Urs Nikhil M, Peterson Sean M, Caron Marc G
Departments of Cell Biology, Duke University Medical Center, Durham, North Carolina.
Departments of Cell Biology, Duke University Medical Center, Durham, North Carolina; Medicine, Duke University Medical Center, Durham, North Carolina; Neurobiology, Duke University Medical Center, Durham, North Carolina.
Biol Psychiatry. 2017 Jan 1;81(1):78-85. doi: 10.1016/j.biopsych.2016.10.011. Epub 2016 Oct 19.
The dopamine D receptor (DR) is a G protein-coupled receptor that is a common target for antipsychotic drugs. Antagonism of DR signaling in the striatum is thought to be the primary mode of action of antipsychotic drugs in alleviating psychotic symptoms. However, antipsychotic drugs are not clinically effective at reversing cortical-related symptoms, such as cognitive deficits in schizophrenia. While the exact mechanistic underpinnings of these cognitive deficits are largely unknown, deficits in cortical dopamine function likely play a contributing role. It is now recognized that similar to most G protein-coupled receptors, DRs signal not only through canonical G protein pathways but also through noncanonical beta-arrestin2-dependent pathways. We review the current mechanistic bases for this dual signaling mode of DRs and how these new concepts might be leveraged for therapeutic gain to target both cortical and striatal dysfunction in dopamine neurotransmission and hence have the potential to correct both positive and cognitive symptoms of schizophrenia.
多巴胺D受体（DR）是一种G蛋白偶联受体，是抗精神病药物的常见靶点。纹状体中DR信号的拮抗作用被认为是抗精神病药物缓解精神病症状的主要作用方式。然而，抗精神病药物在临床上对逆转与皮层相关的症状（如精神分裂症中的认知缺陷）并无效果。虽然这些认知缺陷的确切机制基础在很大程度上尚不清楚，但皮层多巴胺功能缺陷可能起到了一定作用。现在人们认识到，与大多数G蛋白偶联受体一样，DR不仅通过经典的G蛋白途径信号传导，还通过非经典的β-抑制蛋白2依赖性途径信号传导。我们综述了DR这种双重信号模式的当前机制基础，以及如何利用这些新概念实现治疗获益，以针对多巴胺神经传递中的皮层和纹状体功能障碍，从而有可能纠正精神分裂症的阳性和认知症状。
