Syntaxin-1A Binds the Nucleotide-binding Folds of Sulphonylurea Receptor 1 to Regulate the K sub(ATP) Channel

• Published in: The Journal of biological chemistry Vol. 279; no. 6; pp. 4234 - 4240
• Main Authors: Pasyk, E A, Kang, Y, Huang, X, Cui, N, Sheu, L, Gaisano, HY
• Format: Journal Article
• Language: English
• Published: 06.02.2004
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M309667200

ATP-sensitive potassium (K sub(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 super(+) channels. Here we show that Syn-1A acts as an endogenous regulator of K sub(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 sub(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 sub(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 sub(ATP) channels during dynamic changes in cytosolic ATP and ADP concentrations. These actions of Syn-1A on K sub(ATP) channels contribute to the role of Syn-1A in coordinating the sequence of ionic and exocytic events leading to secretion.