Non‐Canonical Signaling by GPCR‐Arrestin‐Gβγ Ternary Complexes

Abstract

The classical model of arrestin‐mediated desensitization of GPCR is thought to be universal. In the current canonical model of GPCR signaling, arrestins terminate receptor signaling by impairing receptor–G protein coupling and promoting receptor internalization. However, this paradigm is incompatible with recent reports that the parathyroid hormone receptor (PTHR), a crucial GPCR for bone biology, sustains cAMP response for prolonged periods after ligand washout. Arrestins prolong GS‐mediated cAMP generation triggered by PTH, a process that correlates with the persistence of arrestin–PTHR complexes on endosomes, and which is thought to be associated with prolonged physiological calcemic and phosphate responses. This presents an inescapable paradox for the canonical model of arrestin‐mediated receptor–G protein decoupling. Here we show that PTHR forms a ternary complex that includes arrestin and Gβγ in response to PTH stimulation, which in turn increases the steady‐state levels of activated GS, leading to prolonged generation of cAMP. The non‐canonical signaling is not unique to the PTHR since we found that arrestin binding to the vasopressin V2 receptor prolonged cAMP production by vasopressin, which ultimately sustained water transport in kidney cells. This work provides a new model of GPCR signaling in which arrestins contribute to sustain agonist actions.Supported by the NIH award R01DK087688.