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Am J Physiol Heart Circ Physiol 292 (6): 2613-2622

Copyright © 2007 by the American Physiological Society.

Protein kinase C regulates vascular myogenic tone through activation of TRPM4

Scott Earley,1 Stephen V. Straub,2 , and Joseph E. Brayden2

1Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado; and 2Department of Pharmacology, University of Vermont College of Medicine, Burlington, Vermont

Received for publication 23 November 2006. Accepted for publication 7 February 2007.

Abstract: Myogenic vasoconstriction results from pressure-induced vascular smooth muscle cell depolarization and Ca2+ influx via voltage-dependent Ca2+ channels, a process that is significantly attenuated by inhibition of protein kinase C (PKC). It was recently reported that the melastatin transient receptor potential (TRP) channel TRPM4 is a critical mediator of pressure-induced smooth muscle depolarization and constriction in cerebral arteries. Interestingly, PKC activity enhances the activation of cloned TRPM4 channels expressed in cultured cells by increasing sensitivity of the channel to intracellular Ca2+. Thus we postulated that PKC-dependent activation of TRPM4 might be a critical mediator of vascular myogenic tone. We report here that PKC inhibition attenuated pressure-induced constriction of cerebral vessels and that stimulation of PKC activity with phorbol 12-myristate 13-acetate (PMA) enhanced the development of myogenic tone. In freshly isolated cerebral artery myocytes, we identified a Ca2+-dependent, rapidly inactivating, outwardly rectifying, iberiotoxin-insensitive cation current with properties similar to those of expressed TRPM4 channels. Stimulation of PKC activity with PMA increased the intracellular Ca2+ sensitivity of this current in vascular smooth muscle cells. To validate TRPM4 as a target of PKC regulation, antisense technology was used to suppress TRPM4 expression in isolated cerebral arteries. Under these conditions, the magnitude of TRPM4-like currents was diminished in cells from arteries treated with antisense oligonucleotides compared with controls, identifying TRPM4 as the molecular entity responsible for the PKC-activated current. Furthermore, the extent of PKC-induced smooth muscle cell depolarization and vasoconstriction was significantly decreased in arteries treated with TRPM4 antisense oligonucleotides compared with controls. We conclude that PKC-dependent regulation of TRPM4 activity contributes to the control of cerebral artery myogenic tone.

Key Words: melastatin transient receptor potential • phorbol 12-myristate 13-acetate • cerebral artery myocytes

Address for reprint requests and other correspondence: S. Earley, Dept. of Biomedical Sciences, Colorado State Univ., Fort Collins, CO USA 80523-1680 (e-mail: Scott.Earley{at}colostate.edu)

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