Gpr19 is a circadian clock-controlled orphan GPCR with a role in modulating free-running period and light resetting capacity of the circadian clock

Background and PurposeGpr19 encodes an evolutionarily conserved orphan G-protein-coupled receptor (GPCR) with no established physiological function in vivo. The purpose of this study was to determine the role of Gpr19 in the circadian clock system. Experimental ApproachWe examined whether and how the master circadian clock neurons in the suprachiasmatic nucleus (SCN) express Gpr19. By analysing Gpr19-deficient (Gpr19-/-) mice, we asked whether Gpr19 has a role in modulating free-running period and light resetting capacity of the circadian clock. Key ResultsCompared with the known common core clock genes, Gpr19 was identified to show several distinct yet limited features related to the circadian clock. Gpr19 mRNA was mainly expressed in the middle-to-dorsal region of the SCN. A conserved cAMP-responsive element within the Gpr19 promoter drove the circadian expression of Gpr19. Gpr19-/- mice exhibited a prolonged circadian period and a delayed initiation of daily locomotor activity in a 12-h light/12-h dark cycle. Gpr19 deficiency caused the downregulation of several genes that normally peak during the night, including Bmal1 and Gpr176. Gpr19-/- mice had a reduced capacity for phase shift to early subjective night light. The defect was only observed for phase-delay, but not phase-advance, and accompanied by reduced response of c-Fos expression in the dorsal region of the SCN, while apparently normal in the ventral part of the SCN, in Gpr19-/- mice. Conclusion and ImplicationsGpr19 is an SCN-enriched orphan GPCR with a distinct role in circadian regulation and thus may be a potential target for alleviating circadian clock disorders. O_LIWhat is already known: Gpr19 is an evolutionarily conserved class-A orphan receptor with no established physiological role in vivo. The SCN is a light-entrainable master circadian pacemaker governing daily rhythms of behaviour and physiology. C_LIO_LIWhat this study adds: Gpr19 is an SCN-enriched orphan GPCR whose levels fluctuate in a circadian fashion. Gpr19 is a functional clock modulator involved in period determination and phase resetting. C_LIO_LIClinical significance: Targeting the orphan receptor Gpr19 may provide a therapeutic approach for alleviating circadian clock disorders. C_LI