Abstract
G-protein-coupled receptors (GPCRs) play an integral role in the neurobiology of psychiatric disorders. Almost all neurotransmitters involved in psychiatric disorders act through GPCRs, and GPCRs are the most common targets of therapeutic drugs currently used in the treatment of psychiatric disorders. However, the roles of GPCRs in the etiology and pathophysiology of psychiatric disorders are not fully understood. Using publically available datasets, we performed a comprehensive analysis of the transcriptomic signatures of G-protein-linked signaling across the major psychiatric disorders: autism spectrum disorder (ASD), schizophrenia (SCZ), bipolar disorder (BP), and major depressive disorder (MDD). We also used the BrainSpan transcriptomic dataset of the developing human brain to examine whether GPCRs that exhibit chronological age-associated expressions have a higher tendency to be dysregulated in psychiatric disorders than age-independent GPCRs. We found that most GPCR genes were differentially expressed in the four disorders and that the GPCR superfamily as a gene cluster was overrepresented in the four disorders. We also identified a greater amplitude of gene expression changes in GPCRs than other gene families in the four psychiatric disorders. Further, dysregulated GPCRs overlapped across the four psychiatric disorders, with SCZ exhibiting the highest overlap with the three other disorders. Finally, the results revealed a greater tendency of age-associated GPCRs to be dysregulated in ASD than random GPCRs. Our results substantiate the central role of GPCR signaling pathways in the etiology and pathophysiology of psychiatric disorders. Furthermore, our study suggests that common GPCRs’ signaling may mediate distinct phenotypic presentations across psychiatric disorders. Consequently, targeting these GPCRs could serve as a common therapeutic strategy to treat specific clinical symptoms across psychiatric disorders.
Highlights
G protein-coupled receptors (GPCRs) comprise the largest family of cell-surface receptors (>800 in the human genome) and mediate the transduction of extracellular signals into intracellular responses [1]
Using the IUPHAR/BPS database, we identified and verified 376 candidate GPCR genes, which belonged to five classes: 290 class A, 15 class B, 22 class C, 11 frizzled, 33 adhesion, and five others
While there was no association between age-dependent expression of GPCRs and their dysregulations in each of SCZ, bipolar disorder (BP), and major depressive disorder (MDD), we found a significantly higher proportion of age-associated GPCR genes in the disease-associated ones compared to the random GPCR (Figure 6f–i)
Summary
G protein-coupled receptors (GPCRs) comprise the largest family of cell-surface receptors (>800 in the human genome) and mediate the transduction of extracellular signals into intracellular responses [1]. GPCRs signaling systems, consisting of the heterotrimeric G-protein subunits, GPCRs, and downstream effector molecules, can transduce molecular signaling of a wide variety of endogenous ligands, including hormones, neurotransmitters, proteins, lipids, and peptides (Figure 1). They mediate cells’ response to exogenous and environmental ligands and stimuli such as photons, tastants, and odorants. The GPCRs constitute the largest family of therapeutic targets, accounting for around 34% of all Food and Drug Administration (FDA)-approved drugs [12,13]
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