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(Circulation Research. 2004;94:1351.)
© 2004 American Heart Association, Inc.

Cellular Biology

Store-Operated Ca²⁺ Entry Activates the CREB Transcription Factor in Vascular Smooth Muscle

Renee A. Pulver, Patricia Rose-Curtis, Michael W. Roe, George C. Wellman, Karen M. Lounsbury

From the Department of Pharmacology (R.A.P., P.R.-C., G.C.W., K.M.L.), University of Vermont, Burlington, Vt; and the Department of Medicine (M.W.R.), University of Chicago, Chicago, Ill.

Correspondence to Karen M. Lounsbury, Department of Pharmacology, University of Vermont, Burlington, VT 05405. E-mail Karen.Lounsbury{at}uvm.edu

Ca²⁺-regulated gene transcription is a critical component of arterial responses to injury, hypertension, and tumor-stimulated angiogenesis. The Ca²⁺/cAMP response element binding protein (CREB), a transcription factor that regulates expression of many genes, is activated by Ca²⁺-induced phosphorylation. Multiple Ca²⁺ entry pathways may contribute to CREB activation in vascular smooth muscle including voltage-dependent Ca²⁺ channels and store-operated Ca²⁺ entry (SOCE). To investigate a role for SOCE in CREB activation, we measured CREB phosphorylation using immunofluorescence, intracellular Ca²⁺ levels using a fluorescence resonance energy transfer (FRET)–based Cameleon indicator, and c-fos transcription using RT-PCR. In this study, we report that SOCE activates CREB in both cultured smooth muscle cells and intact arteries. Depletion of intracellular Ca²⁺ stores with thapsigargin increased nuclear phospho-CREB levels, intracellular Ca²⁺ concentration, and transcription of c-fos. These effects were abolished by inhibiting SOCE through lowering extracellular Ca²⁺ concentration or by application of 2-aminoethoxydiphenylborate and Ni²⁺. Inhibition of Ca²⁺ influx through voltage-dependent Ca²⁺ channels using nimodipine partially blocked intact artery responses, but was without effect in cultured smooth muscle cells. Our findings indicate that Ca²⁺ entry through store-operated Ca²⁺ channels leads to CREB activation, suggesting that SOCE contributes to the regulation of gene expression in vascular smooth muscle.

Key Words: SERCA • gene transcription • calcium channels • arteries

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