title: Urocortin2 prolongs action potential duration and modulates potassium currents in guinea pig myocytes and HEK293 cells.
abstract: We previously reported that activation of corticotropin releasing factor receptor type 2 by urocortin2 up-regulates both L-type Ca(2+) channels and intracellular Ca(2+) concentration in ventricular myocytes and plays an important role in cardiac contractility and arrhythmogenesis. This study goal was to further test the hypothesis that urocortin2 may modulate action potentials as well as rapidly and slowly activating delayed rectifier potassium currents. With whole cell patch-clamp techniques, action potentials and slowly activating delayed rectifier potassium currents were recorded in isolated guinea pig ventricular myocytes, respectively. And rapidly activating delayed rectifier potassium currents were tested in hERG-HEK293 cells. Urocortin2 produced a time- and concentration-dependent prolongation of action potential duration. The EC50 values of action potential duration and action potential duration at 90% of repolarization were 14.73 and 24.3nM respectively. The prolongation of action potential duration of urocortin2 was almost completely or partly abolished by H-89 (protein kinase A inhibitor) or KB-R7943 (Na(+)/Ca(2+) exchange inhibitor) pretreatment respectively. And urocortin2 caused reduction of rapidly activating delayed rectifier potassium currents in hERG-HEK293 cells. In addition, urocortin2 slowed the rate of slowly activating delayed rectifier potassium channel activation, and rightward shifted the threshold of slowly activating delayed rectifier potassium currents to more positive potentials. Urocortin2 prolonged action potential duration via activation of protein kinase A and Na(+)/ Ca(2+) exchange in isolated guinea pig ventricular myocytes in a time- and concentration- dependent manner. In hERG-HEK293 cells, urocortin2 reduced rapidly activating delayed rectifier potassium current density which may contribute to action potential duration prolongation.
authors: Division of Endocrinology, Department of Internal Medicine, Shanghai Ninth People׳s Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China. Electronic address: dryanginsh@yahoo.com.
authors: Li-Zhen
authors: LZ
authors: Yang
authors: Shanghai Key Laboratory of Bioactive Small Molecules, Department of Physiology and Pathophysiology, Research Center on Aging and Medicine, Shanghai Medical College, Fudan University, Shanghai, China.
authors: Yi-Chun
authors: YC
authors: Zhu
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004553:Electric Conductivity; D006168:Guinea Pigs; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects*; D007546:Isoquinolines / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D054832:Urocortins / Q000037:antagonists & inhibitors / Q000494:pharmacology*
chemical_list: C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; D007546:Isoquinolines; D024642:Potassium Channels, Voltage-Gated; D013449:Sulfonamides; D054832:Urocortins; D013890:Thiourea; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D011188:Potassium
keywords: Action potential duration; Myocytes; Potassium currents; Urocortin2; hERG-HEK293 cells