title: NO stimulation of ATP-sensitive potassium channels: Involvement of Ras/mitogen-activated protein kinase pathway and contribution to neuroprotection.
abstract: ATP-sensitive potassium (K(ATP)) channels regulate insulin release, vascular tone, and neuronal excitability. Whether these channels are modulated by NO, a membrane-permeant messenger in various physiological and pathological processes, is not known. The possibility of NO signaling via K(ATP) channel modulation is of interest because both NO and K(ATP) have been implicated in physiological functions such as vasodilation and neuroprotection. In this report, we demonstrate a mechanism that leads to K(ATP) activation via NO/Ras/mitogen-activated protein kinase pathway. By monitoring K(ATP) single-channel activities from human embryonic kidney 293 cell-attached patches expressing sulfonylurea receptor 2B and Kir6.2, we found K(ATP) stimulation by NO donor Noc-18, a specific NO effect abolished by NO scavenger 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO) but not guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). NO stimulation of K(ATP) is indirect and requires Ras and mitogen-activated protein kinase kinase activities. Blockade of Ras activation by pharmacological means or by coexpressing either a dominant-negative or an S-nitrosylation-site mutant Ras protein significantly abrogates the effects of NO. Inhibition of mitogen-activated protein kinase kinase abolishes the NO activation of K(ATP) but suppression of phosphatidylinositol 3-kinase does not. The NO precursor l-Arg also stimulates K(ATP) via endogenous NO synthase and the Ras signaling pathway. In addition, in rat hippocampal neurons, the protective effect of ischemic preconditioning induced by oxygen-glucose deprivation requires K(ATP) and NO synthase activity during preconditioning. Thus, neuroprotection caused by NO released during the short episode of sublethal ischemia may be mediated partly by K(ATP) stimulation.
authors.affiliation: Howard Hughes Medical Institute and Department of Physiology, University of California, San Francisco, CA 94143-0725, USA. yflin@ucdavis.edu
authors.forename: Yu-Fung
authors.initials: YF
authors.lastname: Lin
authors.forename: Kimberly
authors.initials: K
authors.lastname: Raab-Graham
authors.forename: Yuh Nung
authors.initials: YN
authors.lastname: Jan
authors.forename: Lily Yeh
authors.initials: LY
authors.lastname: Jan
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001120:Arginine / Q000378:metabolism; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D015221:Potassium Channels / Q000378:metabolism*; D051381:Rats; D019323:omega-N-Methylarginine / Q000378:metabolism; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D018696:Neuroprotective Agents; D015221:Potassium Channels; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D000255:Adenosine Triphosphate; D001120:Arginine; D019001:Nitric Oxide Synthase; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins