The tolbutamide site of SUR1 and a mechanism for its functional coupling to KATP channel closure
The tolbutamide site of SUR1 and a mechanism for its functional coupling to KATP channel closure
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DOI：
10.1016/s0014-5793(99)01215-6
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发表时间：
1999-10-15
期刊：
影响因子：
3.5
通讯作者：
Bryan, J
中科院分区：
文献类型：
--
作者：
Babenko, AP;Gonzalez, G;Bryan, J
微摩尔浓度的甲苯磺丁脲将抑制胰腺β细胞中的（SUR 1/K（IR）6.2）（4）通道，但不抑制心肌细胞中的（SUR 2A/K（IR）6.2）（4）通道。抑制不需要Mg 2+或核苷酸，并且通过细胞内核苷酸增强。使用SUR 1和SUR 2A之间的嵌合体，我们表明跨膜结构域12-17（TMD 12 -17）是高亲和力甲苯磺丁脲抑制K-ATP通道所必需的。缺失表明参与细胞质N-末端的K（IR）6.2在耦合磺酰脲结合与SUR 1的一个间歇封闭的配置的通道的稳定，甲苯磺丁脲的增加的功效的核苷酸的结果从他们的刺激作用SUR 1，揭示其抑制作用的损害。因此，在治疗非胰岛素依赖型糖尿病期间，磺酰脲类药物抑制β细胞KATP通道的机制涉及两个组分，即通过其N-末端与孔亚基偶联的SUR 1内的药物结合和构象变化，以及调节亚基对孔的核苷酸依赖性刺激作用的破坏。这些发现揭示了SUR 1（一种ATP结合盒（ABC）蛋白）对K（IR）6.2（一种离子通道亚基）抑制作用的分子基础，（C）1999欧洲生物化学学会联合会。
Micromolar concentrations of tolbutamide will inhibit (SUR1/K(IR)6.2)(4) channels in pancreatic beta-cells, but not (SUR2A/K(IR)6.2)(4) channels in cardiomyocytes, Inhibition does not require Mg2+ or nucleotides and is enhanced by intracellular nucleotides. Using chimeras between SUR1 and SUR2A, we show that transmembrane domains 12-17 (TMD12-17) are required for high-affinity tolbutamide inhibition of K-ATP channels. Deletions demonstrate involvement of the cytoplasmic N-terminus of K(IR)6.2 in coupling sulfonylurea-binding with SUR1 to the stabilization of an interburst closed configuration of the channel, The increased efficacy of tolbutamide by nucleotides results from an impairment of their stimulatory action on SUR1 which unmasks their inhibitory effects. The mechanism of inhibition of beta-cell KATP channels by sulfonylureas during treatment of noninsulin-dependent diabetes mellitus thus involves two components, drug-binding and conformational changes within SUR1 which are coupled to the pore subunit through its N-terminus and the disruption of nucleotide-dependent stimulatory effects of the regulatory subunit on the pore. These findings uncover a molecular basis for an inhibitory influence of SUR1, an ATP-binding cassette (ABC) protein, on K(IR)6.2, a ion channel subunit, (C) 1999 Federation of European Biochemical Societies.