Coupling of Ca2+ to CREB activation and gene expression in intact cerebralarteries from mouse - Roles of ryanodine receptors and voltage-dependent Ca2+ channels
L. Cartin et al., Coupling of Ca2+ to CREB activation and gene expression in intact cerebralarteries from mouse - Roles of ryanodine receptors and voltage-dependent Ca2+ channels, CIRCUL RES, 86(7), 2000, pp. 760-767
Pathological changes of the vasculature are characterized by changes in Ca2
+ handling and alterations in gene expression. In neurons and other cell ty
pes, [Ca2+](i) often drives changes in gene expression. However, the relati
onship between Ca2+ signaling and gene expression in vascular smooth muscle
is not well understood. This study examines the ability of Ca2+ influx thr
ough voltage-dependent, L-type Ca2+ channels (VDCCs) and Ca2+ release throu
gh ryanodine receptors (RyRs) to activate the transcription factor, cAMP-re
sponsive element binding protein (CREB), and increase c-fos levels in intac
t cerebral arteries. Membrane depolarization increased the fraction of nucl
ei staining for phosphorylated CREB (P-CREB) and levels of c-fos mRNA in in
tact mouse cerebral arteries. Ryanodine, which inhibits RyRs, increased P-C
REB 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 ki
nase (CaM kinase) blocked increases in P-CREB and c-fos levels seen with me
mbrane depolarization, suggesting that CaM kinase has an important role in
the pathway leading from Ca2+ influx to CREB-mediated changes in c-fos leve
ls. Our data suggest that membrane depolarization increases [Ca2+], 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.