ABCMdb

ABCC8 p.Gln1372Ala

Predicted by SNAP2:	A: D (63%), C: D (63%), D: N (57%), E: N (97%), F: D (71%), G: D (71%), H: N (53%), I: D (71%), K: N (66%), L: D (66%), M: N (82%), N: D (63%), P: D (80%), R: D (75%), S: D (59%), T: D (59%), V: D (66%), W: D (75%), Y: D (66%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: N, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, R: D, S: D, T: D, V: D, W: D, Y: D,

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[hide] The ATP-sensitive K(+) channel ABCC8 S1369A type 2... Diabetes. 2012 Jan;61(1):241-9. Fatehi M, Raja M, Carter C, Soliman D, Holt A, Light PE
The ATP-sensitive K(+) channel ABCC8 S1369A type 2 diabetes risk variant increases MgATPase activity.
Diabetes. 2012 Jan;61(1):241-9., [PMID:22187380]

Abstract [show]
Pancreatic beta-cell ATP-sensitive K(+) (K(ATP)) channels are composed of Kir6.2 and SUR1 subunits encoded by the KCNJ11 and ABCC8 genes, respectively. Although rare monogenic activating mutations in these genes cause overt neonatal diabetes, the common variants E23K (KCNJ11) and S1369A (ABCC8) form a tightly heritable haplotype that is associated with an increased susceptibility to type 2 diabetes (T2D) risk. However, the molecular mechanism(s) underlying this risk remain to be elucidated. A homology model of the SUR1 nucleotide-binding domains (NBDs) indicates that residue 1369 is in close proximity to the major MgATPase site. Therefore, we investigated the intrinsic MgATPase activity of K(ATP) channels containing these variants. Electrophysiological and biochemical techniques were used to study the MgATPase activity of recombinant human K(ATP) channels or glutathione S-transferase and NBD2 fusion proteins containing the E23/S1369 (nonrisk) or K23/A1369 (risk) variant haplotypes. K(ATP) channels containing the K23/A1369 haplotype displayed a significantly increased stimulation by guanosine triphosphate compared with the E23/S1369 haplotype (3.2- vs. 1.8-fold). This effect was dependent on the presence of the A1369 variant and was lost in the absence of Mg(2+) ions or in the presence of the MgATPase inhibitor beryllium fluoride. Direct biochemical assays also confirmed an increase in MgATPase activity in NBD2 fusion proteins containing the A1369 variant. Our findings demonstrate that the A1369 variant increases K(ATP) channel MgATPase activity, providing a plausible molecular mechanism by which the K23/A1369 haplotype increases susceptibility to T2D in humans homozygous for these variants.

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52 The E23K/S1369A variants and the Q1372A mutation were introduced into the KCNJ11 and ABCC8 cDNAs, respectively, using site-directed mutagenesis (QuikChange; Stratagene, La Jolla, CA) and confirmed by sequence analysis. Login to comment
91 Accordingly, we introduced the Q1372A mutation in the presence of S1369 (E23/S1369-Q1372A) to test whether the GTP stimulatory effect is similarly enhanced. Login to comment
92 The Q1372A mutation significantly enhanced the stimulatory effect of GTP compared with KATP channels containing E23/S1369 and Q1372 (2.42 6 0.15vs. 1.83 6 0.14-fold, P , 0.0001) (Fig. 2D and E). Login to comment
102 E: Grouped data showing a significant increase in the stimulatory effect of GTP in channels containing the A1369 variant and in channels containing the E23/S1369 variants with the Q1372A mutation (n = 10-20 patches per group). Login to comment
155 This concept is supported further by our data showing that introduction of the Q1372A mutation into channels containing the S1369 variant enhanced the GTP stimulatory effect (Fig. 2D and E). Login to comment