Dataset Information

Time-Restricted G-Protein Signaling Pathways via GPR176, Gz, and RGS16 Set the Pace of the Master Circadian Clock in the Suprachiasmatic Nucleus.

ABSTRACT: G-protein-coupled receptors (GPCRs) are an important source of drug targets with diverse therapeutic applications. However, there are still more than one hundred orphan GPCRs, whose ligands and functions remain unidentified. The suprachiasmatic nucleus (SCN) is the central circadian clock of the brain, directing daily rhythms in activity-rest behavior and physiology. Malfunction of the circadian clock has been linked to a wide variety of diseases, including sleep-wake disorders, obesity, diabetes, cancer, and hypertension, making the circadian clock an intriguing target for drug development. The orphan receptor GPR176 is an SCN-enriched orphan GPCR that sets the pace of the circadian clock. GPR176 undergoes asparagine (N)-linked glycosylation, a post-translational modification required for its proper cell-surface expression. Although its ligand remains unknown, this orphan receptor shows agonist-independent basal activity. GPR176 couples to the unique G-protein subclass Gz (or Gx) and participates in reducing cAMP production during the night. The regulator of G-protein signaling 16 (RGS16) is equally important for the regulation of circadian cAMP synthesis in the SCN. Genome-wide association studies, employing questionnaire-based evaluations of individual chronotypes, revealed loci near clock genes and in the regions containing RGS16 and ALG10B, a gene encoding an enzyme involved in protein N-glycosylation. Therefore, increasing evidence suggests that N-glycosylation of GPR176 and its downstream G-protein signal regulation may be involved in pathways characterizing human chronotypes. This review argues for the potential impact of focusing on GPCR signaling in the SCN for the purpose of fine-tuning the entire body clock.

SUBMITTER: Nakagawa S

PROVIDER: S-EPMC7404074 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Time-Restricted G-Protein Signaling Pathways via GPR176, G<sub>z</sub>, and RGS16 Set the Pace of the Master Circadian Clock in the Suprachiasmatic Nucleus.

Nakagawa Shumpei S Nguyen Pham Khanh Tien KT Shao Xinyan X Doi Masao M

International journal of molecular sciences 20200717 14

G-protein-coupled receptors (GPCRs) are an important source of drug targets with diverse therapeutic applications. However, there are still more than one hundred orphan GPCRs, whose ligands and functions remain unidentified. The suprachiasmatic nucleus (SCN) is the central circadian clock of the brain, directing daily rhythms in activity-rest behavior and physiology. Malfunction of the circadian clock has been linked to a wide variety of diseases, including sleep-wake disorders, obesity, diabete ...[more]

PMID: 32709014

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Project description:Key pointsLight-responsive neurones in the rat suprachiasmatic nucleus discharge with a harmonic distribution of interspike intervals, whereas unresponsive neurones seldom do. This harmonic patterning has a fundamental frequency of close to 30 Hz, and is the same in light-on cells as in light-off cells, and is unaffected by exposure to light. Light-on cells are more active than light-off cells in both subjective day and subjective night, and both light-on cells and light-off cells respond more strongly to changes in light intensity during the subjective night than during the subjective day. Paired recordings indicate that the discharge of adjacent light-responsive cells is very tightly synchronized. The gap junction inhibitor carbenoxolone increases the spontaneous activity of suprachiasmatic nucleus neurones but does not block the harmonic discharge patterning.AbstractThe suprachiasmatic nucleus (SCN) of the hypothalamus has an essential role in orchestrating circadian rhythms of behaviour and physiology. In the present study, we recorded from single SCN neurons in urethane-anaesthetized rats, categorized them by the statistical features of their electrical activity and by their responses to light, and examined how activity in the light phase differs from activity in the dark phase. We classified cells as light-on cells or light-off cells according to how their firing rate changed in acute response to light, or as non-responsive cells. In both sets of light-responsive neurons, responses to light were stronger at subjective night than in subjective day. Neuronal firing patterns were analysed by constructing hazard functions from interspike interval data. For most light-responsive cells, the hazard functions showed a multimodal distribution, with a harmonic sequence of modes, indicating that spike activity was driven by an oscillatory input with a fundamental frequency of close to 30 Hz; this harmonic pattern was rarely seen in non-responsive SCN cells. The frequency of the rhythm was the same in light-on cells as in light-off cells, was the same in subjective day as at subjective night, and was unaffected by exposure to light. Paired recordings indicated that the discharge of adjacent light-responsive neurons was very tightly synchronized, consistent with electrical coupling.

Project description:The biological master clock, suprachiasmatic nucleus (of rat and mouse), is composed of ~10,000 clock cells which are heterogeneous with respect to their circadian periods. Despite this inhomogeneity, an intact SCN maintains a very good degree of circadian phase (time) coherence which is vital for sustaining various circadian rhythmic activities, and it is supposedly achieved by not just one but a few different cell-to-cell coupling mechanisms, among which action potential (AP)-mediated connectivity is known to be essential. But, due to technical difficulties and limitations in experiments, so far very little information is available about the morphology of the connectivity at a cellular scale. Building upon this limited amount of information, here we exhaustively and systematically explore a large pool (~25,000) of various network morphologies to come up with some plausible network features of SCN networks. All candidates under consideration reflect an experimentally obtained 'indegree distribution' as well as a 'physical range distribution of afferent clock cells.' Then, importantly, with a set of multitude criteria based on the properties of SCN circadian phase waves in extrinsically perturbed as well as in their natural states, we select out appropriate model networks: Some important measures are, 1) level of phase dispersal and direction of wave propagation, 2) phase-resetting ability of the model networks subject to external circadian forcing, and 3) decay rate of perturbation induced "phase-singularities." The successful, realistic networks have several common features: 1) "indegree" and "outdegree" should have a positive correlation; 2) the cells in the SCN ventrolateral region (core) have a much larger total degree than that of the dorsal medial region (shell); 3) The number of intra-core edges is about 7.5 times that of intra-shell edges; and 4) the distance probability density function for the afferent connections fits well to a beta function. We believe that these newly identified network features would be a useful guide for future explorations on the very much unknown AP-mediated clock cell connectome within the SCN.

Dataset Information

Time-Restricted G-Protein Signaling Pathways via GPR176, Gz, and RGS16 Set the Pace of the Master Circadian Clock in the Suprachiasmatic Nucleus.

Publications

Time-Restricted G-Protein Signaling Pathways via GPR176, G<sub>z</sub>, and RGS16 Set the Pace of the Master Circadian Clock in the Suprachiasmatic Nucleus.

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