Syntaxin-1A binds the nucleotide-binding folds of sulphonylurea receptor 1 to regulate the KATP channel
Syntaxin-1A binds the nucleotide-binding folds of sulphonylurea receptor 1 to regulate the KATP channel
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DOI：
10.1074/jbc.m309667200
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发表时间：
2004-02-06
影响因子：
4.8
通讯作者：
Gaisano, HY
中科院分区：
文献类型：
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作者：
Pasyk, EA;Kang, YH;Gaisano, HY
神经元和神经内分泌细胞中的 ATP 敏感钾 (K-ATP) 通道由成孔 Kir6.2 和调节性磺酰脲受体 (SUR1) 亚基组成，受 ATP 和 ADP 调节。 SNARE 蛋白突触蛋白 1A (Syn-1A) 已知可介导胞吐融合，最近还结合和调节膜复极化电压门控 K+ 通道。在这里，我们证明 Syn-1A 作为 K-ATP 通道的内源性调节剂，能够在胞质 ATP 浓度降低时关闭这些通道。肉毒杆菌神经毒素 C1 裂解胰岛素瘤 HIT-T15 细胞中的内源性 Syn-1A，导致 K-ATP 电流增加，随后可被重组 Syn-1A 抑制。尽管 Syn-1A 结合 SUR1 的两个核苷酸结合折叠（NBF-1 和 NBF-2），但 Syn-1A 对大鼠胰岛 β 细胞中 K-ATP 通道的功能性抑制似乎主要是通过其与 NBF-1 的相互作用介导的。 Syn-1A 的这些抑制作用可以通过生理浓度的 ADP 和二氮嗪逆转。因此，Syn-1A 在胞质 ATP 和 ADP 浓度动态变化期间微调 K-ATP 通道的调节。 Syn-1A 对 K-ATP 通道的这些作用有助于 Syn-1A 在协调导致分泌的离子和胞吐事件序列中发挥作用。
ATP-sensitive potassium (K-ATP) channels in neuron and neuroendocrine cells consist of a pore-forming Kir6.2 and regulatory sulfonylurea receptor (SUR1) subunits, which are regulated by ATP and ADP. SNARE protein syntaxin 1A (Syn-1A) is known to mediate exocytic fusion, and more recently, to also bind and modulate membrane-repolarizing voltage-gated K+ channels. Here we show that Syn-1A acts as an endogenous regulator of K-ATP channels capable of closing these channels when cytosolic ATP concentrations were lowered. Botulinum neurotoxin C1 cleavage of endogenous Syn-1A in insulinoma HIT-T15 cells resulted in the increase in K-ATP currents, which could be subsequently inhibited by recombinant Syn-1A. Whereas Syn-1A binds both nucleotide-binding folds (NBF-1 and NBF-2) of SUR1, the functional inhibition of K-ATP channels in rat islet beta-cells by Syn-1A seems to be mediated primarily by its interactions with NBF-1. These inhibitory actions of Syn-1A can be reversed by physiologic concentrations of ADP and by diazoxide. Syn-1A therefore acts to fine-tune the regulation of K-ATP channels during dynamic changes in cytosolic ATP and ADP concentrations. These actions of Syn-1A on K-ATP channels contribute to the role of Syn-1A in coordinating the sequence of ionic and exocytic events leading to secretion.