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.
Highlights
G-protein-coupled receptors (GPCRs) participate in a broad range of physiological functions
We first constructed a list of GPCR genes that are potentially enriched in the suprachiasmatic nucleus (SCN) (Fig. 1a)
In the hope of identifying a new GPCR that tunes the central clock, we searched for orphan GPCRs whose expression is enriched in the SCN
Summary
G-protein-coupled receptors (GPCRs) participate in a broad range of physiological functions. A priority for fundamental and clinical research, 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. These lines of evidence support the potential value of developing drugs that target the circadian clock, and pioneer studies have already identified synthetic compounds that selectively target the key intracellular clock components, cryptochromes (Cry[1] and Cry2)[8] and REV-ERBa and b9 Because their targets are distributed across the body, these compounds can modulate both the central and peripheral clocks [8,9]. The magnitude of this spontaneous activity differs strikingly between GPCRs, some of the orphan GPCRs exhibit significant levels of intrinsic activity[19,20]
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