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Protein kinase C inhibits BKCa channel activity in pulmonary arterial smooth muscle

Scott A Barman1, Shu Zhu, Richard E White

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

American Journal of Physiology. Lung Cellular and Molecular Physiology
|September 30, 2003
PubMed

Insights

Activation of Protein Kinase C (PKC) inhibits cyclic AMP (cAMP)-induced large-conductance, calcium- and voltage-activated potassium (BKCa) channel activity in pulmonary artery smooth muscle cells, impacting pulmonary vasodilatation.

Area of Science:

  • Physiology
  • Molecular Biology
  • Pharmacology

Background:

  • Cyclic AMP (cAMP) signaling activates large-conductance, calcium- and voltage-activated potassium (BKCa) channels, promoting pulmonary vasodilatation.
  • BKCa channel activity is crucial for regulating pulmonary arterial pressure; its inhibition contributes to pulmonary vasoconstriction.
  • Protein Kinase C (PKC) is known to cause pulmonary vasoconstriction, but its direct effect on BKCa channel activity remains unclear.

Purpose of the Study:

  • To investigate the effect of Protein Kinase C (PKC) activation on cyclic AMP (cAMP)-induced BKCa channel activity.
  • To elucidate the role of specific PKC isozymes in modulating BKCa channel function in pulmonary arterial smooth muscle cells.

Main Methods:

  • Utilized patch-clamp studies in pulmonary arterial smooth muscle cells (PASMC) from fawn-hooded rats (FHR), an animal model of pulmonary hypertension.
  • Examined the impact of forskolin (cAMP activator) on BKCa channel activity.
  • Assessed the effects of PKC activators (phorbol 12-myristate 13-acetate, thymeleatoxin) and specific PKC inhibitors (Gö-6983, Gö-6976, rottlerin) on channel activity.

Main Results:

  • Forskolin-induced BKCa channel opening in FHR PASMC was inhibited by PKC activators phorbol 12-myristate 13-acetate and thymeleatoxin.
  • Thymeleatoxin's inhibitory effect was blocked by Gö-6983 and Gö-6976, indicating involvement of PKC-alpha, beta, delta, gamma, zeta, and mu isozymes.
  • Rottlerin, a selective PKC-delta inhibitor, did not block the inhibitory response, suggesting PKC-delta is not primarily involved.

Conclusions:

  • Specific PKC isozyme activation inhibits cAMP-induced BKCa channel activation in pulmonary arterial smooth muscle.
  • This identifies a novel signaling pathway through which PKC modulates BKCa channels and influences cAMP-mediated pulmonary vasodilatation.
  • Findings contribute to understanding pulmonary hypertension mechanisms and potential therapeutic targets.

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