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PKC activates BK_Ca channels in rat pulmonary arterial smooth muscle via cGMP-dependent protein kinase

Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, Georgia 30912

Submitted 28 July 2003 ; accepted in final form 9 February 2004

Normally, signaling mechanisms that activate large-conductance, calcium- and voltage-activated potassium (BK_Ca) channels in pulmonary vascular smooth muscle cause pulmonary vasodilatation. BK_Ca-channel modulation is important in the regulation of pulmonary arterial pressure, and inhibition (decrease in the opening probability) of the BK_Ca channel has been implicated in the development of pulmonary vasoconstriction. Protein kinase C (PKC) causes pulmonary vasoconstriction, but little is known about the effect of PKC on BK_Ca-channel activity in pulmonary vascular smooth muscle. Accordingly, studies were done to determine the effect of PKC on BK_Ca-channel activity using patch-clamp studies in pulmonary arterial smooth muscle cells (PASMCs) of the Sprague-Dawley rat. The PKC activators phorbol myristate acetate (PMA) and thymeleatoxin opened BK_Ca channels in single Sprague-Dawley rat PASMC. The activator response to both PMA and thymeleatoxin on BK_Ca-channel activity was blocked by Gö-6983, which selectively blocks PKC-, -, -, and -, and by rottlerin, which selectively inhibits PKC-. In addition, the specific cyclic GMP-dependent protein kinase antagonist KT-5823 blocked the responses to PMA and thymelatoxin, whereas the specific cyclic AMP-dependent protein kinase blocker KT-5720 had no effect. In isolated pulmonary arterial vessels, both PMA and forskolin caused vasodilatation, which was inhibited by KT-5823, Gö-6983, or the BK_Ca-channel blocker tetraethylammonium. The results of this study indicate that activation of specific PKC isozymes increases BK_Ca-channel activity in Sprague-Dawley rat PASMC via cyclic GMP-dependent protein kinase, which suggests a unique signaling mechanism for vasodilatation.

high-conductance calcium-and voltage-activated potassium channel; pulmonary arterial smooth muscle; protein kinase C isozymes; cyclic GMP-dependent protein kinase; protein kinase G

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