Faculty Opinions recommendation of Dosage-dependent switch from G protein-coupled to G protein-independent signaling by a GPCR.

G-protein-coupled receptors (GPCRs) mostly signal through heterotrimeric G proteins. Increasing evidence suggests that GPCRs could function in a G-protein-independent manner. Here, we show that at low concentrations of an agonist, beta(2)-adrenergic receptors (beta(2)-ARs) signal through Galpha(s) to activate the mitogen-activated protein kinase pathway in mouse embryonic fibroblast cells. At high agonist concentrations, signals are also transduced through beta(2)-ARs via an additional pathway that is G-protein-independent but tyrosine kinase Src-dependent. This new dosage-dependent switch of signaling modes of GPCRs has significant implications for GPCR intrinsic properties and desensitization. PMID: 17170700 Funding information This work was supported by: NIA NIH HHS, United States Grant ID: AG23202 NIA NIH HHS, United States Grant ID: R01 AG023202 NIDDK NIH HHS, United States Grant ID: P30 DK040561-11 NIDDK NIH HHS, United States Grant ID: P30 DK040561