Anatomical Transcriptome of G Protein-Coupled Receptors Leads to the Identification of a Novel Therapeutic Candidate GPR52 for Psychiatric Disorders

Abstract

Many drugs of abuse and most neuropharmacological agents regulate G protein-coupled receptors (GPCRs) in the central nervous system (CNS)_ENREF_1. The striatum, in which dopamine D1 and D2 receptors are enriched, is strongly innervated by the ventral tegmental area (VTA), which is the origin of dopaminergic cell bodies of the mesocorticolimbic dopamine system_ENREF_3 and plays a central role in the development of psychiatric disorders_ENREF_4. Here we report the comprehensive and anatomical transcript profiling of 322 non-odorant GPCRs in mouse tissue by quantitative real-time PCR (qPCR), leading to the identification of neurotherapeutic receptors exclusively expressed in the CNS, especially in the striatum. Among them, GPR6, GPR52, and GPR88, known as orphan GPCRs, were shown to co-localize either with a D2 receptor alone or with both D1 and D2 receptors in neurons of the basal ganglia. Intriguingly, we found that GPR52 was well conserved among vertebrates, is Gs-coupled and responsive to the antipsychotic drug, reserpine. We used three types of transgenic (Tg) mice employing a Cre-lox system under the control of the GPR52 promoter, namely, GPR52-LacZ Tg, human GPR52 (hGPR52) Tg, and hGPR52-GFP Tg mice. Detailed histological investigation suggests that GPR52 may modulate dopaminergic and glutamatergic transmission in neuronal circuits responsible for cognitive function and emotion. In support of our prediction, GPR52 knockout and transgenic mice exhibited psychosis-related and antipsychotic-like behaviors, respectively. Therefore, we propose that GPR52 has the potential of being a therapeutic psychiatric receptor. This approach may help identify potential therapeutic targets for CNS diseases.

Array‐based molecular karyotyping in fetal brain malformations: Identification of novel candidate genes and chromosomal regions

“…GPR52 has been shown to be expressed in the caudate and putamen region of the human brain (Sawzdargo et al, 1999). Recent murine expression studies confirmed GPR52 to be exclusively expressed in brain with highest expression in the striatum (Komatsu et al, 2014). While GPR52 knockout mice displayed normal brain morphology, they showed psychosis-like behavior suggesting GPR52 to modulate cognitive function and emotion (Komatsu et al, 2014).…”

“…Recent murine expression studies confirmed GPR52 to be exclusively expressed in brain with highest expression in the striatum (Komatsu et al, 2014). While GPR52 knockout mice displayed normal brain morphology, they showed psychosis-like behavior suggesting GPR52 to modulate cognitive function and emotion (Komatsu et al, 2014). DECI-PHER database of January 2015 (Database of Chromosomal Imbalance and Phenotype in Humans; https://decipher.sanger.ac.uk/) lists 12 entries with deletions overlapping GPR52, 10 of which contain clinical data, all showing ID/DD or nonisolated brain malformations.…”

Towards a better understanding of the cannabinoid-related orphan receptors GPR3, GPR6, and GPR12

“…As mentioned above, GPR6 is highly expressed in striatopallidal neurons (Lobo et al 2007; Heiman et al 2008; Komatsu et al 2014). Given the importance of striatal involvement in instrumental conditioning (Balleine 2005), Lobo and coworkers decided to explore the role of GPR6 in learning processes (Lobo et al 2007).…”

“…The role of GPR6 in PD arises from its high expression in the striatum, especially in striatopallidal neurons (Lobo et al 2007; Heiman et al 2008; Komatsu et al 2014). Oeckl and collaborators studied the neurochemical and behavioral effects of GPR6 ablation in mice (Oeckl et al 2014).…”

Discovery and Characterization of Novel GPR39 Agonists Allosterically Modulated by Zinc

“…When agonists bind to GPCRs, signals are transduced into cells via a number of Ga proteins, or b-arrestins, and other interacting proteins. In the human genome, there are about 350 nonolfactory GPCRs, of which about 100 are still orphans, i.e., their endogenous ligands are yet unknown (Vassilatis et al, 2003;Fredriksson and Schiöth, 2005;Bjarnadóttir et al, 2006;Regard et al, 2008;Komatsu et al, 2014;Roth and Kroeze, 2015), or alternatively, they are very poorly annotated with respect to ligands, whether endogenous or surrogate. In the current study, we report on the discovery of novel surrogate ligands for GPR39, previously described as a zinc receptor (Holst et al, 2007).…”