NO stimulation of ATP-sensitive potassium channels

Involvement of Ras/mitogen-activated protein kinase pathway and contribution to neuroprotection

Yu-Fung Lin, Kimberly Raab-Graham, Yuh Nung Jan, Lily Yeh Jan

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Abstract

ATP-sensitive potassium (KATP) 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 KATP activation via NO/Ras/mitogen-activated protein kinase pathway. By monitoring KATP single-channel activities from human embryonic kidney 293 cell-attached patches expressing sulfonylurea receptor 2B and Kir6.2, we found KATP 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 KATP 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 KATP but suppression of phosphatidylinositol 3-kinase does not. The NO precursor L-Arg also stimulates KATP 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 KATP and NO synthase activity during preconditioning. Thus, neuroprotection caused by NO released during the short episode of sublethal ischemia may be mediated partly by KATP stimulation.

Original languageEnglish (US)
Pages (from-to)7799-7804
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number20
DOIs
StatePublished - May 18 2004

Fingerprint

KATP Channels
Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinase Kinases
Nitric Oxide Synthase
Adenosine Triphosphate
Sulfonylurea Receptors
Phosphatidylinositol 3-Kinase
Physiological Phenomena
ras Proteins
Ischemic Preconditioning
Guanylate Cyclase
Pathologic Processes
Mutant Proteins
Human Activities
Vasodilation
Blood Vessels
Ischemia
Pharmacology
Insulin
Oxygen

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

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title = "NO stimulation of ATP-sensitive potassium channels: Involvement of Ras/mitogen-activated protein kinase pathway and contribution to neuroprotection",
abstract = "ATP-sensitive potassium (KATP) 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 KATP activation via NO/Ras/mitogen-activated protein kinase pathway. By monitoring KATP single-channel activities from human embryonic kidney 293 cell-attached patches expressing sulfonylurea receptor 2B and Kir6.2, we found KATP 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 KATP 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 KATP but suppression of phosphatidylinositol 3-kinase does not. The NO precursor L-Arg also stimulates KATP 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 KATP and NO synthase activity during preconditioning. Thus, neuroprotection caused by NO released during the short episode of sublethal ischemia may be mediated partly by KATP stimulation.",
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T1 - NO stimulation of ATP-sensitive potassium channels

T2 - Involvement of Ras/mitogen-activated protein kinase pathway and contribution to neuroprotection

AU - Lin, Yu-Fung

AU - Raab-Graham, Kimberly

AU - Jan, Yuh Nung

AU - Jan, Lily Yeh

PY - 2004/5/18

Y1 - 2004/5/18

N2 - ATP-sensitive potassium (KATP) 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 KATP activation via NO/Ras/mitogen-activated protein kinase pathway. By monitoring KATP single-channel activities from human embryonic kidney 293 cell-attached patches expressing sulfonylurea receptor 2B and Kir6.2, we found KATP 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 KATP 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 KATP but suppression of phosphatidylinositol 3-kinase does not. The NO precursor L-Arg also stimulates KATP 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 KATP and NO synthase activity during preconditioning. Thus, neuroprotection caused by NO released during the short episode of sublethal ischemia may be mediated partly by KATP stimulation.

AB - ATP-sensitive potassium (KATP) 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 KATP activation via NO/Ras/mitogen-activated protein kinase pathway. By monitoring KATP single-channel activities from human embryonic kidney 293 cell-attached patches expressing sulfonylurea receptor 2B and Kir6.2, we found KATP 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 KATP 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 KATP but suppression of phosphatidylinositol 3-kinase does not. The NO precursor L-Arg also stimulates KATP 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 KATP and NO synthase activity during preconditioning. Thus, neuroprotection caused by NO released during the short episode of sublethal ischemia may be mediated partly by KATP stimulation.

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JF - Proceedings of the National Academy of Sciences of the United States of America

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