The protein interacting with C‐kinase ( PICK 1) interacts with and attenuates parkin‐associated endothelial‐like ( PAEL ) receptor‐mediated cell death

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. image 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.