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Molecular Pharmacology, Volume 52, Issue 5, 781-787
Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia 30322
Although processes involved in mRNA degradation play a significant role
in dictating steady state mRNA levels, the influence of cell surface
signaling on mRNA stability control is understood incompletely. In this
study, the effects of cAMP-elevating agents on type I angiotensin II
receptor (AT1-R) mRNA levels were assessed in cultured rat
aortic vascular smooth muscle cells (VSMCs). AT1-R mRNA
levels are rapidly reduced by forskolin treatment, in which the maximal
effect yields an 80% reduction in AT1-R mRNA levels after
6 hr of treatment. The rate of AT1-R mRNA decay in response to forskolin is greater than its apparent intrinsic decay, as assessed
in the presence of the transcriptional inhibitor
5,6-dichloro-1-
-D-ribofuranosylbenzimidazole, suggesting
forskolin treatment destabilizes the AT1-R mRNA. Nuclear run-on analysis indicates forskolin treatment does not affect transcription of the AT1-R gene in VSMCs, implying induced
AT1-R mRNA destabilization accounts for the entire effect
of forskolin in decreasing AT1-R mRNA levels. Dose-effect
studies that assessed AT1-R mRNA levels and cAMP production
were conducted using forskolin and the -adrenergic receptor agonist
isoproterenol as agonists. Isoproterenol is almost 3 orders of
magnitude more potent at eliciting the reduction in
AT1-receptor mRNA levels than it is at stimulating cAMP
production. Similarly, forskolin elicits reductions in
AT1-R mRNA, which occur at concentrations that fail to
elicit a detectable production of cAMP. However, protein kinase A
activity is stimulated maximally by isoproterenol and forskolin
concentrations that do not stimulate detectable cAMP production. These
data provide evidence that the mechanism for down-regulation of
AT1-R mRNA levels by cAMP-elevating agents in VSMCs occurs
via a PKA-regulated mRNA destabilization pathway.
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