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Mol Psychiatry. 2017 Aug;22(8):1205-1222. doi: 10.1038/mp.2016.200. Epub 2016 Dec 6.

Endocytosis following dopamine D2 receptor activation is critical for neuronal activity and dendritic spine formation via Rabex-5/PDGFRβ signaling in striatopallidal medium spiny neurons.

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Department of Biofunctional Analysis Laboratory of Molecular Biology, Gifu Pharmaceutical University, Gifu, Japan.
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Department of Pharmacology, Beckman Institute, University of Illinois, Urbana, IL, USA.
Department of Anatomy, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
Department of Research and Drug Discovery, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Department of Comparative and Experimental Medicine, Brain Research Institute, Niigata University, Niigata, Japan.
Department of Molecular Neuroscience, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
Department of Pathology, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Toyama, Japan.


Aberrant dopamine D2 receptor (D2R) activity is associated with neuropsychiatric disorders, making those receptors targets for antipsychotic drugs. Here, we report that novel signaling through the intracellularly localized D2R long isoform (D2LR) elicits extracellular signal-regulated kinase (ERK) activation and dendritic spine formation through Rabex-5/platelet-derived growth factor receptor-β (PDGFRβ)-mediated endocytosis in mouse striatum. We found that D2LR directly binds to and activates Rabex-5, promoting early-endosome formation. Endosomes containing D2LR and PDGFRβ are then transported to the Golgi apparatus, where those complexes trigger Gαi3-mediated ERK signaling. Loss of intracellular D2LR-mediated ERK activation decreased neuronal activity and dendritic spine density in striatopallidal medium spiny neurons (MSNs). 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 in 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, dendritic spine formation and neuronal activity in striatopallidal MSNs of mice.

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