title: Syntaxin-1A inhibits cardiac KATP channels by its actions on nucleotide binding folds 1 and 2 of sulfonylurea receptor 2A.
abstract: ATP-sensitive potassium (KATP) channels couple the metabolic status of the cell to its membrane potential to regulate a number of cell actions, including secretion (neurons and neuroendocrine cells) and muscle contractility (skeletal, cardiac, and vascular smooth muscle). KATP channels consist of regulatory sulfonylurea receptors (SUR) and pore-forming (Kir6.X) subunits. We recently reported (Pasyk, E. A., Kang, Y., Huang, X., Cui, N., Sheu, L., and Gaisano, H. Y. (2004) J. Biol. Chem. 279, 4234-4240) that syntaxin-1A (Syn-1A), known to mediate exocytotic fusion, was capable of binding the nucleotide binding folds (NBF1 and C-terminal NBF2) of SUR1 to inhibit the KATP channels in insulin-secreting pancreatic islet beta cells. This prompted us to examine whether Syn-1A might modulate cardiac SUR2A/KATP channels. Here, we show that Syn-1A is present in the plasma membrane of rat cardiac myocytes and binds the SUR2A protein (of rat brain, heart, and human embryonic kidney 293 cells expressing SUR2A/Kir6. 2) at its NBF1 and NBF2 domains to decrease KATP channel activation. Unlike islet beta cells, in which Syn-1A inhibition of the channel activity was apparently mediated only via NBF1 and not NBF2 of SUR1, both exogenous recombinant NBF1 and NBF2 of SUR2A were found to abolish the inhibitory actions of Syn-1A on K(ATP) channels in rat cardiac myocytes and HEK293 cells expressing SUR2A/Kir6.2. Together with our recent report, this study suggests that Syn-1A binds both NBFs of SUR1 and SUR2A but appears to exhibit distinct interactions with NBF2 of these SUR proteins in modulating the KATP channels in islet beta cells and cardiac myocytes.
authors.affiliation: Department of Medicine, University of Toronto, Toronto M5S 1A8, Canada.
authors.forename: Youhou
authors.initials: Y
authors.lastname: Kang
authors.forename: Yuk-Man
authors.initials: YM
authors.lastname: Leung
authors.forename: Jocelyn E
authors.initials: JE
authors.lastname: Manning-Fox
authors.forename: Fuzhen
authors.initials: F
authors.lastname: Xia
authors.forename: Huanli
authors.initials: H
authors.lastname: Xie
authors.forename: Laura
authors.initials: L
authors.lastname: Sheu
authors.forename: Robert G
authors.initials: RG
authors.lastname: Tsushima
authors.forename: Peter E
authors.initials: PE
authors.lastname: Light
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Gaisano
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000737:chemistry* / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D000954:Antigens, Surface / Q000096:biosynthesis / Q000502:physiology*; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D018613:Microscopy, Confocal; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000502:physiology*; D015221:Potassium Channels / Q000737:chemistry* / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D011955:Receptors, Drug / Q000737:chemistry* / Q000378:metabolism; D064233:Sulfonylurea Receptors; D050827:Syntaxin 1
chemical_list: C577507:ABCC8 protein, human; C577510:ABCC9 protein, human; D018528:ATP-Binding Cassette Transporters; C577509:Abcc8 protein, rat; D000954:Antigens, Surface; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; C494212:STX1A protein, human; C494213:Stx1a protein, rat; D064233:Sulfonylurea Receptors; D050827:Syntaxin 1; D000255:Adenosine Triphosphate; D005982:Glutathione Transferase