Noncanonical GPCR signaling arising from a PTH receptor-arrestin-Gβγ complex

摘要

G protein-coupled receptors (GPCRs) participate in ubiquitous trans-membrane signal transduction processes by activating heterotri-meric G proteins. In the current "canonical" model of GPCR signaling, arrestins terminate receptor signaling by impairing recep-tor-G-protein coupling and promoting receptor internalization. However, parathyroid hormone receptor type 1 (PTHR), an essential GPCR involved in bone and mineral metabolism, does not follow this conventional desensitization paradigm. β-Arrestins prolong G protein (G_s)-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 current model of arrestin-mediated re-ceptor-G-protein decoupling. Here we show that PTHR forms a ternary complex that includes arrestin and the Gβγ dimer in response to PTH stimulation, which in turn causes an accelerated rate of Gs activation and increases the steady-state levels of activated G_s, leading to prolonged generation of cAMP. This work provides the mechanistic basis for an alternative model of GPCR signaling in which arrestins contribute to sustaining the effect of an agonist hormone on the receptor.