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The actions of a novel potent islet beta-cell specific K_ATP channel opener can be modulated by syntaxin-1A acting on sulfonylurea receptor 1

¹Departments of Medicine and Physiology, University of Toronto, Toronto, Canada M5S 1A8
²Novo Nordisk, Malov, Denmark, DK-2760

Correspondence: Herbert.gaisano{at}utoronto.ca

Key Words: K_ATP channels • sulfonylurea receptor • Syntaxin 1A • K_ATP channel opener • thiadiazine dioxides • diazoxide analog • islet beta cell

Objective:Islet ß-cell-specific K_ATP channel openers (KCOs) thiadiazine dioxides induce islet rest to improve insulin secretion, but their molecular basis of action remains unclear. We reported that Syntaxin-1A (Syn-1A) binds nucleotide binding folds (NBFs) of SUR1 in ß-cells to inhibit K_ATP channels. As a strategy to elucidate the molecular mechanism of action of these KCOs, we explored the possibility that NNC 55-0462 might influence Syn-1A-SUR1 interactions or vice versa.

Research Design and Methods:Whole-cell and inside-out patch-clamp electrophysiology was utilized to examine the effects of GST-Syn-1A dialysis or GFP/Syn-1A co-transfection on NNC 55-0462 actions. In vitro pull-down binding studies were used to examine NNC 55-0462 influence on Syn-1A-SUR1 interactions.

Results:Dialysis of GST-Syn-1A into the cell cytoplasm reduced both potency and efficacy of extracellularly perfused NNC55-0462 in a HEK cell-line stably expressing Kir6.2/SUR1 (BA8 cells) and in rat islet ß-cells. Moreover, inside-out membrane patches excised from BA8 cells showed that both GST-Syn-1A and its H3 domain inhibited K_ATP channels previously activated by NNC55-0462. This action on K_ATP channels is isoform-specific to Syn-1A, as Syn-2 was without effect. Furthermore, parent compound diazoxide showed similar sensitivity to GST-Syn-1A inhibition. NNC 55-0462 however did not influence Syn-1A-SUR1 binding interaction.

Conclusion:Our results demonstrated that Syn-1A interactions with SUR1 at its cytoplasmic domains can modulate the actions of KCOs-NNC 55-0462 and diazoxide on K_ATP channels. The reduced levels of islet Syn-1A in diabetes would thus be expected to exert a positive influence on the therapeutic effects of this class of KCOs.

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				Y. M. Leung, E. P. Kwan, B. Ng, Y. Kang, and H. Y. Gaisano SNAREing Voltage-Gated K+ and ATP-Sensitive K+ Channels: Tuning {beta}-Cell Excitability with Syntaxin-1A and Other Exocytotic Proteins Endocr. Rev., October 1, 2007; 28(6): 653 - 663. [Abstract] [Full Text] [PDF]