The protein interacting with C-kinase (PICK1) interacts with and attenuates parkin-associated endothelial-like (PAEL) receptor-mediated cell death

Authors

  • Priyanka Dutta,

    1. Molecular Neuropharmacology, Drug Development, Department of Physiology, School of Medicine, Trinity College Dublin, Dublin, Ireland
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  • Kara E. O'Connell,

    1. Molecular Neuropharmacology, Drug Development, Department of Physiology, School of Medicine, Trinity College Dublin, Dublin, Ireland
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  • Sefika B. Ozkan,

    1. Department of Physics, Center for Biological Physics, Arizona State University, Tempe, Arizona, USA
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  • Andreas W. Sailer,

    1. Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland
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  • Kumlesh K. Dev

    Corresponding author
    1. Molecular Neuropharmacology, Drug Development, Department of Physiology, School of Medicine, Trinity College Dublin, Dublin, Ireland
    • Address correspondence and reprint requests to Kumlesh K. Dev, Department of Physiology, Molecular Neuropharmacology, Drug Development, School of Medicine, Trinity College Dublin, Dublin, Ireland. E-mail: devk@tcd.ie

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Abstract

The parkin-associated endothelial-like receptor (PAELR, GPR37) is an orphan G protein-coupled receptor that interacts with and is degraded by parkin-mediated ubiquitination. Mutations in parkin are thought to result in PAELR accumulation and increase neuronal cell death in Parkinson's disease. In this study, we find that the protein interacting with C-kinase (PICK1) interacts with PAELR. Specifically, the Postsynaptic density protein-95/Discs large/ZO-1 (PDZ) domain of PICK1 interacted with the last three residues of the c-terminal (ct) located PDZ motif of PAELR. Pull-down assays indicated that recombinant and native PICK1, obtained from heterologous cells and rat brain tissue, respectively, were retained by a glutathione S-transferase fusion of ct-PAELR. Furthermore, coimmunoprecipitation studies isolated a PAELR-PICK1 complex from transiently transfected cells. PICK1 interacts with parkin and our data showed that PICK1 reduces PAELR expression levels in transiently transfected heterologous cells compared to a PICK1 mutant that does not interact with PAELR. Finally, PICK1 over-expression in HEK293 cells reduced cell death induced by PAEALR over-expression during rotenone treatment and these effects of PICK1 were attenuated during inhibition of the proteasome. These results suggest a role for PICK1 in preventing PAELR-induced cell toxicity.

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Parkin mutations lead to parkin-associated endothelial-like receptor (PAELR) aggregation resulting in reduced neuronal cell viability. We find protein interacting c-kinase interacts with PAELR, regulating its expression and cell viability. The study adds to the repertoire of protein interacting c-kinase (PICK1) interacting proteins, such as dopamine transporter and parkin, which have been shown to play roles in dopaminergic neuronal function.

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