A vast amount of GPCRs remains without known ligands, a fact that may represent novel opportunities to develop innovative therapeutic strategies for managing diverse pathologies. Amongst these entitled orphan receptors, one of the most enigmatic is parkin-associated endothelin-like receptor (Pael-R), also known as GPR37. GPR37 was first cloned in 1997 from human brain. Within brain, this receptor is particularly enriched in cerebellum (i.e. Purkinje cells), corpus callosum, medulla, putamen, caudate nucleus, substantia nigra and hippocampus (i.e. pyramidal and granule cells of the dentate gyrus). Interestingly, GPR37 has been identified as a parkin substrate. Parkin is a protein-ubiquitin ligase E3 involved in the ubiquitination and proteasome-mediated protein degradation and clearance of aggregated proteins. Therefore, parkin loss of function, as happens in autosomal recessive juvenile Parkinson (AR-JP), prevents degradation of parkin substrates (i.e. GPR37), thus resulting in their toxic accumulation. Indeed, GPR37 has been described to be up-regulated in brains of AR-JP patients. In addition, the presence of GPR37 in the core of Lewy bodies in PD patients has been reported, thus suggesting a role of GPR37 aggregates in PD pathology. Also, viral-mediated GPR37 overexpression in vivo (i.e. in substantia nigra) constitutes a good PD animal model since it results in progressive degeneration of nigral dopaminergic neurons. Conversely, GPR37 has been found to be downregulated in the amygdala and hippocampus of major depressive disorder patients. Thus it seems clear that revealing the function of this receptor constitutes a major challenge to improve the treatment of some neuropsychiatric pathologies. Interestingly, it was recently shown that the surface expression of GPR37 increases upon co-expression with A2AR or D2R. Importantly, 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. Recently, we provided insight about the localization and role of the orphan GPR37 within the hippocampus, which seems to involve a control of A2AR function (i.e. A2AR sensitization). In addition, by using a model for parkisonian tremor, the pilocarpine-induced tremulous jaw movements (TJMs), we showed that the deletion of GPR37 attenuated the TJMs in response to this cholinomimetic. Interestingly, the control that A2AR receptor exerted over TJMs was lost in the absence of GPR37, thus pointing to a pivotal role of this orphan receptor in the adenosinergic control of parkinsonian tremor. Collectively, this initial amount of data suggests that GPR37 might become a promising drug target for these neuropathological conditions involving the dopaminergic and adenosinergic systems.
The Parkinson’s disease-associated GPR37 receptor-mediated cytotoxicity is controlled by its intracellular cysteine-rich domain.
Gandía, J., Fernández-Dueñas, V., Morató, X., Caltabiano, G., González-Muñiz, R., Pardo, L., Stagljar, I. & Ciruela, F.
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On the role of Parkinson’s disease-associated GPR37 in the hippocampus: Functional interplay with the adenosinergic system.
Lopes, J.P., Morató, X., Souza, C., Pinhal, C., Machado, N., Canas, P., Silva, H., Stagljar, I., Gandía, J., Fernández-Dueñas, V., Luján, R., Cunha, R.A. & Ciruela, F.
Journal of Neurochemistry 134(1):135-146 (2015).
Adenosine A2A receptor-mediated control of pilocarpine-induced tremulous jaw movements is Parkinson’s disease-associated GPR37 receptor-dependent.
Gandía, J., Morató, X., Stagljar, I., Fernández-Dueñas, V. & Ciruela, F.
Behavioural Brain Research 288,103-106 (2015).
Cocaine-mediated synaptic depression in corticostriatal synapses is Parkinson's disease-associated GPR37 receptor-dependent.
Rial, D., Morató, X., Real, J.I., Gonçalves, F.Q., Stagljar, I., Fernández-Dueñas, V., Cunha, R.A. & Ciruela, F.. Neuroscience Letters 638, 162–166.(2017).