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Review
.2020 Jun 24;11(6):694.
doi: 10.3390/genes11060694.

Orphan G Protein Coupled Receptors in Affective Disorders

Affiliations
Review

Orphan G Protein Coupled Receptors in Affective Disorders

Lyndsay R Watkins et al. Genes (Basel)..

Abstract

G protein coupled receptors (GPCRs) are the main mediators of signal transduction in the central nervous system. Therefore, it is not surprising that many GPCRs have long been investigated for their role in the development of anxiety and mood disorders, as well as in the mechanism of action of antidepressant therapies. Importantly, the endogenous ligands for a large group of GPCRs have not yet been identified and are therefore known as orphan GPCRs (oGPCRs). Nonetheless, growing evidence from animal studies, together with genome wide association studies (GWAS) and post-mortem transcriptomic analysis in patients, pointed at many oGPCRs as potential pharmacological targets. Among these discoveries, we summarize in this review how emotional behaviors are modulated by the following oGPCRs: ADGRB2 (BAI2), ADGRG1 (GPR56), GPR3, GPR26, GPR37, GPR50, GPR52, GPR61, GPR62, GPR88, GPR135, GPR158, and GPRC5B.

Keywords: G protein coupled receptor (GPCR); G proteins; animal models; antidepressant; anxiety disorders; bipolar disorder (BPD); major depressive disorder (MDD); mood disorders; orphan GPCR (oGPCR).

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Signaling mechanisms of adhesion orphan G protein coupled receptors (oGPCRs) involved in mood disorders. (A) ADGRB2 interacts with the ECM to activate Gi/o/z proteins. In the dentate gyrus of the hippocampus, ADGRB2 activates intracellular GABP and VEGF, leading to increased neurogenesis. (B) Stress decreases ADGRG1 mRNA levels. By coupling with G12/13, ADGRG1 modulates AKT, GSK3, and EIF4 signaling pathways, intracellular signaling molecules previously associated with depression and with the action of antidepressants. AKT, protein kinase B; ECM, extracellular matrix; EIF4, eukaryotic initiation factor 4F; GABP, GA-binding protein; GSK3, glycogen synthase kinase 3; VEGF, vascular endothelial growth factor.
Figure 2
Figure 2
Heteromerization of melatonin receptors and oGPCRs. (A) MLT activation of homo- and heteromers of MT1 and MT2 receptors triggering Gi/o and Gq signaling pathways. (B) Heteromerization of MT1 with GPR50 inhibits melatonin binding to MT1 and recruitment of signaling molecules. (C) Similarly, MT2 heteromerization with GPR61, GPR62, or GPR135 inhibits β-arrestin recruitment but does not affect MLT binding, nor G protein activation. (D) The constitutive Gs signaling of GPR61 and GPR62 counteracts MT2 receptor Gi//o signaling, modulating intracellular cAMP levels. AC, Adenylate Cyclase; βarr, β arrestin; MLT, melatonin; MT1, melatonin receptor 1; MT2, melatonin receptor 2.
Figure 3
Figure 3
GPR88 gene expression regulation and signaling pathways. (A) GPR88 mRNA levels are modulated by antidepressant treatments, mood stabilizers, and by chronic stress in several brain regions. (B) Behavioral studies using conditional KO mice revealed the involvement of GPR88 expressed in the dopamine D2 receptor-expressing medium spiny neurons of the striatum in the development of anxiety-related phenotypes. AC, adenylate cyclase; PKA, protein kinase A.
Figure 4
Figure 4
GPR158/RGS7 complex is a stress-induced modulator of depressive behaviors. GC released by stress bind to intracellular GCR in the mPFC and trigger GPR158 transcription. Increased amounts of GPR158 at the plasma membrane recruit additional RGS7 that regulates many canonical GPCRs (ADRA2A and GABABR have been described). Downstream signaling cascades, modulated by the GPR158/RGS7 complex, include cAMP-PKA, phosphorylation and expression levels of glutamate AMPA receptors, phosphorylation of eEF2, and BDNF local synthesis. Overall, these cellular adaptations are likely responsible for mood regulation. AC, adenylate cyclase; ADRA2A; α2-adrenergic receptor; AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; BDNF, brain derived neurotrophic factor; eEF2, eukaryotic elongation factor 2; GC, glucocorticoids; GCR, glucocorticoid receptor; GRE, glucocorticoid response elements; PKA, protein kinase A; RGS7, regulator of G protein signaling 7.
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