Reconstitution of Angiotensin Receptor mRNA Down-regulation in Vascular Smooth Muscle POST-TRANSCRIPTIONAL CONTROL BY PROTEIN KINASE A BUT NOT MITOGENIC SIGNALING DIRECTED BY THE 59-UNTRANSLATED REGION*

Cell surface receptor activation generally leads to changes in mRNA abundance, which may involve regulatory targets in processes working at the post-transcriptional level. Many types of agonists down-regulate vascular smooth muscle angiotensin receptor (AT1-R) gene expression, but it is unclear which of these activate post-transcriptional mechanisms. To reconstitute faithfully the normal AT1-R mRNA regulatory environment, tetracycline-suppressible promoters drive highly accurate recombinant AT1-R mRNA mimics in vascular smooth muscle cells that co-express an endogenous AT1-R mRNA. Down-regulation of the latter occurs shortly after stimulating mitogenic receptors or by using forskolin, but only cAMP signaling reduces expression of the recombinant AT1-R mRNA. Transcription of the recombinant mRNA is unaffected by cAMP signaling. Deletions of the AT1-R mRNA 3*-untranslated region do not impair cAMP-mediated down-regulation. Both loss of function and gain of function mutants show the response is mediated by the 5*-untranslated region. These observations provide the first direct functional evidence for modulation of vascular AT1-R gene expression by a mechanism involving a protein kinase A-regulated post-transcriptional process.