport annotation from InterPro is consistent with direct participation in a transport complex, but potassium ion transmembrane transport is the appropriate specific process. Human channel reconstitution and structural separation of SUR/Kir roles support the refinement. Proposed replacements: potassium ion transmembrane transport Supporting Evidence: PMID:9831708 ATP- and glibenclamide-sensitive K+ channels were produced when both subunits were coexpressed PMID:34711681 SURx, through induced dimerization of the paired nucleotide binding domains (NBDs), requiring MgADP bound to NBD2 and MgATP bound to noncatalytic NBD1, activates the channel PMID:34711681 They are uniquely evolved hetero-octameric complexes comprising four pore-forming inwardly rectifying potassium channel subunits, Kir6.x, and four regulatory sulfonylurea receptors, SURx |
| GO:0055085 transmembrane transport | ISS GO_REF:0000024 | MODIFY | Summary: SUR2 contributes specifically to potassium movement across the plasma membrane as a channel regulator. Reason: The broad transmembrane-transport annotation from rat SUR2 orthology is consistent with direct participation in a transport complex, but potassium ion transmembrane transport is the appropriate specific process. Human channel reconstitution and structural separation of SUR/Kir roles support the refinement. Proposed replacements: potassium ion transmembrane transport Supporting Evidence: PMID:9831708 ATP- and glibenclamide-sensitive K+ channels were produced when both subunits were coexpressed PMID:34711681 SURx, through induced dimerization of the paired nucleotide binding domains (NBDs), requiring MgADP bound to NBD2 and MgATP bound to noncatalytic NBD1, activates the channel PMID:34711681 They are uniquely evolved hetero-octameric complexes comprising four pore-forming inwardly rectifying potassium channel subunits, Kir6.x, and four regulatory sulfonylurea receptors, SURx |
| GO:0055085 transmembrane transport | TAS Reactome:R-HSA-382556 | MODIFY | Summary: SUR2 contributes specifically to potassium movement across the plasma membrane as a channel regulator. Reason: The broad transmembrane-transport annotation from Reactome:R-HSA-382556 is consistent with direct participation in a transport complex, but potassium ion transmembrane transport is the appropriate specific process. The Reactome parent pathway emphasizes ATP-driven ABC transport; this family-level wording should not be taken as evidence that SUR2 is itself an active pump. Human channel reconstitution and structural separation of SUR/Kir roles support the refinement. Proposed replacements: potassium ion transmembrane transport Supporting Evidence: PMID:9831708 ATP- and glibenclamide-sensitive K+ channels were produced when both subunits were coexpressed PMID:34711681 SURx, through induced dimerization of the paired nucleotide binding domains (NBDs), requiring MgADP bound to NBD2 and MgATP bound to noncatalytic NBD1, activates the channel PMID:34711681 They are uniquely evolved hetero-octameric complexes comprising four pore-forming inwardly rectifying potassium channel subunits, Kir6.x, and four regulatory sulfonylurea receptors, SURx |
| GO:0061337 cardiac conduction | IMP PMID:24439875 ABCC9 is a novel Brugada and early repolarization syndrome s... | KEEP AS NON CORE | Summary: SUR2-dependent potassium conductance can influence cardiac electrical activity and arrhythmic phenotypes. Reason: PMID:24439875 combines human variant observations with altered KATP currents, supporting a cardiac electrophysiological consequence. Retain cardiac conduction as a contextual process rather than the defining molecular function, and do not equate the paperβs candidate susceptibility-gene conclusion with a definitive Mendelian Brugada association. The core activity remains potassium-channel regulation. The family carrying combined ABCC9/SCN5A variants supplies the reported conduction-disease context; it does not isolate an ABCC9-only conduction mechanism. Supporting Evidence: PMID:24439875 Functional expression of the V734I variant yielded a Mg-ATP ICβ
β that was 5-fold that of wild-type (WT). PMID:24439875 overlap syndrome consisting of BrS, ERS, cardiac conduction disease (CCD) and long QT syndrome (LQTS) in a single family. |
| GO:0071805 potassium ion transmembrane transport | IBA GO_REF:0000033 | ACCEPT | Summary: Potassium ion transmembrane transport is a conserved direct role of the SUR2-containing channel complex. Reason: The PTN002795677 IBA is supported by human reconstituted channels and independent regulatory studies. SUR2 contributes an essential gating component to the transport machinery, while potassium crosses the Kir6 pore. This is direct participation rather than an indirect effect of a disease phenotype. Supporting Evidence: PMID:9831708 ATP- and glibenclamide-sensitive K+ channels were produced when both subunits were coexpressed PMID:34711681 SURx, through induced dimerization of the paired nucleotide binding domains (NBDs), requiring MgADP bound to NBD2 and MgATP bound to noncatalytic NBD1, activates the channel PMID:34711681 They are uniquely evolved hetero-octameric complexes comprising four pore-forming inwardly rectifying potassium channel subunits, Kir6.x, and four regulatory sulfonylurea receptors, SURx |
