© 2000 American Heart Association, Inc.
Cellular Biology |
cAMP-Dependent Vasodilators Cross-Activate the cGMP-Dependent Protein Kinase to Stimulate BKCa Channel Activity in Coronary Artery Smooth Muscle Cells
From the Department of Pharmacology and Toxicology (R.E.W., G.H., G.O.C.), Medical College of Georgia, Augusta, Ga; Department of Physiology and Biophysics (J.P.K.), Wright State University School of Medicine, Dayton, Ohio; and School of Pharmacy (A.M.E.-M.), Kuwait University.
Correspondence to Richard E. White, PhD, Department of Pharmacology and Toxicology, Medical College of Georgia, 1120 15th St, Room CB-3730, August, GA 30912-2300. E-mail rwhite{at}mail.mcg.edu
Abstract—cAMP-dependent vasodilators are used to treat a variety of cardiovascular disorders; however, the signal transduction pathways and effector mechanisms stimulated by these agents are not fully understood. In the present study we demonstrate that cAMP-stimulating agents enhance the activity of the large-conductance, calcium-activated potassium (BKCa) channel in single myocytes from coronary arteries by "cross-activation" of the cGMP-dependent protein kinase (protein kinase G, PKG). Single-channel patch-clamp data revealed that 10 µmol/L isoproterenol, forskolin, or dopamine opens BKCa channels in coronary myocytes and that this effect is attenuated by inhibitors of PKG (KT5823; Rp-8-pCPT-cGMPS), but not by inhibiting the cAMP-dependent protein kinase (protein kinase A, PKA). In addition, a membrane-permeable analog, CPT-cAMP, also opened BKCa channels in these myocytes, and this effect was reversed by KT5823. Direct biochemical measurement confirmed that dopamine or forskolin stimulates PKG activity in coronary arteries but does not elevate cGMP. Finally, the stimulatory effect of cAMP on BKCa channels was reconstituted in a cell-free, inside-out patch by addition of purified PKG activated by either cGMP or cAMP. In contrast, channel gating was unaffected by exposure to the purified catalytic subunit of PKA. In summary, findings from on-cell and cell-free patch-clamp experiments provide direct evidence that cAMP-dependent vasodilators open BKCa channels in coronary myocytes by cross-activation of PKG (but not via PKA). Biochemical assay confirmed this cross-activation mechanism of cAMP action in these arteries. This signaling pathway is a novel mechanism for regulation of potassium channel activity in vascular smooth muscle and other cells.
Key Words: cAMP • protein kinase G • BKCa channel • coronary • cross-activation
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