α₁-adrenergic receptor subtype mRNAs are differentially regulated by α₁-Adrenergic and other hypertrophic stimuli in cardiac myocytes in culture and in vivo: Repression of α_1B and α_1D but induction of α_1C

The three cloned α-adrenergic receptor (AR) subtypes, α_1B, α_1C, and α_1D, can all couple to the same effector, phospholipase C, and the reason(s) for conservation of multiple subtypes remain uncertain. All three α₁-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 α₁-AR subtype mRNAs respond in distinctly different ways during prolonged NE exposure (12-72 h). α_1B and α_1D mRNA levels were repressed by NE, whereas α_1C mRNA was induced. Changes in mRNA levels were mediated by an α₁-AR, were not explained by altered mRNA stability, and were reflected in receptor proteins by [³H]prazosin binding. α₁-AR-stimulated phosphoinositide hydrolysis and myocyte growth were not desensitized. Three other hypertrophic agonists in culture, endothelin-1, PGF2α, and phorbol 12-myristate 13-acetate, also induced α_1c mRNA and repressed α_1B mRNA. In myocytes from hearts with pressure overload hypertrophy, α₁ mRNA changes were identical to those produced by NE in culture. These results provide the first example of a difference in regulation among α₁-AR subtypes expressed natively in the same cell. Transcriptional induction of the α_1C-AR could be a mechanism for sustained growth signaling through this receptor and is a common feature of a hypertrophic phenotype in cardiac myoeytes.