alpha sub(1)-adrenergic receptor subtype mRNAs are differentially regulated by alpha sub(1)-adrenergic and other hypertrophic stimuli in cardiac myocytes in culture and in vivo: Repression of alpha sub(1B) and alpha sub(1D) but induction of alpha sub(1C)

The three cloned alpha sub(1)-adrenergic receptor (AR) subtypes, alpha sub(1B), alpha sub(1C), and alpha sub(1D), can all couple to the same effector, phospholipase C, and the reason(s) for conservation of multiple subtypes remain uncertain. All three alpha sub(1)-ARs are expressed natively in cultured neonatal rat cardiac myocytes, where chronic exposure to the agonist catecholamine norepinephrine (NE) induces hypertrophic growth and gene transcription. We show here, using RNase protection, that the alpha sub(1)-AR subtype mRNAs respond in distinctly different ways during prolonged NE exposure (12-72 h). alpha sub(1B) and alpha sub(1D) mRNA levels were repressed by NE, whereas alpha sub(1C) mRNA was induced. Changes in mRNA levels were mediated by an alpha sub(1)-AR, were not explained by altered mRNA stability, and were reflected in receptor proteins by [ super(3)H]prazosin binding. alpha sub(1)-AR-stimulated phosphoinositide hydrolysis and myocyte growth were not desensitized. Three other hypertrophic agonists in culture, endothelin-1, PGF2 alpha , and phorbol 12-myristate 13-acetate, also induced alpha sub(1C) mRNA and repressed alpha sub(1B) mRNA. In myocytes from hearts with pressure overload hypertrophy, alpha sub(1) mRNA changes were identical to those produced by NE in culture. These results provide the first example of a difference in regulation among alpha sub(1)-AR subtypes expressed natively in the same cell. Transcriptional induction of the alpha sub(1C)-AR could be a mechanism for sustained growth signaling through this receptor and is a common feature of a hypertrophic phenotype in cardiac myocytes.