Phenylephrine induces activation of CREB in adult rat cardiac myocytes through MSK1 and PKA signaling pathways.
cAMP responsive element binding protein (CREB) is a stimulus induced transcription factor with possible relevance for the pathophysiology of the heart. In the present study, we provide evidence that the hypertrophic agonist, phenylephrine (PE), promotes phosphorylation of CREB in adult rat cardiac myocytes through alpha(1)- and beta-adrenergic receptors. PE-induced phosphorylation of CREB was partially inhibited by Ro318220 and H89, which were shown to be potent inhibitors of mitogen- and stress-activated protein kinase-1 (MSK1) activation, implicating the involvement of this kinase in the response. Similar results were obtained when cardiac myocytes were treated with the inhibitors of ERK1/2 and p38 MAPK pathways. In addition, inhibition of protein kinase A by RpcAMP reduced phosphorylation of CREB, suggesting that this pathway is also involved. Furthermore, PE stimulation was accompanied by an increase in CRE-binding activity, which was reduced by drugs that prevented phosphorylation of CREB. An enhanced CBP/phospho-CREB complex formation was also observed, suggesting recruitment of CBP to phosphorylated CREB. These results suggest that PE stimulates phosphorylation and DNA binding activity of CREB in adult rat ventricular myocytes through multiple signaling pathways involving ERK1/2, p38 MAPK, MSK1 and PKA. The same pathways seem to regulate atrial natriuretic peptide (ANF) mRNA expression, a highly conserved marker gene of cardiac hypertrophy, suggesting that the PE-stimulated activation of CREB is likely to play an important role in the hypertrophic response.
Markou
Thomais
T
Laboratory of Animal Physiology, Department of Zoology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece.
Hadzopoulou-Cladaras
Margarita
M
Lazou
Antigone
A
D000322:Adrenergic Agonists / Q000494:pharmacology*; D058646:Adrenergic alpha-1 Receptor Agonists; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D050882:CREB-Binding Protein; D006332:Cardiomegaly / Q000235:genetics; D017362:Cyclic AMP Response Element-Binding Protein / Q000276:immunology / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D047468:Immunoprecipitation; D007211:Indoles / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology*; D009687:Nuclear Proteins / Q000276:immunology / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology; D015534:Trans-Activators / Q000276:immunology / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology
D000322:Adrenergic Agonists; D058646:Adrenergic alpha-1 Receptor Agonists; D017362:Cyclic AMP Response Element-Binding Protein; D007211:Indoles; D007546:Isoquinolines; D009687:Nuclear Proteins; D012333:RNA, Messenger; D018340:Receptors, Adrenergic, alpha-1; D011943:Receptors, Adrenergic, beta; D013449:Sulfonamides; D015534:Trans-Activators; D010656:Phenylephrine; D009320:Atrial Natriuretic Factor; D050882:CREB-Binding Protein; C494365:Crebbp protein, rat; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; D017868:Cyclic AMP-Dependent Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; C064758:Ro 31-8220