Published online before print November 29, 2004, doi: 10.1161/01.RES.0000151846.19788.E0
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Submitted on July 14, 2004
Revised on November 9, 2004
Accepted on November 17, 2004
Role of Nitric Oxide in Ca2+ Sensitivity of the Slowly Activating Delayed Rectifier K+ Current in Cardiac Myocytes
Chang-Xi Bai ;
From the Department of Bio-informational Pharmacology (C.-X.B., J.K., T.F.), Medical Research Institute, Tokyo Medical and Dental University, Tokyo; and the Department of Pharmacology (I.N., H.T., K.S.), Toho University School of Pharmaceutical Sciences, Funabashi city, Chiba, Japan.
* To whom correspondence should be addressed. E-mail: t_furukawa.bip{at}mri.tmd.ac.jp.
Sarcolemmal Ca2+ entry is a vital step for contraction of cardiomyocytes, but Ca2+ overload is harmful and may trigger arrhythmias and/or apoptosis. To maintain the amount of Ca2+ entry within an appropriate range, cardiomyocytes have feedback systems that tightly regulate ion channel activities in response to the changes in intracellular Ca2+ concentration ([Ca2+]i), thereby regulating Ca2+ entry. In guinea pig ventricular myocytes, Ca2+ ionophore, A23187, induced suppression of the L-type Ca2+ currents (ICa,L) and enhancement of the slowly activating delayed rectifier K+ currents (IKs). At a low stimulation rate, ICa,L suppression and IKs enhancement contributed to the A23187-induced APD shortening with a similar magnitude, whereas at a high stimulation rate, IKs enhancement dominantly contributed to APD shortening. IKs enhancement induced by A23187 was attributable to actions of nitric oxide (NO), because they were inhibited by an inhibitor of NO synthase (NOS) and by a NO scavenger. A23187-induced alterations of APD and IKs were strongly suppressed by a NOS3 inhibitor, but barely affected by a NOS1 inhibitor, suggesting that NOS3 was responsible for NO release in this phenomenon. Inhibition of calmodulin (CaM), but not Akt, blocked the enhancement of IKs by A23187. Thus, CaM-dependent NOS3 activation confers the selective Ca2+-sensitivity on IKs. Ca2+-induced IKs enhancement and resultant APD shortening potentially act as a physiological regulatory mechanism of Ca2+ recycling, because they were observed at a physiological range of [Ca2+]i in cardiac myocytes and are induced by physiologically relevant Ca2+ loading, such as digitalis application and rise in extracellular Ca2+ concentration.
Key words: ion channels • nitric oxide synthases • calmodulin • protein-protein interaction • caveolin
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