title: The Parkinson's-disease-associated receptor GPR37 undergoes metalloproteinase-mediated N-terminal cleavage and ectodomain shedding.
abstract: The G-protein-coupled receptor 37 ( GPR37) has been implicated in the juvenile form of Parkinson's disease, in dopamine signalling and in the survival of dopaminergic cells in animal models. The structure and function of the receptor, however, have remained enigmatic. Here, we demonstrate that although GPR37 matures and is exported from the endoplasmic reticulum in a normal manner upon heterologous expression in HEK293 and SH-SY5Y cells, its long extracellular N-terminus is subject to metalloproteinase-mediated limited proteolysis between E167 and Q168. The proteolytic processing is a rapid and efficient process that occurs constitutively. Moreover, the GPR37 ectodomain is released from cells by shedding, a phenomenon rarely described for GPCRs. Immunofluorescence microscopy further established that although full-length receptors are present in the secretory pathway until the trans-Golgi network, GPR37 is expressed at the cell surface predominantly in the N-terminally truncated form. This notion was verified by flow cytometry and cell surface biotinylation assays. These new findings on the GPR37 N-terminal limited proteolysis may help us to understand the role of this GPCR in the pathophysiology of Parkinson's disease and in neuronal function in general.
authors: Medical Research Center Oulu, and Cancer and Translational Medicine Research Unit, University of Oulu, Oulu FI-90014, Finland.
authors: S Orvokki
authors: SO
authors: Mattila
authors: Medical Research Center Oulu, and Cancer and Translational Medicine Research Unit, University of Oulu, Oulu FI-90014, Finland.
authors: Jussi T
authors: JT
authors: Tuusa
authors: Medical Research Center Oulu, and Cancer and Translational Medicine Research Unit, University of Oulu, Oulu FI-90014, Finland ulla.petaja-repo@oulu.fi.
authors: Ulla E
authors: UE
authors: Petäjä-Repo
mesh_terms: D002460:Cell Line; D004151:Dipeptides / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D045726:Metalloproteases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010300:Parkinson Disease / Q000473:pathology*; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*
chemical_list: D004151:Dipeptides; C480827:GPR37 receptor, human; D008565:Membrane Proteins; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D043562:Receptors, G-Protein-Coupled; D045726:Metalloproteases
keywords: Ectodomain shedding; GPR37; Metalloproteinase; N-terminal cleavage; Pael receptor; Parkinson's disease