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.
Highlights
G-protein-coupled receptors (GPCRs) constitute the largest family of cell surface receptors that participate in signal transduction for a range of stimulants, including light, odorants, peptide and non-peptide neurotransmitters, hormones, growth factors, and lipids
This review focuses on the function of GPR176 and its downstream signaling pathways regulating the circadian clock in the suprachiasmatic nucleus (SCN)
This review argues for the potential merit of focusing on GPCRs in the SCN with the purpose of remodeling the entire body clock
Summary
G-protein-coupled receptors (GPCRs) constitute the largest family of cell surface receptors that participate in signal transduction for a range of stimulants, including light, odorants, peptide and non-peptide neurotransmitters, hormones, growth factors, and lipids. Activated GPCR signals control various downstream processes, which include sensory transduction, cell–cell communication, neuronal transmission, and hormonal signaling Consistent with their versatile roles in physiology and disease, GPCRs are the therapeutic targets of nearly a third of US Food and Drug Administration (FDA)-approved drugs [1,2]. Despite their prominent clinical relevance, of the 356 non-olfactory GPCRs encoded in the human genome, approximately 38% are still regarded as ‘orphans’ whose cognate ligands are not known [3]. This review argues for the potential merit of focusing on GPCRs in the SCN with the purpose of remodeling the entire body clock
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