Syntaxin-1A binds the nucleotide-binding folds of sulphonylurea receptor 1 to regulate the KATP channel.
ATP-sensitive potassium (KATP) 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+ channels. Here we show that Syn-1A acts as an endogenous regulator of KATP 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 KATP 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 KATP 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 KATP channels during dynamic changes in cytosolic ATP and ADP concentrations. These actions of Syn-1A on KATP channels contribute to the role of Syn-1A in coordinating the sequence of ionic and exocytic events leading to secretion.
Pasyk
Ewa A
EA
Department of Medicine of the University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Kang
Youhou
Y
Huang
Xiaohang
X
Cui
Ningren
N
Sheu
Laura
L
Gaisano
Herbert Y
HY
D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D002460:Cell Line; D006224:Cricetinae; D066298:In Vitro Techniques; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011955:Receptors, Drug; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D064233:Sulfonylurea Receptors; D050827:Syntaxin 1; D014162:Transfection
D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate; D000954:Antigens, Surface; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009419:Nerve Tissue Proteins; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D011994:Recombinant Proteins; D064233:Sulfonylurea Receptors; D050827:Syntaxin 1; C577509:Abcc8 protein, rat; C494213:Stx1a protein, rat