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

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.
Hidetoshi Komatsu 1,  Minoru Maruyama 2,  Shuuhei Yao 3,  Tokuyuki Shinohara 4,  Kensuke Sakuma 2,  Sachiko Imaichi 4,  Tomoko Chikatsu 2,  Kanako Kuniyeda 5,  Foo Kok Siu 6,  Lam Sock Peng 6,  Katherine Zhuo 7,  Lay Sock Mun 7,  Tan Min Han 7,  Yoshio Matsumoto 3,  Tadatoshi Hashimoto 8,  Nobuyuki Miyajima 3,  Yasuaki Itoh 9,  Kazuhiro Ogi 4,  Yugo Habata 2,  Masaaki Mori 2
Affiliations

Affiliations

  • 1 Central Nervous System Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
  • 2 Cardiovascular and Metabolic Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
  • 3 Biomolecular Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
  • 4 Advanced Science Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
  • 5 Extra Value Generation and General Medicine Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
  • 6 TSP CNS Phenotyping, Takeda Pharmaceutical Company Limited, Singapore.
  • 7 TSP Transgenic pipeline, Takeda Pharmaceutical Company Limited, Singapore.
  • 8 Research Administration Department, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
  • 9 Pharmaceutical Marketing Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
PMID: 24587241 DOI: 10.1371/journal.pone.0090134
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.

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