title: The protein interacting with C-kinase (PICK1) interacts with and attenuates parkin-associated endothelial-like (PAEL) receptor-mediated cell death.
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.
authors.affiliation: Molecular Neuropharmacology, Drug Development, Department of Physiology, School of Medicine, Trinity College Dublin, Dublin, Ireland.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Dutta
authors.forename: Kara E
authors.initials: KE
authors.lastname: O'Connell
authors.forename: Sefika B
authors.initials: SB
authors.lastname: Ozkan
authors.forename: Andreas W
authors.initials: AW
authors.lastname: Sailer
authors.forename: Kumlesh K
authors.initials: KK
authors.lastname: Dev
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism / Q000502:physiology*; D016923:Cell Death / Q000502:physiology*; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005982:Glutathione Transferase / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000502:physiology*; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D054731:PDZ Domains; D016133:Polymerase Chain Reaction; D011487:Protein Conformation; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D018076:DNA, Complementary; C119905:Gpr37 protein, rat; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C498298:PICK1 protein, rat; D043562:Receptors, G-Protein-Coupled; D005982:Glutathione Transferase
keywords: GPR37; parkin-associated endothelial-like receptor (PAEL receptor); parkinson's disease (PD); protein interacting with C-Kinase (PICK1)