| GO:0071805 potassium ion transmembrane transport | IEA GO_REF:0000117 | ACCEPT | Summary: The electronic potassium-transmembrane-transport inference matches SUR2 channel function. Reason: ARBA00028321 agrees with human SUR2A/Kir6.2 currents and structural evidence for a regulatory subunit in a potassium-conducting complex (PMID:9831708; PMID:34711681). The process does not require SUR2 itself to form the pore. Supporting Evidence: PMID:9831708 ATP- and glibenclamide-sensitive K+ channels were produced when both subunits were coexpressed PMID:34711681 SURx, through induced dimerization of the paired nucleotide binding domains (NBDs), requiring MgADP bound to NBD2 and MgATP bound to noncatalytic NBD1, activates the channel PMID:34711681 They are uniquely evolved hetero-octameric complexes comprising four pore-forming inwardly rectifying potassium channel subunits, Kir6.x, and four regulatory sulfonylurea receptors, SURx |
| GO:0071805 potassium ion transmembrane transport | IMP PMID:24439875 ABCC9 is a novel Brugada and early repolarization syndrome s... | ACCEPT | Summary: ABCC9 perturbation alters potassium transmembrane currents in reconstituted channels. Reason: PMID:24439875 directly measures changes in KATP channel activity with human SUR2 variants. This supports participation in potassium transmembrane transport independently of the proposed clinical disease classification. Supporting Evidence: PMID:24439875 Functional expression of the V734I variant yielded a Mg-ATP ICβ
β that was 5-fold that of wild-type (WT). |
| GO:0071805 potassium ion transmembrane transport | NAS PMID:28842488 Conserved functional consequences of disease-associated muta... | ACCEPT | Summary: SUR2A-containing channels mediate potassium flux in the cited functional system. Reason: PMID:28842488 includes Kir6.2/SUR2A wild-type and mutant-containing channels in rubidium-efflux and patch-clamp experiments (Results/Figures 5β6). Human SUR2A reconstitution independently establishes the potassium-channel role. This is channel-mediated transport, not an ATP-coupled pumping reaction. Supporting Evidence: PMID:9831708 ATP- and glibenclamide-sensitive K+ channels were produced when both subunits were coexpressed |
| GO:0098655 monoatomic cation transmembrane transport | ISS PMID:26621776 Differential mechanisms of CantΓΊ syndrome-associated gain of... | MODIFY | Summary: The cited rat SUR2A channels mediate potassium, a specific cation, across the membrane. Reason: PMID:26621776 engineers human CantΓΊ-equivalent variants into rat SUR2A and coexpresses mouse Kir6.2, measuring rubidium efflux and channel currents. The cation-transport assertion is sound but can be refined to potassium ion transmembrane transport, without pretending the rat experiments directly assayed human protein. Proposed replacements: potassium ion transmembrane transport Supporting Evidence: PMID:26621776 we studied Kir6.2+SUR2A channels in the present experiments, and by means of 86Rb+ efflux assays in intact cells transiently transfected with WT or mutant subunits, we confirm that all three mutations result in overactive KATP channels. |
| GO:0099104 potassium channel activator activity | ISS PMID:26621776 Differential mechanisms of CantΓΊ syndrome-associated gain of... | ACCEPT | Summary: SUR2 can activate Kir6 channel opening through Mg-nucleotide-dependent regulation. Reason: PMID:26621776 compares wild-type and CantΓΊ-equivalent rat SUR2A channels and directly tests MgADP activation; some variants increase that activation. Together with wild-type reconstitution and SUR2 structural work, this supports the native activator capability. The term does not imply that SUR2 is constitutively activating or cannot mediate inhibitory drug responses. Supporting Evidence: PMID:26621776 For P429L and A475V mutants, sensitivity to ATP inhibition was comparable to WT channels, but activation by MgADP was significantly greater. PMID:34711681 SURx, through induced dimerization of the paired nucleotide binding domains (NBDs), requiring MgADP bound to NBD2 and MgATP bound to noncatalytic NBD1, activates the channel |
