VPS35 regulates cell surface recycling and signaling of dopamine receptor D1

Chen Wang, Mengxi Niu, Zehua Zhou, Xiaoyuan Zheng, Lingzhi Zhang, Ye Tian, Xiaojun Yu, Guojun D Bu, Huaxi Xu, Qilin Ma, Yun wu Zhang

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)22-31
Number of pages10
JournalNeurobiology of Aging
Volume46
DOIs
StatePublished - Oct 1 2016

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Dopamine Receptors
Recycling
Protein Transport
Dopamine D1 Receptors
Cyclic AMP Response Element-Binding Protein
Dopamine
Protein Kinases
Phosphorylation
Parkinson Disease
Down-Regulation
Dopaminergic Neurons
Brain
Substantia Nigra
Mutant Proteins
Endocytosis
Membrane Proteins

Keywords

  • Dopamine
  • Dopamine receptor D1
  • Dopamine signaling
  • Parkinson's disease
  • Trafficking
  • Vacuolar protein sorting 35

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)
  • Aging
  • Developmental Biology
  • Geriatrics and Gerontology

Cite this

Wang, C., Niu, M., Zhou, Z., Zheng, X., Zhang, L., Tian, Y., ... Zhang, Y. W. (2016). VPS35 regulates cell surface recycling and signaling of dopamine receptor D1. Neurobiology of Aging, 46, 22-31. https://doi.org/10.1016/j.neurobiolaging.2016.05.016

VPS35 regulates cell surface recycling and signaling of dopamine receptor D1. / Wang, Chen; Niu, Mengxi; Zhou, Zehua; Zheng, Xiaoyuan; Zhang, Lingzhi; Tian, Ye; Yu, Xiaojun; Bu, Guojun D; Xu, Huaxi; Ma, Qilin; Zhang, Yun wu.

In: Neurobiology of Aging, Vol. 46, 01.10.2016, p. 22-31.

Research output: Contribution to journalArticle

Wang, C, Niu, M, Zhou, Z, Zheng, X, Zhang, L, Tian, Y, Yu, X, Bu, GD, Xu, H, Ma, Q & Zhang, YW 2016, 'VPS35 regulates cell surface recycling and signaling of dopamine receptor D1', Neurobiology of Aging, vol. 46, pp. 22-31. https://doi.org/10.1016/j.neurobiolaging.2016.05.016
Wang, Chen ; Niu, Mengxi ; Zhou, Zehua ; Zheng, Xiaoyuan ; Zhang, Lingzhi ; Tian, Ye ; Yu, Xiaojun ; Bu, Guojun D ; Xu, Huaxi ; Ma, Qilin ; Zhang, Yun wu. / VPS35 regulates cell surface recycling and signaling of dopamine receptor D1. In: Neurobiology of Aging. 2016 ; Vol. 46. pp. 22-31.
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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.",
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