ACTIVATION OF MITOGEN-ACTIVATED PROTEIN-KINASES (P38-MAPKS, SAPKS JNKS AND ERKS) BY THE G-PROTEIN-COUPLED RECEPTOR AGONIST PHENYLEPHRINE INTHE PERFUSED RAT-HEART/

We investigated the ability of phenylephrine (PE), an alpha-adrenergic agonist and promoter of hypertrophic growth in the ventricular myocyt e, to activate the three best-characterized mitogen-activated protein kinase (MAPK) subfamilies, namely p38-MAPKs, SAPKs/JNKs (i.e. stress-a ctivated protein kinases/c-Jun N-terminal kinases) and ERKs (extracell ularly responsive kinases), in perfused contracting rat hearts. Perfus ion of hearts with 100 mu M PE caused a rapid (maximal at 10 min) 12-f old activation of two p38-MAPK isoforms, as measured by subsequent pho sphorylation of a F38-MAPK substrate, recombinant MAPK-activated prote in kinase 2 (MAPKAPK2). This activation coincided with phosphorylation of p38-MAPK. Endogenous MAPKAPK2 was activated 4-5-fold in these perf usions and this was inhibited completely by the p38-MAPK inhibitor, SB 203580 (10 mu M). Activation of p38-MAPK and MAPKAPK2 was also detecte d in non-contracting hearts perfused with PE, indicating that the effe cts were not dependent on the positive inotropic/chronotropic properti es of the agonist. Although SAPKs/JNKs were also rapidly activated, th e activation (2-3-fold) was less than that of p38-MAPK. The ERKs were activated by perfusion with PE and the activation was at least 50% of that seen with 1 mu M PMA, the most powerful activator of the ERKs yet identified in cardiac myocytes. These results indicate that, in addit ion to the ERKs, two MAPK subfamilies, whose activation is more usuall y associated with cellular stresses, are activated by the G(q/11)-prot ein-coupled receptor (G(q/11)PCR) agonist, PE, in whole hearts. These data indicate that G(q/11)PCR agonists activate multiple MAPK signalli ng pathways in the heart, all of which may contribute to the overall r esponse (e.g. the development of the hypertrophic phenotype).