Dosage-dependent switch from G protein-coupled to G protein-independent signaling by a GPCR

Abstract

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, β2‐adrenergic receptors (β2‐ARs) signal through Gαs to activate the mitogen‐activated protein kinase pathway in mouse embryonic fibroblast cells. At high agonist concentrations, signals are also transduced through β2‐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.