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

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

Research output: Contribution to journalArticle

59 Scopus citations

Abstract

Normally, signaling mechanisms that activate large-conductance, calcium- and voltage-activated potassium (BKCa) channels in pulmonary vascular smooth muscle cause pulmonary vasodilatation. BKCa-channel modulation is important in the regulation of pulmonary arterial pressure, and inhibition (decrease in the opening probability) 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 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 BKCa channels in single Sprague-Dawley rat PASMC. The activator response to both PMA and thymeleatoxin on BKCa-channel activity was blocked by Gö-6983, which selectively blocks PKC-α, -δ, -γ and -ζ, and by rottlerin, which selectively inhibits PKC-δ. 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 BKCa-channel blocker tetraethylammonium. The results of this study indicate that activation of specific PKC isozymes increases BKCa-channel activity in Sprague-Dawley rat PASMC via cyclic GMP-dependent protein kinase, which suggests a unique signaling mechanism for vasodilatation.

Original languageEnglish (US)
Pages (from-to)L1275-L1281
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume286
Issue number6 30-6
DOIs
StatePublished - Jun 1 2004

Keywords

  • Cyclic GMP-dependent protein kinase
  • High-conductance calcium-and voltage-activated potassium channel
  • Protein kinase C isozymes
  • Protein kinase G
  • Pulmonary arterial smooth muscle

ASJC Scopus subject areas

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

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