title: VPS35 regulates cell surface recycling and signaling of dopamine receptor D1.
abstract: 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.
authors.affiliation: 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.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Mengxi
authors.initials: M
authors.lastname: Niu
authors.affiliation: 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.
authors.forename: Zehua
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Zheng
authors.affiliation: 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.
authors.forename: Lingzhi
authors.initials: L
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Ye
authors.initials: Y
authors.lastname: Tian
authors.affiliation: 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.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Yu
authors.affiliation: 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.
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
authors.affiliation: 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.
authors.forename: Huaxi
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China. Electronic address: qilinma@yeah.net.
authors.forename: Qilin
authors.initials: Q
authors.lastname: Ma
authors.affiliation: 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.
authors.forename: Yun-Wu
authors.initials: YW
authors.lastname: Zhang
mesh_terms: D000818:Animals; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology / Q000502:physiology*; D004843:Epistasis, Genetic; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology; D017447:Receptors, Dopamine D1 / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014407:Tumor Cells, Cultured; D033921:Vesicular Transport Proteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*
chemical_list: C583260:DRD1 protein, human; D017447:Receptors, Dopamine D1; C419573:VPS35 protein, human; D033921:Vesicular Transport Proteins
keywords: Dopamine; Dopamine receptor D1; Dopamine signaling; Parkinson's disease; Trafficking; Vacuolar protein sorting 35