Protein kinase D links Gq-coupled receptors to cAMP response element-binding protein (CREB)-Ser133 phosphorylation in the heart.
Many growth regulatory stimuli promote cAMP response element-binding protein (CREB) Ser(133) phosphorylation, but the physiologically relevant CREB-Ser(133) kinase(s) in the heart remains uncertain. This study identifies a novel role for protein kinase D (PKD) as an in vivo cardiac CREB-Ser(133) kinase. We show that thrombin activates a PKCdelta-PKD pathway leading to CREB-Ser(133) phosphorylation in cardiomyocytes and cardiac fibroblasts. alpha(1)-Adrenergic receptors also activate a PKCdelta-PKD-CREB-Ser(133) phosphorylation pathway in cardiomyocytes. Of note, while the epidermal growth factor (EGF) promotes CREB-Ser(133) phosphorylation via an ERK-RSK pathway in cardiac fibroblasts, the thrombin-dependent EGFR transactivation pathway leading to ERK-RSK activation does not lead to CREB-Ser(133) phosphorylation in this cell type. Adenoviral-mediated overexpression of PKCdelta (but not PKCepsilon or PKCalpha) activates PKD; PKCdelta and PKD1-S744E/S748E overexpression both promote CREB-Ser(133) phosphorylation. Pasteuralla multocida toxin (PMT), a direct Galpha(q) agonist that induces robust cardiomyocyte hypertrophy, also activates the PKD-CREB-Ser(133) phosphorylation pathway, leading to the accumulation of active PKD and Ser(133)-phosphorylated CREB in the nucleus, activation of a CRE-responsive promoter, and increased Bcl-2 (CREB target gene) expression in cardiomyocyte cultures. Cardiac-specific Galpha(q) overexpression also leads to an increase in PKD-Ser(744)/Ser(748) and CREB-Ser(133) phosphorylation as well as increased Bcl-2 protein expression in the hearts of transgenic mice. Collectively, these studies identify a novel Galpha(q)-PKCdelta-PKD-CREB-Ser(133) phosphorylation pathway that is predicted to contribute to cardiac remodeling and could be targeted for therapeutic advantage in the setting of heart failure phenotypes.
Ozgen
Nazira
N
Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
Obreztchikova
Maria
M
Guo
Jianfen
J
Elouardighi
Hasnae
H
Dorn
Gerald W
GW
Wilson
Brenda A
BA
Steinberg
Susan F
SF
D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000737:chemistry*; D004789:Enzyme Activation; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism*; D005786:Gene Expression Regulation; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism*; D016979:Pasteurella multocida / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015533:Transcriptional Activation
D017362:Cyclic AMP Response Element-Binding Protein; C089212:protein kinase D; D011493:Protein Kinase C; D043802:GTP-Binding Protein alpha Subunits, Gq-G11