PHORBOL ESTERS AND NOREPINEPHRINE DESTABILIZE ALPHA(1B)-ADRENERGIC RECEPTOR MESSENGER-RNA IN VASCULAR SMOOTH-MUSCLE CELLS

The mechanism by which norepinephrine (NE) down-regulates alpha1B-adre nergic receptor (alpha-AR) mRNA was studied in rabbit aortic smooth mu scle cells. NE, phorbol esters, and bradykinin each decreased alpha-AR mRNA levels by 70-80%. The protein kinase C inhibitor (+)-1-5-isoquin olinesulfonyl)-2-methylpiperazine dihydrochloride (H-7) abolished the effects of phorbol esters and NE and decreased basal mRNA levels by 52 +/- 3%. Neither ryanodine nor EGTA inhibited down-regulation of alpha -AR mRNA by NE. Actinomycin D caused alpha-AR mRNA level to decrease w ith a half-life of 3.2 +/- 0.4 h and blocked the effect of H-7 to decr ease basal alpha-AR mRNA level. Both NE and phorbol esters increased t he rate of alpha-AR mRNA degradation. In NE-desensitized cells, phorbo l esters and bradykinin each caused the expected down-regulation of al pha-AR mRNA. The protein phosphatase inhibitor okadaic acid prolonged the normally transient effect of NE for at least 24 h. We conclude tha t protein kinase C exerts two opposing effects on alpha-AR mRNA levels , 1) a decrease in the stability of the mRNA that requires the sustain ed phosphorylation of a protein kinase C substrate and 2) a permissive effect on alpha-AR gene transcription.