The analysis for the circuits of L-DOPA-containing neurons in the central nervous system

2023 Fiscal Year Final Research Report

• Project/Area Number: 21H02673
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 48030:Pharmacology-related
• Research Institution: Yokohama City University
• Principal Investigator: GOSHIMA Yoshio 横浜市立大学, 医学研究科, 客員教授 (00153750)
• Co-Investigator(Kenkyū-buntansha): 増川 太輝 横浜市立大学, 医学部, 助教 (10711898) ; 笠原 由佳 九州大学, 医学研究院, 特任助教 (50838208)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: L-ドーパ / GPR143 / ドパミン / D2受容体 / 神経伝達物質

Outline of Final Research Achievements

We proposed that L-DOPA (DOPA) is by itself a neurotransmitter. We here demonstrated that GPR143/OA1, the receptor of DOPA, when coupled with dopamine D2 receptors (D2R) enhanced D2R-mediated signaling in vitro and in vivo. Quinpirole (QNP), a D2R agonist decreased locomotor activity in mice, and this effect was attenuated in Gpr143 gene-deficient mice. GPR143 interacted with D2R at its 5th transmembrane (TM5) region, and TM5 peptide that interrupted association between GPR143 and D2R mitigated the effect of QNP in vitro and in vivo. DOPA enhanced interaction between GPR143 and D2R and ehnaced QNP-induced decrease in cAMP production in cell lines coexpressing D2R and GPR143 but not in cells expressing D2R alone. These finding indicate that GPR143 plays a role in modulating the functions of D2Rs, one of the most important targets for pharmacological agents for neurological and psychiatric disorders.

Free Research Field

薬理学

Academic Significance and Societal Importance of the Research Achievements

我々は、それ自体は活性がないと考えられてきたL-ドーパ(DOPA)それ自体が神経伝達物質であるとの作業仮説を提起してきた。DOPAはパーキンソン病（PD)の最も有効な治療薬である。本研究は、DOPAが、DOPA受容体であるGPR143を介して、ドパミンD2受容体(D2R)を生理学的に修飾することを示すものである。またこの事実は、DOPA神経伝達物質仮説をさらに支持するとともに、GPR143が、PDおよび精神神経疾患の新たな創薬ターゲットとなる可能性を示すものである。