ABCC8 p.Glu1305Ala
| Predicted by SNAP2: | A: D (80%), C: D (85%), D: D (85%), F: D (91%), G: D (91%), H: D (91%), I: D (91%), K: D (91%), L: D (91%), M: D (85%), N: D (91%), P: D (95%), Q: D (80%), R: D (91%), S: D (85%), T: D (85%), V: D (91%), W: D (91%), Y: D (85%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Three C-terminal residues from the sulphonylurea r... J Physiol. 2008 Jul 1;586(13):3075-85. Epub 2008 May 1. Dupuis JP, Revilloud J, Moreau CJ, Vivaudou M
Three C-terminal residues from the sulphonylurea receptor contribute to the functional coupling between the K(ATP) channel subunits SUR2A and Kir6.2.
J Physiol. 2008 Jul 1;586(13):3075-85. Epub 2008 May 1., [PMID:18450778]
Abstract [show]
Cardiac ATP-sensitive potassium (K(ATP)) channels are metabolic sensors formed by the association of the inward rectifier potassium channel Kir6.2 and the sulphonylurea receptor SUR2A. SUR2A adjusts channel gating as a function of intracellular ATP and ADP and is the target of pharmaceutical openers and blockers which, respectively, up- and down-regulate Kir6.2. In an effort to understand how effector binding to SUR2A translates into Kir6.2 gating modulation, we examined the role of a 65-residue SUR2A fragment linking transmembrane domain TMD2 and nucleotide-binding domain NBD2 that has been shown to interact with Kir6.2. This fragment of SUR2A was replaced by the equivalent residues of its close homologue, the multidrug resistance protein MRP1. The chimeric construct was expressed in Xenopus oocytes and characterized using the patch-clamp technique. We found that activation by MgADP and synthetic openers was greatly attenuated although apparent affinities were unchanged. Further chimeragenetic and mutagenetic studies showed that mutation of three residues, E1305, I1310 and L1313 (rat numbering), was sufficient to confer this defective phenotype. The same mutations had no effects on channel block by the sulphonylurea glibenclamide or by ATP, suggesting a role for these residues in activatory--but not inhibitory--transduction processes. These results indicate that, within the K(ATP) channel complex, the proximal C-terminal of SUR2A is a critical link between ligand binding to SUR2A and Kir6.2 up-regulation.
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No. Sentence Comment
53 The exact amino acid composition of SUR2A-MRP1 chimeric constructs and mutants were: S1M, SUR2A(M1-V1275) + MRP1(E1262-R1342) + SUR2A(M1358-K1545); S2M, SUR2A(M1-V1275) + MRP1(E1262-L1300) + SUR2A(R1316-K1545); S3M, SUR2A(M1-V1315) + MRP1(R1301-R1342) + SUR2A(M1358-K1545); S4M, SUR2A(M1-V1275) + MRP1(E1262-E1271) + SUR2A(S1286-K1545); S5M, SUR2A(M1-E1285) + MRP1(K1272-P1283) + SUR2A(P1299-K1545); S6M, SUR2A(M1-V1298) + MRP1(P1284-G1291) + SUR2A(E1307-K1545); S7M, SUR2A(M1-Q1304) + MRP1(V1290-L1300) + SUR2A(R1316-K1545); SUR2A(EIL/VFY), SUR2A with mutations E1305V, I1310F and L1313Y; S7M(VFY/EIL), S7M with mutations V1305E, F1310I and Y1313L; SUR2A(EIL/AAA), SUR2A with mutations E1305A, I1310A and L1313A.
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ABCC8 p.Glu1305Ala 18450778:53:687
status: NEW[hide] Kir6.2 activation by sulfonylurea receptors: a dif... Physiol Rep. 2015 Sep;3(9). pii: e12533. doi: 10.14814/phy2.12533. Principalli MA, Dupuis JP, Moreau CJ, Vivaudou M, Revilloud J
Kir6.2 activation by sulfonylurea receptors: a different mechanism of action for SUR1 and SUR2A subunits via the same residues.
Physiol Rep. 2015 Sep;3(9). pii: e12533. doi: 10.14814/phy2.12533., [PMID:26416970]
Abstract [show]
ATP-sensitive potassium channels (K-ATP channels) play a key role in adjusting the membrane potential to the metabolic state of cells. They result from the unique combination of two proteins: the sulfonylurea receptor (SUR), an ATP-binding cassette (ABC) protein, and the inward rectifier K(+) channel Kir6.2. Both subunits associate to form a heterooctamer (4 SUR/4 Kir6.2). SUR modulates channel gating in response to the binding of nucleotides or drugs and Kir6.2 conducts potassium ions. The activity of K-ATP channels varies with their localization. In pancreatic beta-cells, SUR1/Kir6.2 channels are partly active at rest while in cardiomyocytes SUR2A/Kir6.2 channels are mostly closed. This divergence of function could be related to differences in the interaction of SUR1 and SUR2A with Kir6.2. Three residues (E1305, I1310, L1313) located in the linker region between transmembrane domain 2 and nucleotide-binding domain 2 of SUR2A were previously found to be involved in the activation pathway linking binding of openers onto SUR2A and channel opening. To determine the role of the equivalent residues in the SUR1 isoform, we designed chimeras between SUR1 and the ABC transporter multidrug resistance-associated protein 1 (MRP1), and used patch clamp recordings on Xenopus oocytes to assess the functionality of SUR1/MRP1 chimeric K-ATP channels. Our results reveal that the same residues in SUR1 and SUR2A are involved in the functional association with Kir6.2, but they display unexpected side-chain specificities which could account for the contrasted properties of pancreatic and cardiac K-ATP channels.
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No. Sentence Comment
64 V1290Q, F1295I, and Y1298L, SUR1(QIL/III) = Q1342I, I1347I, and L1350I, SUR1(QIL/AAA) = Q1342A, I1347A, and L1350A, SUR1(QIL/GGG) = Q1342G, I1347G, and L1350G, SUR2A(EIL/III) = E1305I, I1310I, and L1313I, SUR2A(EIL/AAA) = E1305A, I1310A, and L1313A, SUR2A(EIL/GGG) = E1305G, I1310G, and L1313G.
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ABCC8 p.Glu1305Ala 26416970:64:222
status: NEW