Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, OR 97239, USA.
J Gen Physiol. 2012 Aug;140(2):175-87. doi: 10.1085/jgp.201210803. Epub 2012 Jul 16.
The ATP-sensitive potassium (K(ATP)) channel consisting of the inward rectifier Kir6.2 and SUR1 (sulfonylurea receptor 1) couples cell metabolism to membrane excitability and regulates insulin secretion. Inhibition by intracellular ATP is a hallmark feature of the channel. ATP sensitivity is conferred by Kir6.2 but enhanced by SUR1. The mechanism by which SUR1 increases channel ATP sensitivity is not understood. In this study, we report molecular interactions between SUR1 and Kir6.2 that markedly alter channel ATP sensitivity. Channels bearing an E203K mutation in SUR1 and a Q52E in Kir6.2 exhibit ATP sensitivity ∼100-fold higher than wild-type channels. Cross-linking of E203C in SUR1 and Q52C in Kir6.2 locks the channel in a closed state and is reversible by reducing agents, demonstrating close proximity of the two residues. Our results reveal that ATP sensitivity in K(ATP) channels is a dynamic parameter dictated by interactions between SUR1 and Kir6.2.
ATP 敏感性钾 (K(ATP)) 通道由内向整流钾通道 Kir6.2 和 SUR1（磺酰脲受体 1）组成，它将细胞代谢与膜兴奋性偶联起来，并调节胰岛素分泌。细胞内 ATP 的抑制是该通道的一个显著特征。Kir6.2 赋予通道对 ATP 的敏感性，但 SUR1 增强了这种敏感性。SUR1 增加通道对 ATP 敏感性的机制尚不清楚。在这项研究中，我们报告了 SUR1 和 Kir6.2 之间的分子相互作用，这些相互作用显著改变了通道对 ATP 的敏感性。在 SUR1 中的 E203K 突变和 Kir6.2 中的 Q52E 的通道表现出比野生型通道高约 100 倍的 ATP 敏感性。在 SUR1 中的 E203C 和 Kir6.2 中的 Q52C 之间的交联将通道锁定在关闭状态，并且可以通过还原剂逆转，这表明这两个残基非常接近。我们的结果表明，K(ATP)通道的 ATP 敏感性是由 SUR1 和 Kir6.2 之间的相互作用决定的动态参数。
