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

Goto, Kaoru; Doi, Masao; Wang, Tianyu; Kunisue, Sumihiro; Murai, Ichiro; Okamura, Hitoshi

doi:10.1507/endocrj.ej17-0130

Cited by 11 publications

(7 citation statements)

References 47 publications

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“…Specifically, RGS16 plays a crucial role in the circadian regulation of cyclic AMP (cAMP) in the suprachiasmatic nucleus [32]. This brain region, located in the ventral part of the anterior hypothalamus, coordinates and synchronizes the daily rhythms of sleep and wakefulness as well as circadian rhythms of a wide range of homeostatic functions [32]. Intriguingly, a large body of evidence supports an involvement of circadian rhythm disturbances in BD.…”

Section: Discussionmentioning

confidence: 99%

Whole Genome Expression Analyses of miRNAs and mRNAs Suggest the Involvement of miR-320a and miR-155-3p and their Targeted Genes in Lithium Response in Bipolar Disorder

Pisanu

Papadima

Melis

et al. 2019

IJMS

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Lithium is the mainstay in the maintenance of bipolar disorder (BD) and the most efficacious pharmacological treatment in suicide prevention. Nevertheless, its use is hampered by a high interindividual variability and important side effects. Genetic and epigenetic factors have been suggested to modulate lithium response, but findings so far have not allowed identifying molecular targets with predictive value. In this study we used next generation sequencing to measure genome-wide miRNA expression in lymphoblastoid cell lines from BD patients excellent responders (ER, n = 12) and non-responders (NR, n = 12) to lithium. These data were integrated with microarray genome-wide expression data to identify pairs of miRNA/mRNA inversely and significantly correlated. Significant pairs were prioritized based on strength of association and in-silico miRNA target prediction analyses to select candidates for validation with qRT-PCR. Thirty-one miRNAs were differentially expressed in ER vs. NR and inversely correlated with 418 genes differentially expressed between the two groups. A total of 331 of these correlations were also predicted by in-silico algorithms. miR-320a and miR-155-3p, as well as three of their targeted genes (CAPNS1 (Calpain Small Subunit 1) and RGS16 (Regulator of G Protein Signaling 16) for miR-320, SP4 (Sp4 Transcription Factor) for miR-155-3p) were validated. These miRNAs and mRNAs were previously implicated in psychiatric disorders (miR-320a and SP4), key processes of the central nervous system (CAPNS1, RGS16, SP4) or pathways involved in mental illnesses (miR-155-3p). Using an integrated approach, we identified miRNAs and their targeted genes potentially involved in lithium response in BD.

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Section: Discussionmentioning

confidence: 99%

Whole Genome Expression Analyses of miRNAs and mRNAs Suggest the Involvement of miR-320a and miR-155-3p and their Targeted Genes in Lithium Response in Bipolar Disorder

Pisanu

Papadima

Melis

et al. 2019

IJMS

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“…GPR176 is an SCN-enriched orphan GPCR that sets the pace of normal circadian behavior (see Figure 3 ) [ 7 , 35 ]. Genetic ablation of GPR176 in mice shortens the circadian period of locomotor activity rhythm.…”

Section: Gpr176 Is a G Z -Linked Orphan Gpcr Thmentioning

confidence: 99%

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

Nakagawa

Pham

Shao

et al. 2020

IJMS

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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.

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“…RGS16 is involved in trafficking and migration of T lymphocytes (Estes et al, 2004) in response to an allergen challenge (Lippert et al, 2003), and RGS16 knockout mice have an enhanced inflammatory response in the lung (Shankar et al, 2012). Apart from its defined roles in allergic responses, RGS16 also has an intriguing role in regulating circadian systems (Goto et al, 2017). Within the brain, RGS16 is expressed in both the suprachiasmatic nucleus (SCN) and the thalamus (Grafstein-Dunn et al, 2001;Ueda et al, 2002).…”

Section: Rgs17 Brainmentioning

confidence: 99%

Genetic Analysis of Rare Human Variants of Regulators of G Protein Signaling Proteins and Their Role in Human Physiology and Disease

et al. 2018

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Regulators of G protein signaling (RGS) proteins modulate the physiologic actions of many neurotransmitters, hormones, and other signaling molecules. Human RGS proteins comprise a family of 20 canonical proteins that bind directly to G protein-coupled receptors/G protein complexes to limit the lifetime of their signaling events, which regulate all aspects of cell and organ physiology. Genetic variations account for diverse human traits and individual predispositions to disease. RGS proteins contribute to many complex polygenic human traits and pathologies such as hypertension, atherosclerosis, schizophrenia, depression, addiction, cancers, and many others. Recent analysis indicates that most human diseases are due to extremely rare genetic variants. In this study, we summarize physiologic roles for RGS proteins and links to human diseases/traits and report rare variants found within each human RGS protein exome sequence derived from global population studies. Each RGS sequence is analyzed using recently described bioinformatics and proteomic tools for measures of missense tolerance ratio paired with combined annotation-dependent depletion scores, and protein post-translational modification (PTM) alignment cluster analysis. We highlight selected variants within the well-studied RGS domain that likely disrupt RGS protein functions and provide comprehensive variant and PTM data for each RGS protein for future study. We propose that rare variants in functionally sensitive regions of RGS proteins confer profound change-of-function phenotypes that may contribute, in newly appreciated ways, to complex human diseases and/or traits. This information provides investigators with a valuable database to explore variation in RGS protein function, and for targeting RGS proteins as future therapeutic targets.

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

Cited by 11 publications

References 47 publications

Whole Genome Expression Analyses of miRNAs and mRNAs Suggest the Involvement of miR-320a and miR-155-3p and their Targeted Genes in Lithium Response in Bipolar Disorder

Whole Genome Expression Analyses of miRNAs and mRNAs Suggest the Involvement of miR-320a and miR-155-3p and their Targeted Genes in Lithium Response in Bipolar Disorder

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

Genetic Analysis of Rare Human Variants of Regulators of G Protein Signaling Proteins and Their Role in Human Physiology and Disease

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