Alpha1-adrenergic receptor subtype mRNAs are differentially regulated by alpha1-adrenergic and other hypertrophic stimuli in cardiac myocytes in culture and in vivo. Repression of alpha1B and alpha1D but induction of alpha1C.
The three cloned alpha1-adrenergic receptor (AR) subtypes, alpha1B, alpha1C, and alpha1D, can all couple to the same effector, phospholipase C, and the reason(s) for conservation of multiple subtypes remain uncertain. All three alpha1-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 alpha1-AR subtype mRNAs respond in distinctly different ways during prolonged NE exposure (12 72 h). Alpha1B and alpha1D mRNA levels were repressed by NE, whereas alpha1C mRNA was induced. Changes in mRNA levels were mediated by an alpha1-AR, were not explained by altered mRNA stability, and were reflected in receptor proteins by [3H]prazosin binding. alpha1-AR-stimulated phosphoinositide hydrolysis and myocyte growth were not desensitized. Three other hypertrophic agonists in culture, endothelin-1, PGF2alpha, and phorbol 12-myristate 13-acetate, also induced alpha1C mRNA and repressed alpha1B mRNA. In myocytes from hearts with pressure overload hypertrophy, alpha1 mRNA changes were identical to those produced by NE in culture. These results provide the first example of a difference in regulation among alpha1-AR subtypes expressed natively in the same cell. Transcriptional induction of the alpha1C-AR could be a mechanism for sustained growth signaling through this receptor and is a common feature of a hypertrophic phenotype in cardiac myocytes.
Rokosh
D G
DG
Cardiology Division and Research Service, Veterans Affairs Medical Center, San Francisco, California 94121, USA.
Stewart
A F
AF
Chang
K C
KC
Bailey
B A
BA
Karliner
J S
JS
Camacho
S A
SA
Long
C S
CS
Simpson
P C
PC
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D006332:Cardiomegaly; D002478:Cells, Cultured; D016232:Endothelins / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006321:Heart / Q000187:drug effects; D007700:Kinetics; D009206:Myocardium / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology*; D011224:Prazosin / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000096:biosynthesis* / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
C547718:Adra1b protein, rat; C547721:Adra1d protein, rat; D000316:Adrenergic alpha-Agonists; D016232:Endothelins; D012333:RNA, Messenger; D018340:Receptors, Adrenergic, alpha-1; D013755:Tetradecanoylphorbol Acetate; D009638:Norepinephrine; D011224:Prazosin