beta(2)-adrenergic receptor-induced p38 MAPK activation is mediated by protein kinase A rather than by G(i) or G beta gamma in adult mouse cardiomyocytes

Increasing evidence shows that stimulation of p-adrenergic receptor (AR) ac tivates mitogen-activated protein kinases (MAPKs), in addition to the class ical G(s) adenylyl cyclase-cAMP-dependent protein kinase (PKA) signaling ca scade. In the present study, we demonstrate a novel beta (2)-AR-mediated cr oss-talk between PKA and p38 MAPK in adult mouse cardiac myocytes expressin g beta (2)-AR, with a null background of beta (1)beta (2)-AR double knockou t. 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 b eta (2)-AR-induced p38 MAPK activation. In contrast, a specific peptide inh ibitor of PKA, PKI (5 muM), completely abolished the stimulatory effect of beta (2)-AR, suggesting that beta (2)-AR-induced p38 MAPK activation is med iated via a PKA-dependent mechanism, rather than by G(i) or G beta gamma. T his conclusion was further supported by the ability of forskolin (10 muM), an adenylyl cyclase activator, to elevate p38 MAPK activity in a PKI-sensit ive manner. Furthermore, inhibition of p38 MAPK with SB203580 (10 muM) mark edly enhanced the beta (2)-AR-mediated contractile response, without alteri ng base-line contractility. These results provide the first evidence that c ardiac 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.