Circadian regulation of intracellular G-protein signalling mediates intercellular synchrony and rhythmicity in the suprachiasmatic nucleus

Abstract

Synchronous oscillations of thousands of cellular clocks in the suprachiasmatic nucleus (SCN), the circadian centre, are coordinated by precisely timed cell–cell communication, the principle of which is largely unknown. Here we show that the amount of RGS16 (regulator of G protein signalling 16), a protein known to inactivate Gαi, increases at a selective circadian time to allow time-dependent activation of intracellular cyclic AMP signalling in the SCN. Gene ablation of Rgs16 leads to the loss of circadian production of cAMP and as a result lengthens circadian period of behavioural rhythm. The temporally precise regulation of the cAMP signal by clock-controlled RGS16 is needed for the dorsomedial SCN to maintain a normal phase-relationship to the ventrolateral SCN. Thus, RGS16-dependent temporal regulation of intracellular G protein signalling coordinates the intercellular synchrony of SCN pacemaker neurons and thereby defines the 24 h rhythm in behaviour.

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

“…Gene knockout and knockdown of RGS16 both compromise the periodicity of behavioral rhythm [9,10]. Moreover, RGS16 knockout leads to the loss of circadian production of cAMP in the SCN [9], implying an intimate link between RGS16 and Gpr176. Biochemically, RGS16 functions as a GTPaseaccelerating protein (GAP) for Gi [37][38][39].…”

“…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]. Developing drugs that specifically target the SCN remains an unfulfilled opportunity for the circadian clock therapy.…”

“…The SCN-GENE PROJECT focusing on this family [9] revealed a role of RGS16 in determining the pace of the SCN clock. Gene knockout and knockdown of RGS16 both compromise the periodicity of behavioral rhythm [9,10].…”

“…The SCN-GENE PROJECT focusing on this family [9] revealed a role of RGS16 in determining the pace of the SCN clock. Gene knockout and knockdown of RGS16 both compromise the periodicity of behavioral rhythm [9,10]. Moreover, RGS16 knockout leads to the loss of circadian production of cAMP in the SCN [9], implying an intimate link between RGS16 and Gpr176.…”

“…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.…”