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

Scott A Barman, Shu Zhu, Richard E. White

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume286
Issue number1 30-1
StatePublished - Jan 1 2004

Fingerprint

Large-Conductance Calcium-Activated Potassium Channels
Protein Kinase C
Smooth Muscle
Lung
Cyclic AMP
Colforsin
Vasoconstriction
Vasodilation
Isoenzymes
Smooth Muscle Myocytes
Cyclic GMP-Dependent Protein Kinases
Vascular Smooth Muscle
Pulmonary Hypertension
Adenylyl Cyclases
Potassium
Arterial Pressure
Acetates
Animal Models
Calcium

Keywords

  • Cyclic adenosine 5′-monophosphate
  • Forskolin
  • High-conductance calcium- and voltage-activated potassium channel
  • Protein kinase C isozymes

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

Cite this

Protein kinase C inhibits BK Ca channel activity in pulmonary arterial smooth muscle . / Barman, Scott A; Zhu, Shu; White, Richard E.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 286, No. 1 30-1, 01.01.2004.

Research output: Contribution to journalArticle

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abstract = "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 G{\"o}-6983, which selectively blocks the α, β, δ, γ, and ζ PKC isozymes, and G{\"o}-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.",
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