Anatomical transcriptome of G protein-coupled receptors leads to the identification of a novel therapeutic candidate GPR52 for psychiatric disorders

PLoS One. 2014 Feb 28;9(2):e90134. doi: 10.1371/journal.pone.0090134. eCollection 2014.

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.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antipsychotic Agents / pharmacology
  • Behavior, Animal / drug effects
  • Cognition / drug effects
  • Conserved Sequence
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism
  • Corpus Striatum / physiopathology
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / metabolism
  • Dopaminergic Neurons / pathology
  • Emotions / drug effects
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Humans
  • Mice
  • Mice, Transgenic
  • Molecular Sequence Data
  • Psychotic Disorders / drug therapy
  • Psychotic Disorders / genetics*
  • Psychotic Disorders / metabolism
  • Psychotic Disorders / physiopathology
  • Receptors, Dopamine D1 / genetics
  • Receptors, Dopamine D1 / metabolism
  • Receptors, Dopamine D2 / genetics
  • Receptors, Dopamine D2 / metabolism
  • Receptors, G-Protein-Coupled / genetics*
  • Receptors, G-Protein-Coupled / metabolism
  • Reserpine / pharmacology
  • Signal Transduction
  • Transcriptome*
  • Ventral Tegmental Area / drug effects
  • Ventral Tegmental Area / metabolism
  • Ventral Tegmental Area / physiopathology

Substances

  • Antipsychotic Agents
  • GPR52 protein, human
  • GPR6 protein, mouse
  • Gpr52 protein, mouse
  • Gpr88 protein, mouse
  • Receptors, Dopamine D1
  • Receptors, Dopamine D2
  • Receptors, G-Protein-Coupled
  • Reserpine

Grants and funding

These authors have no support or funding to report.