Gpr176 is a Gz-linked orphan G-protein-coupled receptor that sets the pace of circadian behaviour

Abstract

G-protein-coupled receptors (GPCRs) participate in a broad range of physiological functions. A priority for fundamental and clinical research, therefore, is to decipher the function of over 140 remaining orphan GPCRs. The suprachiasmatic nucleus (SCN), the brain's circadian pacemaker, governs daily rhythms in behaviour and physiology. Here we launch the SCN orphan GPCR project to (i) search for murine orphan GPCRs with enriched expression in the SCN, (ii) generate mutant animals deficient in candidate GPCRs, and (iii) analyse the impact on circadian rhythms. We thereby identify Gpr176 as an SCN-enriched orphan GPCR that sets the pace of circadian behaviour. Gpr176 is expressed in a circadian manner by SCN neurons, and molecular characterization reveals that it represses cAMP signalling in an agonist-independent manner. Gpr176 acts independently of, and in parallel to, the Vipr2 GPCR, not through the canonical Gi, but via the unique G-protein subclass Gz.

G-protein-coupled receptor signaling through Gpr176, Gz, and RGS16 tunes time in the center of the circadian clock [Review]

“…Temporal expression profiles of Gpr176 and Vipr2 reveal that while these two receptors exist in the same SCN neurons, they are opposite in peak expression phase. Namely, Gpr176 peaks at night, whereas Vipr2 during the day [7,21]. These spatiotemporal expression profiles of Gpr176 and Vipr2 are congruent with their antiphasic, opposite actions on cAMP signaling in the SCN (see below).…”

“…Gpr176 is an SCN-enriched orphan GPCR that sets the pace of the central clock in the SCN [7]. Gpr176 couples to Gz, and even in the absence of known ligand, it possesses an agonist-independent basal activity to repress cAMP signaling [7,8]. Besides Gpr176 and Gz, this review also emphasizes a role for the regulator of G-protein signaling 16 (RGS16) in the temporal regulation of G-protein-cAMP signaling in the SCN [9,10].…”

“…Gpr176 is an SCN-enriched orphan GPCR that sets the pace of the central clock in the SCN [7]. Gpr176 couples to Gz, and even in the absence of known ligand, it possesses an agonist-independent basal activity to repress cAMP signaling [7,8].…”

“…In order to identify a new GPCR that tunes the central clock, we launched the SCN-orphan GPCR project [7,9], in which we (i) searched for the orphan GPCRs whose expression is enriched in the SCN, (ii) generated knockout mice of candidate GPCR genes of interest, and (iii) asked whether there is a defect in their circadian rhythms in behavior. Based on this screening strategy, Gpr176 was identified as an SCN-enriched orphan GPCR that sets the pace of circadian behavior (Fig.…”

“…Gpr176 bears an agonist-independent activity to counteract with Vipr2-cAMP signaling Molecular characterization of Gpr176 revealed that this orphan receptor has an agonist-independent constitutive activity to repress cAMP production [7]. In general, all GPCRs display two distinct structural conformations, active and inactive.…”