Proteolytic processing of G protein-coupled receptor 37 by ADAM10 and furin

Thesis event information

Date and time of the thesis defence

Place of the thesis defence

F202, Faculty of Medicine, Aapistie 5B. Remote access: https://oulu.zoom.us/j/69794364440?pwd=QzF0VittUGg4K2tOOHBJOTFub2FJUT09

Topic of the dissertation

Proteolytic processing of G protein-coupled receptor 37 by ADAM10 and furin

Doctoral candidate

Master of Science Orvokki Mattila

Faculty and unit

University of Oulu Graduate School, Faculty of Medicine, Research Unit of Biomedicine

Subject of study

Biomedicine

Opponent

Professor Pertti Panula, University of Helsinki

Custos

Docent Ulla Petäjä-Repo, University of Oulu

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Proteolytic processing of a Parkinson’s disease-associated receptor GPR37

G protein-coupled receptors are cell surface receptors that transfer messages from extracellular space to the cell interior. These receptors participate in many vital physiological processes and form a major class of drug targets. G protein-coupled receptor 37 (GPR37) is abundantly expressed in the brain and has been linked to several important signaling pathways. Moreover, the receptor has been implicated in certain brain pathologies, the most notable of which is Parkinson’s disease. Therefore, it is a potential drug target to treat neurological diseases. However, the mechanism of action of GPR37 is poorly understood and its therapeutic potential remains unexplored.

This study aimed to investigate mechanisms that may regulate the function of GPR37. The biosynthesis and processing of GPR37 were studied using cell models and various biochemical and cell biological methods.

The results show that the extracellular part of GPR37 is subject to proteolytic cleavage at three distinct sites, and the cleaved fragment is released from the cells. The receptor is found at the cell surface predominantly in this proteolytically cleaved form. Characterization of the cleaving enzymes revealed that GPR37 is processed by furin and ADAM10. These findings were confirmed using various complementary methods and cultured cell lines of diverse tissue origin. Importantly, the ADAM10-mediated cleavage was also found to occur in a more physiological context of mouse brain tissue. Since proteolytic processing of some G protein-coupled receptors is intimately related to their mechanism of action, it is likely that the cleavage of GPR37 has similar functional significance for the receptor.

This study reveals a novel processing mechanism for GPR37. N-terminal cleavage is likely an important element for receptor regulation, and the results pave way for strategies to exploit GPR37 as a therapeutic target.
Last updated: 19.4.2021