RRC ID 47309
Author Shioda N, Yabuki Y, Wang Y, Uchigashima M, Hikida T, Sasaoka T, Mori H, Watanabe M, Sasahara M, Fukunaga K.
Title 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.
Journal Mol Psychiatry
Abstract 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.
Volume 22(8)
Pages 1205-1222
Published 2017-8-1
DOI 10.1038/mp.2016.200
PII mp2016200
PMID 27922607
MeSH Animals Cell Culture Techniques Corpus Striatum / drug effects Dendritic Spines / metabolism Dendritic Spines / physiology Dopamine Agonists / pharmacology Endocytosis / physiology Extracellular Signal-Regulated MAP Kinases / metabolism Guanine Nucleotide Exchange Factors / genetics Guanine Nucleotide Exchange Factors / metabolism* HEK293 Cells Haloperidol / pharmacology Humans MAP Kinase Signaling System Male Mice Mice, Knockout Mice, Transgenic Neurons / metabolism Phosphorylation Protein Isoforms Quinpirole / pharmacology Receptor, Platelet-Derived Growth Factor beta / metabolism Receptors, Dopamine D1 / metabolism Receptors, Dopamine D2 / metabolism* Signal Transduction / drug effects Synaptic Transmission / drug effects
IF 12.384
Times Cited 11
Mice RBRC01081