ABCMdb

ABCC8 p.Ser1571Asp

Predicted by SNAP2:	A: D (63%), C: D (75%), D: D (80%), E: D (80%), F: D (85%), G: N (93%), H: D (80%), I: D (85%), K: D (80%), L: D (85%), M: D (80%), N: D (71%), P: D (91%), Q: D (80%), R: D (75%), T: D (63%), V: D (80%), W: D (85%), Y: D (85%),
Predicted by PROVEAN:	A: N, C: D, D: D, E: D, F: D, G: N, H: D, I: D, K: D, L: D, M: D, N: N, P: D, Q: D, R: D, T: N, V: D, W: D, Y: D,

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Publications
[hide] PKA-mediated phosphorylation of the human K(ATP) c... EMBO J. 1999 Sep 1;18(17):4722-32. Beguin P, Nagashima K, Nishimura M, Gonoi T, Seino S
PKA-mediated phosphorylation of the human K(ATP) channel: separate roles of Kir6.2 and SUR1 subunit phosphorylation.
EMBO J. 1999 Sep 1;18(17):4722-32., [PMID:10469651]

Abstract [show]
ATP-sensitive potassium (K(ATP)) channels play important roles in many cellular functions such as hormone secretion and excitability of muscles and neurons. Classical ATP-sensitive potassium (K(ATP)) channels are heteromultimeric membrane proteins comprising the pore-forming Kir6.2 subunits and the sulfonylurea receptor subunits (SUR1 or SUR2). The molecular mechanism by which hormones and neurotransmitters modulate K(ATP) channels via protein kinase A (PKA) is poorly understood. We mutated the PKA consensus sequences of the human SUR1 and Kir6.2 subunits and tested their phosphorylation capacities in Xenopus oocyte homogenates and in intact cells. We identified the sites responsible for PKA phosphorylation in the C-terminus of Kir6.2 (S372) and SUR1 (S1571). Kir6.2 can be phosphorylated at its PKA phosphorylation site in intact cells after G-protein (Gs)-coupled receptor or direct PKA stimulation. While the phosphorylation of Kir6.2 increases channel activity, the phosphorylation of SUR1 contributes to the basal channel properties by decreasing burst duration, interburst interval and open probability, and also increasing the number of functional channels at the cell surface. Moreover, the effect of PKA could be mimicked by introducing negative charges in the PKA phosphorylation sites. These data demonstrate direct phosphorylation by PKA of the K(ATP) channel, and may explain the mechanism by which Gs-coupled receptors stimulate channel activity. Importantly, they also describe a model of heteromultimeric ion channels in which there are functionally distinct roles of the phosphorylation of the different subunits.

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No. Sentence Comment
67 In contrast, the phosphorylation in the S1571A mutant in response to PKA was completely abolished (Figure 3B, compare lane 4 with 7). Login to comment
68 PKA-mediated phosphorylation of human SUR1 was also abolished by the substitution of serine-1571 with aspartic acid (unpublished data). Login to comment
169 In contrast, no significant change was observed in open probability (0.12 Ϯ 0.06 and 0.09 Ϯ 0.03, for wt Kir6.2/SUR1 and wt Kir6.2/ SUR1 S1571D, respectively, n ϭ 4-7) or channel kinetics (unpublished data) for the SUR1 S1571D mutant, as would be expected if SUR1 is already phosphorylated under basal conditions. Login to comment
201 Since the PKA action of each subunit can be mimicked by the Kir6.2 (S372D) or SUR1 (S1571D) mutant, the negative charges carried by both subunits seem to be good candidates for this structural change. Login to comment
168 In contrast, no significant change was observed in open probability (0.12 afe; 0.06 and 0.09 afe; 0.03, for wt Kir6.2/SUR1 and wt Kir6.2/ SUR1 S1571D, respectively, n afd; 4-7) or channel kinetics (unpublished data) for the SUR1 S1571D mutant, as would be expected if SUR1 is already phosphorylated under basal conditions. Login to comment