Fine-tuning role of L-DOPA and its receptor GPR143 for dopamine D2 receptor in the striatal indirect pathway

Abstract

Levodopa (L-DOPA) therapy is the gold standard for the treatment with Parkinson's disease. The pharmacological actions of L-DOPA have been believed to be mediated through its conversion to dopamine. On the contrary, we propose that L-DOPA is a neurotransmitter. We identified G-protein coupled receptor (GPCR) GPR143, a gene product of ocular albinism-1, as a receptor for L-DOPA. In the course of our phenotypic analysis of Gpr143 gene-deficient (Gpr143-/y) mice, we found that behavioral response to quinpirole, a dopamine D2 receptor (D2R) agonist, was attenuated in Gpr143-/y mice when compared to wild type (WT) mice. This phenotype was also observed in the striatal indirect pathway specific Gpr143 gene-deficient (A2A-cre;Gpr143flox/y) mice. To investigate the physiological role of GPR143, we performed anxiety behavior using zero maze test. The anxiety behavior was attenuated in Gpr143-/y and A2A-cre;Gpr143flox/y mice when compared to corresponding control animals, as was reported in the striatal indirect pathway specific D2R deficient mice. These results suggest that L-DOPA-GPR143 fine-tunes the dopamine D2R in the striatal indirect pathway.