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

Scott A Barman1, Shu Zhu, Richard E White

  • 1Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA 30912, USA. sbarman@mail.mcg.edu

American Journal of Physiology. Lung Cellular and Molecular Physiology
|February 18, 2004
PubMed

Insights

Protein kinase C (PKC) activation in rat pulmonary arteries increases large-conductance, calcium- and voltage-activated potassium (BK(Ca)) channel activity. This pathway, mediated by cyclic GMP-dependent protein kinase, promotes pulmonary vasodilatation.

Area of Science:

  • Physiology
  • Molecular Biology
  • Pharmacology

Background:

  • Large-conductance, calcium- and voltage-activated potassium (BK(Ca)) channels regulate pulmonary vascular tone.
  • Inhibition of BK(Ca) channels is linked to pulmonary vasoconstriction.
  • Protein kinase C (PKC) is known to cause pulmonary vasoconstriction, but its effect on BK(Ca) channels in pulmonary vasculature is unclear.

Purpose of the Study:

  • To investigate the effect of PKC on BK(Ca)-channel activity in pulmonary arterial smooth muscle cells (PASMCs).
  • To elucidate the signaling pathway involved in PKC-mediated BK(Ca)-channel modulation in pulmonary vasculature.

Main Methods:

  • Patch-clamp electrophysiology was used to study BK(Ca)-channel activity in rat PASMCs.
  • PKC activators (phorbol myristate acetate, thymeleatoxin) and inhibitors (Gö-6983, rottlerin) were employed.
  • Specific protein kinase antagonists (KT-5823 for cGMP-dependent kinase, KT-5720 for cAMP-dependent kinase) were used.
  • Vasodilatation was assessed in isolated pulmonary arterial vessels.

Main Results:

  • PKC activators (PMA, thymeleatoxin) increased BK(Ca)-channel activity in PASMCs.
  • The effects of PMA and thymeleatoxin were blocked by PKC inhibitors (Gö-6983, rottlerin).
  • The response to PKC activation was inhibited by a cGMP-dependent protein kinase antagonist (KT-5823) but not by a cAMP-dependent protein kinase antagonist (KT-5720).
  • In isolated vessels, PMA and forskolin induced vasodilatation, which was attenuated by KT-5823, Gö-6983, or a BK(Ca)-channel blocker (tetraethylammonium).

Conclusions:

  • Specific PKC isozymes activate BK(Ca) channels in rat PASMCs.
  • This activation occurs via a pathway involving cyclic GMP-dependent protein kinase.
  • This represents a novel signaling mechanism contributing to pulmonary vasodilatation.

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