Research on mechanisms of intracellular D2LR signaling

2015 Fiscal Year Final Research Report

• Project/Area Number: 25460090
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pharmacology in pharmacy
• Research Institution: Tohoku University
• Principal Investigator: Shioda Norifumi 東北大学, 薬学研究科(研究院), 特任准教授 (00374950)
• Co-Investigator(Kenkyū-buntansha): FUKUNAGA Kohji 東北大学, 大学院薬学研究科, 教授 (90136721)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: 精神疾患 / ドパミン D2 受容体 / シグナル伝達

Outline of Final Research Achievements

Aberrant dopamine D2 receptor (D2R) activity is associated with neuropsychiatric disorders, making those receptors targets for antipsychotic drugs. We found that novel signaling through the intracellularly localized D2R long isoform (D2LR) elicits ERK activation and dendritic spine formation through Rabex-5/PDGFRβ-mediated endocytosis in mouse striatum. We found that D2LR directly binds to and activates Rabex-5, promoting early endosome formation. In addition, dendritic spine density in striatopallidal MSNs significantly increased following treatment of striatal slices from wild-type mice with quinpirole, a D2R agonist, but those changes were lacking D2LR knockout mice. Moreover, intracellular D2LR signaling mediated effects of a typical antipsychotic drug, haloperidol, in inducing catalepsy behavior. Taken together, intracellular D2LR signaling through Rabex-5/PDGFRβ is critical for ERK activation and neuronal activity in striatopallidal MSNs of mice.

Free Research Field

薬学、薬理学、神経科学