| GO:0140359 ABC-type transporter activity | IBA GO_REF:0000033 | MODIFY | Summary: The ancestral ABC-transporter inference does not capture SUR2βs experimentally established regulatory specialization. Reason: The supplied ancestral source is PTN009085477. GO:0140359 explicitly denotes ATP-hydrolysis-driven primary active substrate transport. SUR2 retains ABC architecture and ATPase capability but is a nontransporting regulatory subunit of Kir6 channels (PMID:34711681; PMID:26181369). This is target-specific functional divergence requiring a SUR-clade exception to transporter propagation, not an objection to donor count or self-support. Replace with potassium channel regulator activity; the precise historical PAINT gain/loss placement has not been independently reconstructed. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE ROLE CONFLATION Sources checked: PANTHER:PTN009085477 UNRESOLVED PTN supplied by GOA is retained as the proximate ancestral source. Target-specific SUR2 structural/functional evidence contradicts active transport; exact PAINT gain/loss placement has not been independently reconstructed. Proposed replacements: potassium channel regulator activity Supporting Evidence: PMID:34711681 nontransporting members of the ABCC subfamily of ABC transporters PMID:26181369 MgATPase activities of NBD2 dimers were determined by monitoring ADP formation PMID:34711681 SURx, through induced dimerization of the paired nucleotide binding domains (NBDs), requiring MgADP bound to NBD2 and MgATP bound to noncatalytic NBD1, activates the channel |
| GO:0140359 ABC-type transporter activity | IEA GO_REF:0000002 | MODIFY | Summary: An ABC transmembrane domain is insufficient to assign primary active transport to SUR2. Reason: InterPro:IPR011527 correctly identifies the ABC1 transmembrane architecture, but SUR2 has specialized as a channel regulator. Structural and electrophysiological evidence separates the SUR regulatory module from the conducting Kir6 pore. Replace ABC-type transporter activity with potassium channel regulator activity while retaining independently supported ATP binding and hydrolysis. Propagation Review Root cause: PROPAGATION BAD Failure modes: FUNCTIONAL DIVERGENCE Sources checked: InterPro:IPR011527 SUPPORTS SOURCE BUT NOT TARGET The ABC1 transmembrane domain is present; the family-to-function mapping overgeneralizes primary active transport to the nontransporting SUR2 regulatory specialization. Proposed replacements: potassium channel regulator activity Supporting Evidence: PMID:34711681 nontransporting members of the ABCC subfamily of ABC transporters PMID:34711681 SURx, through induced dimerization of the paired nucleotide binding domains (NBDs), requiring MgADP bound to NBD2 and MgATP bound to noncatalytic NBD1, activates the channel |
| GO:0150104 transport across blood-brain barrier | NAS PMID:30280653 Blood-Brain Barrier: From Physiology to Disease and Back. | MARK AS OVER ANNOTATED | Summary: The cited review places ABCC9 in pericyte ion-channel regulation, not demonstrated transport of solutes across the blood-brain barrier. Reason: The cached publication is truncated despite its full-text flag, so the actual PMC article was retrieved and its pericyte ion-transport section read separately. PMID:30280653 discusses ABCC9/Kir6.1 expression, pericyte hyperpolarization/relaxation and cerebral blood-flow control. These functions are relevant to the neurovascular unit, but they do not establish that SUR2 performs transendothelial blood-to-brain transport as defined by GO:0150104. The decision rests on the recovered full section, not the article title or abstract. Supporting Evidence: |
| GO:1990573 potassium ion import across plasma membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Inward potassium flux is an experimentally available mode of SUR2-containing channels, not their universal physiological direction. Reason: The rat Q63563 donor traces to IDA PMID:8630239. Human SUR2A/Kir6.2 channels conduct at -40 mV in quasi-symmetrical approximately 150 mmol/L potassium solutions and show weak inward rectification (PMID:9831708), supporting inward flux under those assay conditions. Retain potassium import as a conditional transport direction; in muscle at typical physiological potentials, channel opening commonly produces outward potassium flux and hyperpolarization. The direction-neutral potassium-transmembrane-transport term represents the core role more generally. Supporting Evidence: PMID:9831708 The single-channel conductance of approximately 80 pS measured at -40 mV in quasi-symmetrical approximately 150 mmol/L K+ solutions, the intraburst kinetics that were dependent on K+ driving force, and the weak inward rectification were indistinguishable for both channels. |
Loading supporting contentβ¦
Download this section (compressed HTML)Q: Can GO:0015272 nomenclature/definition more clearly distinguish ATP inhibition at Kir6 from Mg-nucleotide activation through SUR in KATP channels?
Q: Does full PMID:11934987 substantiate the P70170 protein-complex-binding donor annotation, or does the shared Sur2 name require a donor-side correction?
Q: Which short human ABCC9 splice products localize to mitochondria, and how do they relate to the major O60706-1/O60706-2 isoforms and native mitochondrial potassium-channel composition?
Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)Loading supporting contentβ¦
Download this section (compressed HTML)