title: 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.
authors.affiliation: Central Nervous System Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Komatsu
authors.affiliation: Cardiovascular and Metabolic Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Maruyama
authors.affiliation: Biomolecular Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
authors.forename: Shuuhei
authors.initials: S
authors.lastname: Yao
authors.affiliation: Advanced Science Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
authors.forename: Tokuyuki
authors.initials: T
authors.lastname: Shinohara
authors.affiliation: Cardiovascular and Metabolic Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Sakuma
authors.affiliation: Advanced Science Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Imaichi
authors.affiliation: Cardiovascular and Metabolic Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Chikatsu
authors.affiliation: Extra Value Generation and General Medicine Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
authors.forename: Kanako
authors.initials: K
authors.lastname: Kuniyeda
authors.affiliation: TSP CNS Phenotyping, Takeda Pharmaceutical Company Limited, Singapore.
authors.forename: Foo Kok
authors.initials: FK
authors.lastname: Siu
authors.affiliation: TSP CNS Phenotyping, Takeda Pharmaceutical Company Limited, Singapore.
authors.forename: Lam Sock
authors.initials: LS
authors.lastname: Peng
authors.affiliation: TSP Transgenic pipeline, Takeda Pharmaceutical Company Limited, Singapore.
authors.forename: Katherine
authors.initials: K
authors.lastname: Zhuo
authors.affiliation: TSP Transgenic pipeline, Takeda Pharmaceutical Company Limited, Singapore.
authors.forename: Lay Sock
authors.initials: LS
authors.lastname: Mun
authors.affiliation: TSP Transgenic pipeline, Takeda Pharmaceutical Company Limited, Singapore.
authors.forename: Tan Min
authors.initials: TM
authors.lastname: Han
authors.affiliation: Biomolecular Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Matsumoto
authors.affiliation: Research Administration Department, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
authors.forename: Tadatoshi
authors.initials: T
authors.lastname: Hashimoto
authors.affiliation: Biomolecular Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Miyajima
authors.affiliation: Pharmaceutical Marketing Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Itoh
authors.affiliation: Advanced Science Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ogi
authors.affiliation: Cardiovascular and Metabolic Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
authors.forename: Yugo
authors.initials: Y
authors.lastname: Habata
authors.affiliation: Cardiovascular and Metabolic Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Mori
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D003071:Cognition / Q000187:drug effects; D017124:Conserved Sequence; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004644:Emotions / Q000187:drug effects; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011618:Psychotic Disorders / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D012110:Reserpine / Q000494:pharmacology; D015398:Signal Transduction; D059467:Transcriptome; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology
chemical_list: D014150:Antipsychotic Agents; C000621576:GPR52 protein, human; C578533:GPR6 protein, mouse; C000592538:Gpr52 protein, mouse; C485998:Gpr88 protein, mouse; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D043562:Receptors, G-Protein-Coupled; D012110:Reserpine