Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

G-protein-coupled receptors (GPCRs) constitute an immensely important class of drug targets with diverse clinical applications. There are still more than 120 orphan GPCRs whose cognate ligands and physiological functions are not known. A set of circadian pacemaker neurons that governs daily rhythms in behavior and physiology resides in the suprachiasmatic nucleus (SCN) in the brain. Malfunction of the circadian clock has been linked to a multitude of diseases, such as sleeping disorders, obesity, diabetes, cardiovascular diseases, and cancer, which makes the clock an attractive target for drug development. Here, we review a recently identified role of Gpr176 in the SCN. Gpr176 is an SCN-enriched orphan GPCR that sets the pace of the circadian clock in the SCN. Even without known ligand, this orphan receptor has an agonist-independent basal activity to reduce cAMP signaling. A unique cAMP-repressing G-protein subclass Gz is required for the activity of Gpr176. We also provide an overview on the circadian regulation of G-protein signaling, with an emphasis on a role for the regulator of G-protein signaling 16 (RGS16). RGS16 is indispensable for the circadian regulation of cAMP in the SCN. Developing drugs that target the SCN remains an unfulfilled opportunity for the circadian pharmacology. This review argues for the potential impact of focusing on GPCRs in the SCN for the purpose of tuning the body clock.
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PMID:G-protein-coupled receptor signaling through Gpr176, Gz, and RGS16 tunes time in the center of the circadian clock [Review]. 2850 23

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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PMID:Time-Restricted G-Protein Signaling Pathways via GPR176, Gz, and RGS16 Set the Pace of the Master Circadian Clock in the Suprachiasmatic Nucleus. 3270 14