© 2000 American Heart Association, Inc.
Integrative Physiology |
Coupling of Ca2+ to CREB Activation and Gene Expression in Intact Cerebral Arteries From Mouse
Roles of Ryanodine Receptors and Voltage-Dependent Ca2+ Channels
From the Department of Pharmacology, University of Vermont, Burlington, Vt.
Correspondence to Dr Mark T. Nelson, Department of Pharmacology, University of Vermont College of Medicine, Given Building, Room B303, Burlington, VT 05405. E-mail nelson{at}salus.med.uvm.edu
Abstract—Pathological changes of the vasculature are characterized by changes in Ca2+ handling and alterations in gene expression. In neurons and other cell types, [Ca2+]i often drives changes in gene expression. However, the relationship between Ca2+ signaling and gene expression in vascular smooth muscle is not well understood. This study examines the ability of Ca2+ influx through voltage-dependent, L-type Ca2+ channels (VDCCs) and Ca2+ release through ryanodine receptors (RyRs) to activate the transcription factor, cAMP-responsive element binding protein (CREB), and increase c-fos levels in intact cerebral arteries. Membrane depolarization increased the fraction of nuclei staining for phosphorylated CREB (P-CREB) and levels of c-fos mRNA in intact mouse cerebral arteries. Ryanodine, which inhibits RyRs, increased P-CREB staining and c-fos levels. Forskolin, an activator of adenylyl cyclase, and sodium nitroprusside, an NO donor, increased P-CREB and c-fos levels. Nisoldipine, an inhibitor of VDCCs, reversed the effects of depolarization and ryanodine on P-CREB and c-fos levels, but not the effects of forskolin or sodium nitroprusside. Inhibition of Ca2+/calmodulin-dependent protein kinase (CaM kinase) blocked increases in P-CREB and c-fos levels seen with membrane depolarization, suggesting that CaM kinase has an important role in the pathway leading from Ca2+ influx to CREB-mediated changes in c-fos levels. Our data suggest that membrane depolarization increases [Ca2+]i through activation of VDCCs, leading to increased P-CREB and c-fos, and that RyRs have a profound effect on this pathway by indirectly regulating Ca2+ entry through VDCCs. These results provide the first evidence of Ca2+ regulation of CREB and c-fos in arterial smooth muscle.
Key Words: Ca2+ sparks • CREB • gene expression • receptors, ryanodine • arterial smooth muscle
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