Protein kinase C inhibits BKCa channel activity in pulmonary arterial smooth muscle.
Signaling mechanisms that elevate cyclic AMP (cAMP) activate large-conductance, calcium- and voltage-activated potassium (BKCa) channels in pulmonary vascular smooth muscle and cause pulmonary vasodilatation. BKCa channel modulation is important in the regulation of pulmonary arterial pressure, and inhibition (closing) of the BKCa 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 BKCa channel activity. Accordingly, studies were done to determine the effect of PKC activation on cAMP-induced BKCa channel activity using patch-clamp studies in pulmonary arterial smooth muscle cells (PASMC) of the fawn-hooded rat (FHR), a recognized animal model of pulmonary hypertension. Forskolin (10 microM), a stimulator of adenylate cyclase and an activator of cAMP, opened BKCa channels in single FHR PASMC, which were blocked by the PKC activators phorbol 12-myristate 13-acetate (100 nM) and thymeleatoxin (100 nM). The inhibitory response by thymeleatoxin on forskolin-induced BKCa channel activity was blocked by Gö-6983, which selectively blocks the alpha, beta, delta, gamma, and zeta PKC isozymes, and Gö-6976, which selectively inhibits PKC-alpha, PKC-beta, and PKC-mu, but not by rottlerin, which selectively inhibits PKC-delta. Collectively, these results indicate that activation of specific PKC isozymes inhibits cAMP-induced activation of the BKCa channel in pulmonary arterial smooth muscle, which suggests a unique signaling pathway to modulate BKCa channels and subsequently cAMP-induced pulmonary vasodilatation.
D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017380:Hypertrophy, Right Ventricular / Q000378:metabolism / Q000503:physiopathology; D051036:Large-Conductance Calcium-Activated Potassium Channels; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010703:Phorbol Esters / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000502:physiology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D011651:Pulmonary Artery / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains
D004791:Enzyme Inhibitors; D051036:Large-Conductance Calcium-Activated Potassium Channels; D010703:Phorbol Esters; D024681:Potassium Channels, Calcium-Activated; C080287:thymeleatoxin; D000242:Cyclic AMP; C497260:Prkcd protein, rat; C089212:protein kinase D; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta