Abstract
We recently demonstrated that fatty acid-binding protein 3 (FABP3) and Rabex-5, a GTP exchange factor for Rab 5 bind to the dopamine D2 receptor long isoform (D2LR) , which has 29-amino acid insert region in the third cytoplasmic loop. We then reported that fatty acid binding protein 3 (FABP3) knock-out (Fabp3-/-) mice exhibit abnormal dopamine-related behaviors such as enhanced dopamine D2 receptor antagonist-induced catalepsy behaviors. Fabp3 null mice also exhibit cognitive deficits, hyperlocomotion and impaired fear extinction, and thus show post-traumatic stress disorder (PTSD) -like behaviors. Notably, chronic administration of ramelteon (1.0 mg/kg, p.o.) , a melatonin receptor agonist, improved all PTSD-like behaviors tested in Fabp3-/- mice. We also 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. Moreover, intracellular D2LR signaling mediated catalepsy behavior by a typical antipsychotic drug, haloperidol. 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.
