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SNAREing Voltage-Gated K⁺ and ATP-Sensitive K⁺ Channels: Tuning ß-Cell Excitability with Syntaxin-1A and Other Exocytotic Proteins

Department of Physiology (Y.M.L.) and Graduate Institute of Neural and Cognitive Sciences (Y.M.L.), China Medical University, Taichung 40402, Taiwan; and Departments of Medicine and Physiology (E.P.K., B.N., Y.K., H.Y.G.), University of Toronto, Toronto, Canada M5S 2A8

Correspondence: Address all correspondence and requests for reprints to: Dr. Herbert Gaisano, Room 7226, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada M5S 2A8. E-mail: herbert.gaisano{at}utoronto.ca; or Dr. Yuk-Man Leung, Department of Physiology, China Medical University, Taichung 40402, Taiwan. E-mail: ymleung{at}mail.cmu.edu.tw

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 Ca²⁺ channels to form an excitosome that precisely regulates calcium entry at the site of exocytosis. In pancreatic islet ß-cells, ATP-sensitive K⁺ (K_ATP) channel closure by high ATP concentration leads to membrane depolarization, voltage-dependent Ca²⁺ 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 ß-cells) and the sulfonylurea receptor subunit of ß-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 ß-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 ß-cell excitability via modulation of ion channel gating.

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