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
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
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GPR143 和多巴胺 D2 受体之间的偶联是背侧纹状体中 L-3,4-二羟基苯丙氨酸选择性增强多巴胺 D2 受体功能所必需的
作者：
Masukawa D;Kitamura S;Tajika R;Uchimura H;Arai M;Takada Y;Arisawa T;Otaki M;Kanai K;Kobayashi K;Miyazaki T;Goshima Y
多巴胺（DA）参与神经和生理功能，如运动控制。L-3，4-二羟基苯丙氨酸（L-DOPA）是DA的前体，通常认为是DA的惰性氨基酸前体，其对帕金森病（PD）的主要治疗作用是通过转化为DA来介导的。我们在这里表明，L-DOPA通过GPR 143增强DA D2受体（DRD 2）信号传导，GPR 143是X连锁眼白化病1的基因产物，是L-DOPA的G蛋白偶联受体。在Gpr 143基因缺陷型（Gpr 143 −/y）小鼠中，与野生型（WT）小鼠相比，DRD 2/DRD 3激动剂喹吡罗诱导的运动功能减退减弱。给予无效剂量的左旋多巴甲酯可增强WT小鼠中喹吡罗诱导的运动功能减退，但对Gpr 143 −/小鼠无此作用。在共表达GPR 143和DRD 2的细胞中，L-DOPA增强了GPR 143和DRD 2之间的相互作用，并增强了喹吡罗诱导的cAMP水平降低。在共表达GPR 143和DRD 1或DRD 3的细胞中未观察到L-DOPA的这种增强作用。嵌合体分析，其中GPR 143的结构域被替换为GPR 37揭示GPR 143与DRD 2在第五跨膜结构域相互作用。脑室内注射一种破坏这种相互作用的肽，可以减轻WT小鼠中喹吡罗诱导的行为变化，但对Gpr 143 −/ymice没有影响。这些发现提供了证据，证明GPR 143和DRD 2之间的偶联是背侧纹状体中L-DOPA选择性DRD 2调节所必需的。
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. InGpr143‐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 inWTmice but not inGpr143−/ymice. 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 inWTmice but not inGpr143−/ymice. These findings provide evidence that coupling between GPR143 and DRD2 is required for selective DRD2 modulation by L‐DOPA in the dorsal striatum.