More Than One Way to Signal

Abstract

Although defined by the ability to activate heterotrimeric guanine nucleotide-binding proteins (G proteins), G protein-coupled receptors (GPCRs) can also signal through G protein-independent pathways. Sun et al . used mouse embryo fibroblasts lacking various proteins to investigate the mechanistic relation between G protein-dependent and -independent activation of extracellular signal-regulated kinase (ERK) in response to stimulation of the β 2 -adrenergic receptor (β 2 -AR). Analysis of ERK activation in response to various concentrations of the β 2 -AR agonist isoproterenol revealed a biphasic response. ERK activation in response to low concentrations of isoproterenol was lost in cells lacking Gα s , whereas ERK activation in response to high concentrations was maintained (both required expression of the β 2 -AR). Moreover, ERK activation in response to high concentrations of agonist did not depend on other heterotrimeric G proteins or on β-arrestins. In contrast, low concentrations of isoproterenol stimulated ERK activation in cells lacking Src-family tyrosine kinases, but high concentrations failed to increase the response. Isoproterenol activated Src even in cells lacking both Gα s and β-arrestins. In vitro analysis indicated that Src bound to and phosphorylated the C-terminal tail of the β 2 -AR; further, c-Src coimmunoprecipitated with the β 2 -AR from human embryonic kidney (HEK) 293 cells. When expressed in cells lacking the β 2 -AR, a β 2 -AR mutant that could not bind Src activated Gα s and ERK in response to low concentrations of isoproterenol but failed to elicit enhanced activation of ERK in response to high concentrations. Thus, the authors conclude that low concentrations of agonist activate ERK through a Gα s -mediated pathway, whereas high concentrations turn on a second, Src-dependent, pathway to ERK activation; they speculate that coupling to these two pathways depends on distinct conformations of the β 2 -AR . Y. Sun, J. Huang, Y. Xiang, M. Bastepe, H. Jüppner, B. K. Kobilka, J. J. Zhang, X.-Y. Huang, Dosage-dependent switch from G protein-coupled to G protein-independent signaling by a GPCR. EMBO J. 26 , 53–64 (2007). [PubMed]