Division of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy.
"C. Golgi" Women Health Center, University of Brescia, 25123 Brescia, Italy.
Biomolecules. 2020 Jul 9;10(7):1016. doi: 10.3390/biom10071016.
The dopamine (DA) D3 receptor (D3R) plays a pivotal role in the control of several functions, including motor activity, rewarding and motivating behavior and several aspects of cognitive functions. Recently, it has been reported that the D3R is also involved in the regulation of neuronal development, in promoting structural plasticity and in triggering key intracellular events with neuroprotective potential. A new role for D3R-dependent neurotransmission has thus been proposed both in preserving DA neuron homeostasis in physiological conditions and in preventing pathological alterations that may lead to neurodegeneration. Interestingly, there is evidence that nicotinic acetylcholine receptors (nAChR) located on DA neurons also provide neurotrophic support to DA neurons, an effect requiring functional D3R and suggesting the existence of a positive cross-talk between these receptor systems. Increasing evidence suggests that, as with the majority of G protein-coupled receptors (GPCR), the D3R directly interacts with other receptors to form new receptor heteromers with unique functional and pharmacological properties. Among them, we recently identified a receptor heteromer containing the nAChR and the D3R as the molecular effector of nicotine-mediated neurotrophic effects. This review summarizes the functional and pharmacological characteristics of D3R, including the capability to form active heteromers as pharmacological targets for specific neurodegenerative disorders. In particular, the molecular and functional features of the D3R-nAChR heteromer will be especially discussed since it may represent a possible key etiologic effector for DA-related pathologies, such as Parkinson's disease (PD), and a target for drug design.
多巴胺（DA）D3 受体（D3R）在控制多种功能方面发挥着关键作用，包括运动活动、奖励和激励行为以及认知功能的几个方面。最近，据报道 D3R 还参与了神经元发育的调节，促进结构可塑性，并触发具有神经保护潜力的关键细胞内事件。因此，D3R 依赖性神经递质传递在维持生理条件下 DA 神经元的内稳态和预防可能导致神经退行性变的病理改变方面具有新的作用。有趣的是，有证据表明，位于 DA 神经元上的烟碱型乙酰胆碱受体（nAChR）也为 DA 神经元提供神经营养支持，这种作用需要功能性 D3R，并表明这些受体系统之间存在正的交叉对话。越来越多的证据表明，与大多数 G 蛋白偶联受体（GPCR）一样，D3R 直接与其他受体相互作用，形成具有独特功能和药理学特性的新受体异质体。其中，我们最近鉴定出一种包含 nAChR 和 D3R 的受体异质体，作为尼古丁介导的神经营养作用的分子效应器。这篇综述总结了 D3R 的功能和药理学特征，包括形成活性异质体作为特定神经退行性疾病的药理学靶点的能力。特别是，将特别讨论 D3R-nAChR 异质体的分子和功能特征，因为它可能代表与 DA 相关的病理学（如帕金森病（PD））相关的潜在关键病因效应因子，并且是药物设计的目标。
