β2-adrenergic receptor-induced p38 MAPK activation is mediated by protein kinase A rather than by Gi or Gβγ in adult mouse cardiomyocytes

Increasing evidence shows that stimulation of p-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 MARK activity in a time- and dose-dependent manner. Inhibiting G(i) with pertussis toxin or scavenging G beta gamma with beta ARK-ct overexpression could not prevent beta (2)-AR-induced p38 MAPK activation. In contrast, a specific peptide inhibitor of PKA, PKI (5 muM), 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 G beta gamma. This conclusion was further supported by the ability of forskolin (10 muM), an adenylyl cyclase activator, to elevate p38 MAPK activity in a PKI-sensitive manner. Furthermore, inhibition of p38 MAPK with SB203580 (10 muM) 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 G beta gamma, and reveal a novel role of p38 MAPK in regulating cardiac contractility.