Volume 4 Supplement 1

European Society for Neurochemistry Biannual Conference: Molecular Mechanisms of Regulation in the Nervous System

Open Access

N-terminal proteolytic processing of G proteiin-coupled receptor 37 (GPR37)

  • Orvokki Mattila1 and
  • Ulla Petäjä-Repo1
SpringerPlus20154(Suppl 1):P26


Published: 12 June 2015



GPR37 is a G protein-coupled receptor that is abundantly expressed in the brain and has been implicated in dopaminergic signaling [1]. The receptor has been identified as a substrate of the ubiquitin ligase parkin and it has been linked to the autosomal recessive juvenile parkinsonism (AR-JP), an early onset familial Parkinson’s disease. The loss of parkin function and deficits in the ubiquitin proteasome pathway were proposed to cause intracellular accumulation of unfolded GPR37 leading to the AR-JP pathogenesis. [2] Here, we found that while GPR37 appears to mature normally in a heterologous expression system, the receptor is subject to proteolytic cleavage at its large N-terminal extracellular region. To study this proteolytic processing, we used stably and transiently transfected human embryonic kidney (HEK) 293 and SH-SY5Y neuroblastoma cells that express N- and C-terminally epitope-tagged human GPR37. N-terminal sequencing of the cleaved C-terminal receptor fragment revealed that GPR37 is cleaved between Glu187and Gln188 and the metabolic pulse-chase data suggests that receptor cleavage is a rapid and efficient process. Moreover, our results indicate that the receptor N-terminus is released from the cells by shedding, a phenomenon rarely described for GPCRs. Immunofluorescence microscopy with subcellular markers indicates that GPR37 is still in the full-length form in the trans-Golgi network but is predominantly expressed in the cleaved form at the cell surface. Additionally, experiments with various proteinase inhibitors imply that the receptor is cleaved by a metalloproteinase. As proteolytic processing is involved in the regulation of many cell surface receptors, our findings provide valuable information about GPR37 that help to understand its function and role in AR-JP at the molecular level.

Authors’ Affiliations

University of Oulu


  1. Marazziti , et al.: . the FASEB J 2011, 25: 2071-2081. 10.1096/fj.10-175737View ArticleGoogle Scholar
  2. Imai , et al.: . Cell 2001, 105: 891-902. 10.1016/S0092-8674(01)00407-XView ArticleGoogle Scholar


© Mattila and Petäjä-Repo. 2015

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.