title: Carbon monoxide inhibits inward rectifier potassium channels in cardiomyocytes.
abstract: Reperfusion-induced ventricular fibrillation (VF) severely threatens the lives of post-myocardial infarction patients. Carbon monoxide (CO)--produced by haem oxygenase in cardiomyocytes--has been reported to prevent VF through an unknown mechanism of action. Here, we report that CO prolongs action potential duration (APD) by inhibiting a subset of inward-rectifying potassium (Kir) channels. We show that CO blocks Kir2.2 and Kir2.3 but not Kir2.1 channels in both cardiomyocytes and HEK-293 cells transfected with Kir. CO directly inhibits Kir2.3 by interfering with its interaction with the second messenger phosphatidylinositol (4,5)-bisphosphate (PIP2). As the inhibition of Kir2.2 and Kir2.3 by CO prolongs APD in myocytes, cardiac Kir2.2 and Kir2.3 are promising targets for the prevention of reperfusion-induced VF.
authors.affiliation: Laboratory of Molecular Pharmacology, Institute of Molecular Medicine, Peking University, Peking 100871, China.
authors.forename: Shenghui
authors.initials: S
authors.lastname: Liang
authors.affiliation: 1] Laboratory of Molecular Pharmacology, Institute of Molecular Medicine, Peking University, Peking 100871, China [2] Department of Biopharmaceutics, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Quanyi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Laboratory of Molecular Pharmacology, Institute of Molecular Medicine, Peking University, Peking 100871, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Hebei Medical University, Hebei 050017, China.
authors.forename: Hailin
authors.initials: H
authors.lastname: Zhang
authors.affiliation: MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.
authors.forename: Shengjiang
authors.initials: S
authors.lastname: Tan
authors.affiliation: Vascular Medicine Unit, Aston Medical School, Aston University, Birmingham B4 7ET, UK.
authors.forename: Asif
authors.initials: A
authors.lastname: Ahmed
authors.affiliation: Laboratory of Molecular Pharmacology, Institute of Molecular Medicine, Peking University, Peking 100871, China.
authors.forename: Yuchun
authors.initials: Y
authors.lastname: Gu
mesh_terms: D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D002248:Carbon Monoxide / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D023421:Models, Animal; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D024661:Potassium Channels, Inwardly Rectifying / Q000037:antagonists & inhibitors* / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D014162:Transfection
chemical_list: C575188:KCNJ2 protein, rat; C490968:Kcnj4 protein, rat; C489463:Kir2.2 channel; D024661:Potassium Channels, Inwardly Rectifying; D002248:Carbon Monoxide