Leung Yuk M, Kwan Edwin P, Ng Betty, Kang Youhou, Gaisano Herbert Y
Departmnet of Physiology, China Medical University, Taichung 40402, Taiwan.
Endocr Rev. 2007 Oct;28(6):653-63. doi: 10.1210/er.2007-0010. Epub 2007 Sep 18.
The three SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins, syntaxin, SNAP25 (synaptosome-associated protein of 25 kDa), and synaptobrevin, constitute the minimal machinery for exocytosis in secretory cells such as neurons and neuroendocrine cells by forming a series of complexes prior to and during vesicle fusion. It was subsequently found that these SNARE proteins not only participate in vesicle fusion, but also tether with voltage-dependent Ca(2+) channels to form an excitosome that precisely regulates calcium entry at the site of exocytosis. In pancreatic islet beta-cells, ATP-sensitive K(+) (K(ATP)) channel closure by high ATP concentration leads to membrane depolarization, voltage-dependent Ca(2+) channel opening, and insulin secretion, whereas subsequent opening of voltage-gated K(+) (Kv) channels repolarizes the cell to terminate exocytosis. We have obtained evidence that syntaxin-1A physically interacts with Kv2.1 (the predominant Kv in beta-cells) and the sulfonylurea receptor subunit of beta-cell K(ATP) channel to modify their gating behaviors. A model has proposed that the conformational changes of syntaxin-1A during exocytosis induce distinct functional modulations of K(ATP) and Kv2.1 channels in a manner that optimally regulates cell excitability and insulin secretion. Other proteins involved in exocytosis, such as Munc-13, tomosyn, rab3a-interacting molecule, and guanyl nucleotide exchange factor II, have also been implicated in direct or indirect regulation of beta-cell ion channel activities and excitability. This review discusses this interesting aspect that exocytotic proteins not only promote secretion per se, but also fine-tune beta-cell excitability via modulation of ion channel gating.
三种SNARE（可溶性N - 乙基马来酰亚胺敏感因子附着蛋白受体）蛋白，即 syntaxin、SNAP25（25 kDa的突触体相关蛋白）和突触小泡蛋白，通过在囊泡融合之前及过程中形成一系列复合物，构成了神经元和神经内分泌细胞等分泌细胞中胞吐作用的最小机制。随后发现，这些SNARE蛋白不仅参与囊泡融合，还与电压依赖性Ca(2+)通道相连，形成一个精确调节胞吐作用位点钙内流的兴奋体。在胰岛β细胞中，高ATP浓度导致ATP敏感性钾（K(ATP)）通道关闭，进而引起膜去极化、电压依赖性Ca(2+)通道开放以及胰岛素分泌，而随后电压门控钾（Kv）通道的开放使细胞复极化以终止胞吐作用。我们已获得证据表明，syntaxin - 1A与Kv2.1（β细胞中主要的Kv通道）以及β细胞K(ATP)通道的磺酰脲受体亚基发生物理相互作用，从而改变它们的门控行为。有人提出了一个模型，即胞吐作用期间syntaxin - 1A的构象变化以一种最佳调节细胞兴奋性和胰岛素分泌的方式，诱导K(ATP)和Kv2.1通道产生不同的功能调节。其他参与胞吐作用的蛋白，如Munc - 13、tomosyn、rab3a相互作用分子和鸟苷酸交换因子II，也与β细胞离子通道活性和兴奋性的直接或间接调节有关。本综述讨论了这一有趣的方面，即胞吐蛋白不仅本身促进分泌，还通过调节离子通道门控来微调β细胞的兴奋性。
