title: The Parkinson's disease-associated GPR37 receptor-mediated cytotoxicity is controlled by its intracellular cysteine-rich domain.
abstract: GPR37, also known as parkin-associated endothelin-like receptor (Pael-R), is an orphan G protein-coupled receptor (GPCR) that aggregates intracellularly in a juvenile form of Parkinson's disease. However, little is known about the structure or function of this receptor. Here, in order to better understand the functioning of this receptor, we focused on the GPR37 C-terminal tail, in particular on a cystein-enriched region. Thus, we aimed to reveal the role of these residues on receptor plasma membrane expression and function, and also whether the presence of this cysteine-rich domain is linked to the previously described receptor-mediated cytotoxicity. Interestingly, while the deletion of six cysteine residues within this region did not affect receptor internalization it promoted GPR37 plasma membrane expression and signaling. Furthermore, the removal of the C-terminal cysteine-rich domain protected against GPR37-mediated apoptosis and cell death. Overall, we identified a GPR37 domain, namely the C-terminal tail cysteine-rich domain, which played a critical role in receptor cell surface expression, function and GPR37-mediated cytotoxicity. These results might contribute to better comprehend the pathophysiology (i.e. in Parkinson's disease) of this rather unknown member of the GPCR family.
authors: Unitat de Farmacologia, Departament de Patologia i Terapèutica Experimental, Facultat de Medicina, IDIBELL, Universitat de Barcelona, Barcelona, Spain.
authors: Jorge
authors: J
authors: Gandía
authors: Víctor
authors: V
authors: Fernández-Dueñas
authors: Xavier
authors: X
authors: Morató
authors: Gianluigi
authors: G
authors: Caltabiano
authors: Rosario
authors: R
authors: González-Muñiz
authors: Leonardo
authors: L
authors: Pardo
authors: Igor
authors: I
authors: Stagljar
authors: Francisco
authors: F
authors: Ciruela
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D000704:Analysis of Variance; D000906:Antibodies / Q000494:pharmacology; D019921:Biotinylation; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D003545:Cysteine / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009479:Neuropeptides / Q000494:pharmacology; D017434:Protein Structure, Tertiary / Q000502:physiology; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D019284:Thapsigargin / Q000494:pharmacology; D014162:Transfection
chemical_list: C497109:ATF4 protein, human; D000906:Antibodies; D004791:Enzyme Inhibitors; C480827:GPR37 receptor, human; D009479:Neuropeptides; D043562:Receptors, G-Protein-Coupled; D051701:Activating Transcription Factor 4; D019284:Thapsigargin; C032522:head activator peptide; D000242:Cyclic AMP; D053148:Caspase 3; D003545:Cysteine; D002118:Calcium; D011761:Pyrrolidonecarboxylic Acid