Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, SE-171 76, Stockholm, Sweden.
Trends Pharmacol Sci. 2017 Aug;38(8):749-760. doi: 10.1016/j.tips.2017.05.006. Epub 2017 Jun 16.
Since conformational flexibility, which is required for the function of a protein, comes at the expense of structural stability, many proteins, including G-protein-coupled receptors (GPCRs), are under constant risk of misfolding and aggregation. In this regard GPR37 (also named PAEL-R and ETBR-LP-1) takes a prominent role, particularly in relation to Parkinson disease (PD). GPR37 is a substrate for parkin and accumulates abnormally in autosomal recessive juvenile parkinsonism, contributing to endoplasmic reticulum stress and death of dopaminergic neurons. GPR37 also constitutes a core structure of Lewy bodies, demonstrating a more general involvement in PD pathology. However, if folded and matured properly, GPR37 seems to be neuroprotective. Moreover, GPR37 modulates functionality of the dopamine transporter and the dopamine D2 receptor and stimulates dopamine neurotransmission. Here we review the multiple roles of GPR37 with relevance to potential disease modification and symptomatic therapies of PD and highlight unsolved issues in this field.
由于构象灵活性是蛋白质功能所必需的，但其代价是结构稳定性，因此许多蛋白质，包括 G 蛋白偶联受体 (GPCR)，一直面临错误折叠和聚集的风险。在这方面，GPR37（也称为 PAEL-R 和 ETBR-LP-1）起着突出的作用，特别是与帕金森病 (PD) 有关。GPR37 是 parkin 的底物，在常染色体隐性青少年型帕金森病中异常积累，导致内质网应激和多巴胺能神经元死亡。GPR37 还构成路易体的核心结构，表明其更广泛地参与 PD 病理学。然而，如果正确折叠和成熟，GPR37 似乎具有神经保护作用。此外，GPR37 调节多巴胺转运体和多巴胺 D2 受体的功能，并刺激多巴胺神经传递。在这里，我们回顾了 GPR37 的多种作用，这些作用与 PD 的潜在疾病修饰和症状治疗有关，并强调了该领域未解决的问题。
