Published online before print April 8, 2004, doi: 10.1161/01.RES.0000127618.34500.FD
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Submitted on December 29, 2003
Revised on March 26, 2004
Accepted on March 29, 2004
Store-Operated Ca2+ Entry Activates the CREB Transcription Factor in Vascular Smooth Muscle
Renee A. Pulver ;
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.
* To whom correspondence should be addressed. 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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