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Protein kinase C inhibits BK Ca channel activity in pulmonary arterial smooth muscle

2004; American Physical Society; Volume: 286; Issue: 1 Linguagem: Inglês

10.1152/ajplung.00207.2003

1522-1504

Scott A. Barman, Shu Zhu, Richard E. White,

Nitric Oxide and Endothelin Effects

Signaling mechanisms that elevate cyclic AMP (cAMP) activate large-conductance, calcium- and voltage-activated potassium (BK Ca ) channels in pulmonary vascular smooth muscle and cause pulmonary vasodilatation. BK Ca channel modulation is important in the regulation of pulmonary arterial pressure, and inhibition (closing) 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. Accordingly, studies were done to determine the effect of PKC activation on cAMP-induced BK Ca 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 μM), a stimulator of adenylate cyclase and an activator of cAMP, opened BK Ca 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 BK Ca channel activity was blocked by Gö-6983, which selectively blocks the α, β, δ, γ, and ζ PKC isozymes, and Gö-6976, which selectively inhibits PKC-α, PKC-β, and PKC-μ, but not by rottlerin, which selectively inhibits PKC-δ. Collectively, these results indicate that activation of specific PKC isozymes inhibits cAMP-induced activation of the BK Ca channel in pulmonary arterial smooth muscle, which suggests a unique signaling pathway to modulate BK Ca channels and subsequently cAMP-induced pulmonary vasodilatation.