Coupling between GPR143 and dopamine D2 receptor is required for selective potentiation of dopamine D2 receptor function by L‐3,4‐dihydroxyphenylalanine in the dorsal striatum

• Published in: Journal of neurochemistry Vol. 165; no. 2; pp. 177 - 195
• Main Authors: Masukawa, Daiki, Kitamura, Satoshi, Tajika, Rei, Uchimura, Hiraku, Arai, Masami, Takada, Yuuki, Arisawa, Tetsu, Otaki, Momoyo, Kanai, Kaori, Kobayashi, Kenta, Miyazaki, Tomoyuki, Goshima, Yoshio
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01-04-2023
• Subjects: 4‐dihydroxyphenylalanine; Albinism; Amino acids; Animals; Caudate-putamen; Corpus Striatum - metabolism; Coupling; Dihydroxyphenylalanine; Domains; Dopamine; Dopamine - metabolism; Dopamine D1 receptors; Dopamine D2 receptor; Dopamine D2 receptors; Dopamine D3 receptors; GPCR; GPR143; Intracerebroventricular administration; Levodopa; Levodopa - pharmacology; L‐3; Mice; Motor task performance; Movement disorders; Neostriatum; Neurodegenerative diseases; Neurotransmitters; Ocular albinism; Parkinson Disease - metabolism; Parkinson's disease; Potentiation; Precursors; Quinpirole; Quinpirole - metabolism; Quinpirole - pharmacology; Receptors; Receptors, Dopamine D1 - metabolism; Receptors, Dopamine D2 - metabolism; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; striatum; GPR143; Dopamine D2 receptor; L-3; striatum; 4-dihydroxyphenylalanine; GPCR; dopamine
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.15789

Dopamine (DA) is involved in neurological and physiological functions such as motor control. L‐3,4‐dihydroxyphenylalanine (L‐DOPA), a precursor of DA, is conventionally believed to be an inert amino acid precursor of DA, and its major therapeutic effects in Parkinson's disease (PD) are mediated through its conversion to DA. On the contrary, accumulating evidence suggests that L‐DOPA itself is a neurotransmitter. We here show that L‐DOPA potentiates DA D2 receptor (DRD2) signaling through GPR143, the gene product of X‐linked ocular albinism 1, a G‐protein‐coupled receptor for L‐DOPA. In Gpr143‐gene‐deficient (Gpr143−/y) mice, quinpirole, a DRD2/DRD3 agonist, ‐induced hypolocomotion was attenuated compared to wild‐type (WT) mice. Administration of non‐effective dose of L‐DOPA methyl ester augmented the quinpirole‐induced hypolocomotion in WT mice but not in Gpr143−/y mice. In cells co‐expressing GPR143 and DRD2, L‐DOPA enhanced the interaction between GPR143 and DRD2 and augmented quinpirole‐induced decrease in cAMP levels. This augmentation by L‐DOPA was not observed in cells co‐expressing GPR143 and DRD1 or DRD3. Chimeric analysis in which the domain of GPR143 was replaced with GPR37 revealed that GPR143 interacted with DRD2 at the fifth transmembrane domain. Intracerebroventricular administration of a peptide that disrupted the interaction mitigated quinpirole‐induced behavioral changes in WT mice but not in Gpr143−/y mice. These findings provide evidence that coupling between GPR143 and DRD2 is required for selective DRD2 modulation by L‐DOPA in the dorsal striatum.
Dopamine (DA) is involved in neurological and physiological functions such as motor control. L‐3,4‐dihydroxyphenylalanine (L‐DOPA) is believed to be an inert amino acid, and its major therapeutic effects in Parkinson's disease (PD) are mediated through its conversion to DA. On the contrary, we propose that L‐DOPA is a neurotransmitter. L‐DOPA potentiated DA D2 receptor (DRD2) signaling through GPR143, a G protein‐coupled receptor for L‐DOPA. Fifth transmembrane region of GPR143 was required for the interaction between GPR143 and DRD2. Our findings provide evidence that coupling between GPR143 and DRD2 is required for DRD2 modulation by L‐DOPA.