Stabilization of the B-type natriuretic peptide mRNA in cardiac myocytes by alpha-adrenergic receptor activation: potential roles for protein kinase C and mitogen-activated protein kinase.
In cardiac myocytes, B-type natriuretic peptide (BNP) expression is induced with the rapid kinetics of a primary response gene. Like many other primary response gene transcripts, the BNP mRNA possesses destabilizing elements and is believed to be short-lived. The rapid induction of a short-lived transcript could be achieved partty by agonist-mediated increases in mRNA t1/2. Accordingly, the present study was undertaken to evaluate whether the alpha 1-adrenergic receptor agonist, phenylephrine (PE), a known inducer of BNP expression, could stabilize the BNP mRNA and, if so, what signaling pathways might be involved. In primary myocardial cells treated with a transcription inhibitor, the t1/2 of the BNP mRNA was found to be about 1 h in the absence of PE; however, in the presence of PE, the t1/2 increased to 5 h. It was shown that neither the calmodulin kinase inhibitor, KN-62, nor the protein tyrosine kinase inhibitor, tyrphostin, blocked PE-mediated stabilization of the BNP mRNA. However, either the protein kinase C (PKC) inhibitor, GF 109203X, or the mitogen-activated protein kinase kinase (MAPKK) inhibitor, PD 098059, effected some blockade of the stabilizing effects of PE. While maximal doses of PD 098059 nearly completely blocked PE-activated MAPK, stabilization was only partially inhibited. Moreover, maximal doses of GF 109203X, which only partially blocked PE-activated MAPK, nearly completely inhibited stabilization. Thus, while MAPK appears to be required for maximal agonist-mediated stabilization, PKC seems to play a dominant role, participating through both MAPK-dependent and -independent pathways. These results establish roles for both the PKC and MAPK families in alpha 1-adrenergic receptor-mediated stabilization of the BNP mRNA, suggesting that the rapid induction of BNP expression might be due, in part, to this agonist-mediated increase in mRNA t1/2.
Hanford
D S
DS
Department of Biology, San Diego State University, California 92182, USA.
Glembotski
C C
CC
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000187:drug effects / Q000235:genetics*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006207:Half-Life; D006321:Heart / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D020097:Natriuretic Peptide, Brain; D010656:Phenylephrine / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction
D000316:Adrenergic alpha-Agonists; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007211:Indoles; D008301:Maleimides; D011942:Receptors, Adrenergic, alpha; D020097:Natriuretic Peptide, Brain; D005576:Colforsin; D010656:Phenylephrine; D009320:Atrial Natriuretic Factor; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C070515:bisindolylmaleimide I; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one