PMID- 27460146 OWN - NLM STAT- MEDLINE DCOM- 20170928 LR - 20181113 IS - 1558-1497 (Electronic) IS - 0197-4580 (Print) IS - 0197-4580 (Linking) VI - 46 DP - 2016 Oct TI - VPS35 regulates cell surface recycling and signaling of dopamine receptor D1. PG - 22-31 LID - S0197-4580(16)30085-9 [pii] LID - 10.1016/j.neurobiolaging.2016.05.016 [doi] AB - Vacuolar protein sorting 35 (VPS35) is a retromer complex component regulating membrane protein trafficking and retrieval. Mutations or dysfunction of VPS35 have been linked to Parkinson's disease (PD), which is pathologically characterized by the loss of dopamine neurons in brain substantia nigra region. Dopamine plays a key role in regulating various brain physiological functions by binding to its receptors and triggering their endocytosis and signaling pathways. However, it is unclear whether there is a link between VPS35 and dopamine signaling in PD. Herein, we found that VPS35 interacted with dopamine receptor D1 (DRD1). Notably, overexpression and downregulation of VPS35 increased and decreased steady-state cell surface levels of DRD1 and phosphorylation of cAMP-response element binding protein (CREB) and extracellular regulated protein kinases (ERK) that are important dopamine signaling effectors, respectively. In addition, overexpression of VPS35 promoted cell surface recycling of endocytic DRD1. Furthermore, downregulation of VPS35 abolished dopamine-induced CREB/ERK phosphorylation. More importantly, although the PD-associated VPS35 mutant VPS35 (D620N) still interacted with DRD1, its expression did not affect cell surface recycling of DRD1 and phosphorylation of CREB/ERK nor rescue the reduction of CREB/ERK phosphorylation caused by VPS35 downregulation. These results demonstrate that VPS35 regulates DRD1 trafficking and DRD1-mediated dopamine signaling pathway, and that the PD-associated VPS35 (D620N) mutant loses such functions, providing a novel molecular mechanism underlying PD pathogenesis. CI - Copyright (c) 2016 Elsevier Inc. All rights reserved. FAU - Wang, Chen AU - Wang C AD - Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Collaborative Innovation Center for Brain Science, College of Medicine, Xiamen University, Xiamen, Fujian, China; Department of Neurology, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China. FAU - Niu, Mengxi AU - Niu M AD - Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Collaborative Innovation Center for Brain Science, College of Medicine, Xiamen University, Xiamen, Fujian, China. FAU - Zhou, Zehua AU - Zhou Z AD - Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Collaborative Innovation Center for Brain Science, College of Medicine, Xiamen University, Xiamen, Fujian, China. FAU - Zheng, Xiaoyuan AU - Zheng X AD - Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Collaborative Innovation Center for Brain Science, College of Medicine, Xiamen University, Xiamen, Fujian, China. FAU - Zhang, Lingzhi AU - Zhang L AD - Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Collaborative Innovation Center for Brain Science, College of Medicine, Xiamen University, Xiamen, Fujian, China. FAU - Tian, Ye AU - Tian Y AD - Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Collaborative Innovation Center for Brain Science, College of Medicine, Xiamen University, Xiamen, Fujian, China. FAU - Yu, Xiaojun AU - Yu X AD - Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Collaborative Innovation Center for Brain Science, College of Medicine, Xiamen University, Xiamen, Fujian, China. FAU - Bu, Guojun AU - Bu G AD - Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Collaborative Innovation Center for Brain Science, College of Medicine, Xiamen University, Xiamen, Fujian, China; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. FAU - Xu, Huaxi AU - Xu H AD - Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Collaborative Innovation Center for Brain Science, College of Medicine, Xiamen University, Xiamen, Fujian, China; Degenerative Diseases Program, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, CA, USA. FAU - Ma, Qilin AU - Ma Q AD - Department of Neurology, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China. Electronic address: qilinma@yeah.net. FAU - Zhang, Yun-Wu AU - Zhang YW AD - Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Collaborative Innovation Center for Brain Science, College of Medicine, Xiamen University, Xiamen, Fujian, China. Electronic address: yunzhang@xmu.edu.cn. LA - eng GR - R01 AG021173/AG/NIA NIH HHS/United States GR - R01 AG038710/AG/NIA NIH HHS/United States GR - R01 AG044420/AG/NIA NIH HHS/United States GR - R01 NS046673/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20160521 PL - United States TA - Neurobiol Aging JT - Neurobiology of aging JID - 8100437 RN - 0 (DRD1 protein, human) RN - 0 (Receptors, Dopamine D1) RN - 0 (VPS35 protein, human) RN - 0 (Vesicular Transport Proteins) SB - IM MH - Animals MH - Dopaminergic Neurons/*metabolism/pathology/*physiology MH - Epistasis, Genetic MH - HEK293 Cells MH - Humans MH - Mice MH - Mice, Inbred C57BL MH - *Mutation MH - Parkinson Disease/*genetics/pathology MH - Receptors, Dopamine D1/*metabolism/physiology MH - Signal Transduction/genetics/physiology MH - Tumor Cells, Cultured MH - Vesicular Transport Proteins/deficiency/*genetics/*physiology PMC - PMC5018432 MID - NIHMS789307 OTO - NOTNLM OT - Dopamine OT - Dopamine receptor D1 OT - Dopamine signaling OT - Parkinson's disease OT - Trafficking OT - Vacuolar protein sorting 35 EDAT- 2016/07/28 06:00 MHDA- 2017/09/29 06:00 PMCR- 2017/10/01 CRDT- 2016/07/28 06:00 PHST- 2016/02/05 00:00 [received] PHST- 2016/04/24 00:00 [revised] PHST- 2016/05/15 00:00 [accepted] PHST- 2016/07/28 06:00 [entrez] PHST- 2016/07/28 06:00 [pubmed] PHST- 2017/09/29 06:00 [medline] PHST- 2017/10/01 00:00 [pmc-release] AID - S0197-4580(16)30085-9 [pii] AID - 10.1016/j.neurobiolaging.2016.05.016 [doi] PST - ppublish SO - Neurobiol Aging. 2016 Oct;46:22-31. doi: 10.1016/j.neurobiolaging.2016.05.016. Epub 2016 May 21.