ALPHA(1)-ADRENERGIC RECEPTOR SUBTYPE MESSENGER-RNAS ARE DIFFERENTIALLY REGULATED BY ALPHA(1)-ADRENERGIC AND OTHER HYPERTROPHIC STIMULI IN CARDIAC MYOCYTES IN CULTURE AND IN-VIVO - REPRESSION OF ALPHA(1B) AND ALPHA(1D) BUT INDUCTION OF ALPHA(1C)

The three cloned alpha(1)-adrenergic receptor (AR) subtypes, alpha(1B) , alpha(1C), alpha(1D), can all couple to the same effector, phospholi pase C, and the reason(s) for conservation of multiple subtypes remain uncertain. All three alpha(1)-ARs are expressed natively in cultured neonatal rat cardiac myocytes, where chronic exposure to the agonist c atecholamine norepinephrine (NE) induces hypertrophic growth and gene transcription. We show here, using RNase protection, that the alpha(1) -AR subtype mRNAs respond in distinctly different ways during prolonge d NE exposure (12-72 h). alpha(1B) and alpha(1D) mRNA levels were repr essed by NE, whereas alpha(1C) mRNA was induced. Changes in mRNA level s were mediated by an alpha(1)-AR, were not explained by altered mRNA stability, and were reflected in receptor proteins by [H-3]prazosin bi nding. alpha(1)-AR-stimulated phosphoinositide hydrolysis and myocyte growth were not desensitized. Three other hypertrophic agonists in cul ture, endothelin-1, PGF2 alpha, and phorbol 12-myristate 13-acetate, a lso induced alpha(1C) mRNA and repressed alpha(1B) mRNA. In myocytes f rom hearts with pressure overload hypertrophy, alpha(1) mRNA changes w ere identical to those produced by NE in culture. These results provid e the first example of a difference in regulation among alpha(1)-AR su btypes expressed natively in the same cell. Transcriptional induction of the alpha(1C)-AR could be a mechanism for sustained growth signalin g through this receptor and is a common feature of a hypertrophic phen otype in cardiac myocytes.