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Coupling of Ca(2+) to CREB activation and gene expression in intact cerebral arteries from mouse : roles of ryanodine receptors and voltage-dependent Ca(2+) channels.
Cartin L, Lounsbury K, Nelson MT
Circulation Research. 2000;86( 7):760-7.
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Abstract
Pathological changes of the vasculature are characterized by changes in Ca(2+) handling and alterations in gene expression. In neurons and other cell types, [Ca(2+)](i) often drives changes in gene expression. However, the relationship between Ca(2+) signaling and gene expression in vascular smooth muscle is not well understood. This study examines the ability of Ca(2+) influx through voltage-dependent, L-type Ca(2+) channels (VDCCs) and Ca(2+) 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 Ca(2+)/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 Ca(2+) influx to CREB-mediated changes in c-fos levels. Our data suggest that membrane depolarization increases [Ca(2+)](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 Ca(2+) entry through VDCCs. These results provide the first evidence of Ca(2+) regulation of CREB and c-fos in arterial smooth muscle.
Keyword(s)
Animals; Genes, fos; Mice; Transcription, Genetic; antagonists & inhibitors: Calmodulin; drug effects: Calcium Channels, L-Type; drug effects: Gene Expression Regulation; drug effects: Middle Cerebral Artery; drug effects: Posterior Cerebral Artery; drug effects: Ryanodine Receptor Calcium Release Channel; genetics: Proto-Oncogene Proteins c-fos; genetics: RNA, Messenger; metabolism: Ca(2+)-Calmodulin Dependent Protein Kinase; metabolism: Cyclic AMP Response Element-Binding Protein; pharmacology: Benzylamines; pharmacology: Diltiazem; pharmacology: Enzyme Inhibitors; pharmacology: Forskolin; pharmacology: Imidazoles; pharmacology: Nisoldipine; pharmacology: Nitroprusside; pharmacology: Potassium; pharmacology: Sulfonamides; physiology: Calcium; physiology: Membrane Potentials