ATP modulates interaction of syntaxin-1A with sulfonylurea receptor 1 to regulate pancreatic β-Cell KATP channels

Youhou Kang, Yi Zhang, Tao Liang, Yuk Man Leung, Betty Ng, Huanli Xie, Nathan Chang, Joseph Chan, Show Ling Shyng, Robert G. Tsushima, Herbert Y. Gaisano

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

ATP-sensitive potassium (KATP) channels are regulated by a variety of cytosolic factors (adenine nucleotides, Mg2+, phospholipids, and pH). We previously reported that KATP channels are also regulated by endogenous membrane-bound SNARE protein syntaxin-1A (Syn-1A), which binds both nucleotide-binding folds of sulfonylurea receptor (SUR)1 and 2A, causing inhibition of KATP channel activity in pancreatic islet β-cells and cardiac myocytes, respectively. In this study, we show that ATP dose-dependently inhibits Syn-1A binding to SUR1 at physiological concentrations, with the addition of Mg2+ causing a decrease in the ATP-induced inhibitory effect. This ATP disruption of Syn-1A binding to SUR1 was confirmed by FRET analysis in living HEK293 cells. Electrophysiological studies in pancreatic β-cells demonstrated that reduced ATP concentrations increased KATP channel sensitivity to Syn-1A inhibition. Depletion of endogenous Syn-1A in insulinoma cells by botulinum neurotoxin C1 proteolysis followed by rescue with exogenous Syn-1A showed that Syn-1A modulates K ATP channel sensitivity to ATP. Thus, our data indicate that although both ATP and Syn-1A independently inhibit β-cell KATP channel gating, they could also influence the sensitivity of KATP channels to each other. These findings provide new insight into an alternate mechanism by which ATP regulates pancreatic β-cell KATP channel activity, not only by its direct actions on Kir6.2 pore subunit, but also via ATP modulation of Syn-1A binding to SUR1.

Original languageEnglish (US)
Pages (from-to)5876-5883
Number of pages8
JournalJournal of Biological Chemistry
Volume286
Issue number7
DOIs
StatePublished - Feb 18 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Kang, Y., Zhang, Y., Liang, T., Leung, Y. M., Ng, B., Xie, H., Chang, N., Chan, J., Shyng, S. L., Tsushima, R. G., & Gaisano, H. Y. (2011). ATP modulates interaction of syntaxin-1A with sulfonylurea receptor 1 to regulate pancreatic β-Cell KATP channels. Journal of Biological Chemistry, 286(7), 5876-5883. https://doi.org/10.1074/jbc.M109.089607