Activation of p38 mitogen-activated protein kinase by signaling through G protein-coupled receptors. Involvement of Gbetagamma and Galphaq/11 subunits.

Various extracellular stimuli activate three classes of mitogen-activated protein kinases (MAPKs): extracellular signal-regulated kinase, c-Jun N-terminal kinase, and p38 MAPK. In mammalian cells, p38 MAPK is activated by endotoxins, inflammatory cytokines, and environmental stresses. We show here that p38 MAPK is also activated upon stimulation of G protein-coupled receptors (Gq/G11-coupled m1 and Gi-coupled m2 muscarinic acetylcholine and Gs-coupled beta-adrenergic receptors) in human embryonal kidney 293 cells. The activation of p38 MAPK through the m2 and beta-adrenergic receptors was completely inhibited by coexpression of Galphao, whereas the activation by the m1 receptor was only partially inhibited. Furthermore, we show that overexpression of Gbetagamma or a constitutively activated mutant of Galpha11, but not Galphas and Galphai, can stimulate p38 MAPK. These results suggest that the signal from the m2 and beta-adrenergic receptors to p38 MAPK is mediated by Gbetagamma, whereas the signal from the m1 receptor is mediated by both Gbetagamma and Galphaq/11.