RGS16 attenuates G alpha(q)-dependent p38 mitogen-activated protein kinaseactivation by platelet-activating factor

The large gene family encoding the regulators of G protein signaling (RGS) proteins has been implicated in the fine tuning of a variety of cellular ev ents in response to G protein-coupled receptor activation. Several studies have shown that the RGS proteins can attenuate Gr protein-activated extrace llular signal-regulated kinase (ERK) group of mitogen-activated protein kin ases. We demonstrate herein that the production of inositol trisphosphate a nd the activation of the p38 group of mitogen-activated protein kinases by the G; protein-coupled platelet-activating factor (PAF) receptor was attenu ated by RGS16 in both CHO cells transiently and stably expressing RGS16. Th e inhibition was not observed with RGS2, RGS5, and a functionally defective form of RGS16, RGS16(R169S/F170C). The PAF-induced p38 and ERK pathways ap peared to be preferentially regulated by RGS16 and RGS1, respectively. Over expression of a constitutively active form of G alpha(11) (G alpha(11)Q209L ) prevented the RGS16-mediated attenuation of p38 activity, suggesting that G alpha(q/11) is involved in PAF activation of p38. The G(alpha q/11) invo lvement is further supported by the observation that p38 activation by PAF was pertussis toxin-insensitive. These results demonstrate for the first ti me that apart from ERK, p38 activation by a G protein-coupled receptor can be attenuated by an RGS protein and provide further evidence for the specif icity of RGS function in G protein signaling pathways.