beta 2-adrenergic receptor-induced p38 MAPK activation is mediated by protein kinase A rather than by Gi or gbeta gamma in adult mouse cardiomyocytes.
Increasing evidence shows that stimulation of beta-adrenergic receptor (AR) activates mitogen-activated protein kinases (MAPKs), in addition to the classical G(s)-adenylyl cyclase-cAMP-dependent protein kinase (PKA) signaling cascade. In the present study, we demonstrate a novel beta(2)-AR-mediated cross-talk between PKA and p38 MAPK in adult mouse cardiac myocytes expressing beta(2)-AR, with a null background of beta(1)beta(2)-AR double knockout. beta(2)-AR stimulation by isoproterenol increased p38 MAPK activity in a time- and dose-dependent manner. Inhibiting G(i) with pertussis toxin or scavenging Gbetagamma with betaARK-ct overexpression could not prevent beta(2)-AR-induced p38 MAPK activation. In contrast, a specific peptide inhibitor of PKA, PKI (5 microm), completely abolished the stimulatory effect of beta(2)-AR, suggesting that beta(2)-AR-induced p38 MAPK activation is mediated via a PKA-dependent mechanism, rather than by G(i) or Gbetagamma. This conclusion was further supported by the ability of forskolin (10 microm), an adenylyl cyclase activator, to elevate p38 MAPK activity in a PKI-sensitive manner. Furthermore, inhibition of p38 MAPK with SB203580 (10 microm) markedly enhanced the beta(2)-AR-mediated contractile response, without altering base-line contractility. These results provide the first evidence that cardiac beta(2)-AR activates p38 MAPK via a PKA-dependent signaling pathway, rather than by G(i) or Gbetagamma, and reveal a novel role of p38 MAPK in regulating cardiac contractility.
Zheng
M
M
Laboratory of Cardiovascular Science, Gerontology Research Center, NIA, National Institutes of Health, Baltimore, Maryland 21224, USA.
Zhang
S J
SJ
Zhu
W Z
WZ
Ziman
B
B
Kobilka
B K
BK
Xiao
R P
RP
D000818:Animals; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004789:Enzyme Activation; D019204:GTP-Binding Proteins / Q000378:metabolism*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases
D018343:Receptors, Adrenergic, beta-2; D017868:Cyclic AMP-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins