Adenosine A2A receptor-mediated control of pilocarpine-induced tremulous jaw movements is Parkinson's disease-associated GPR37 receptor-dependent

Gandía, Jorge; Morató, Xavier; Štagljar, Igor; Fernández-Dueñas, Víctor; Ciruela, Francisco

doi:10.1016/j.bbr.2015.04.001

Cited by 17 publications

(11 citation statements)

References 25 publications

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“…While locomotion and both Akt and ERK1/2 striatal signatures were differentially affected by cocaine and amphetamine, GPR37 KO mice failed to respond to either stimulus when used as an incentive in the conditional place preference behavioral test and did not develop behavioral sensitization over time ( Marazziti et al, 2011 ). Finally, when measuring pilocarpine-induced tremulous jaw movement, a mouse model of PD tremor, GPR37 KO mice had significantly reduced tremulous jaw movements when compared to wild type mice, suggesting that a GPR37 antagonist could be an additional therapeutic approach for the treatment of classical PD tremor ( Gandia et al, 2015 ). It should be noted, however, that the extent of DA involvement in PD tremor is unclear ( Hallett, 2012 ).…”

Section: Potential Roles Of Gpr37 In Health and Diseasementioning

confidence: 99%

Drug Discovery Opportunities at the Endothelin B Receptor-Related Orphan G Protein-Coupled Receptors, GPR37 and GPR37L1

Smith

2015

Front. Pharmacol.

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Orphan G protein-coupled receptors (GPCRs) represent a largely untapped resource for the treatment of a variety of diseases, despite sophisticated advances in drug discovery. Two promising orphan GPCRs are the endothelin B receptor-like proteins, GPR37 [ET(B)R-LP, Pael-R] and GPR37L1 [ET(B)R-LP-2]. Originally identified through searches for homologs of endothelin and bombesin receptors, neither GPR37 nor GPR37L1 were found to bind endothelins or related peptides. Instead, GPR37 was proposed to be activated by head activator (HA) and both GPR37 and GPR37L1 have been linked to the neuropeptides prosaposin and prosaptide, although these pairings are yet to be universally acknowledged. Both orphan GPCRs are widely expressed in the brain, where GPR37 has received the most attention for its link to Parkinson’s disease and parkinsonism, while GPR37L1 deletion leads to precocious cerebellar development and hypertension. In this review, the existing pharmacology and physiology of GPR37 and GPR37L1 is discussed and the potential therapeutic benefits of targeting these receptors are explored.

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Section: Potential Roles Of Gpr37 In Health and Diseasementioning

confidence: 99%

Drug Discovery Opportunities at the Endothelin B Receptor-Related Orphan G Protein-Coupled Receptors, GPR37 and GPR37L1

Smith

2015

Front. Pharmacol.

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“…In such way, it has been shown that GPR37 deletion increases pre-synaptic dopamine transporter (DAT) cell surface expression in the striatum 15 . Similarly, it has been described that the adenosinergic-dependent control of anxiety behavior is modified in GPR37 deficient mice (GPR37−/−) 2 , and that upon deletion of GPR37, adenosine A 2A receptors (A 2A R) antagonists cannot revert pilocarpine-induced tremor, which is a model for parkinsonism 16 . On the other hand, some data point to the existence of direct receptor-receptor interactions involving GPR37.…”

Section: Introductionmentioning

confidence: 96%

The Parkinson’s disease-associated GPR37 receptor interacts with striatal adenosine A2A receptor controlling its cell surface expression and function in vivo

Morató

Luján

López-Cano

et al. 2017

Sci Rep

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G protein-coupled receptor 37 (GPR37) is an orphan receptor associated to Parkinson’s disease (PD) neuropathology. Here, we identified GPR37 as an inhibitor of adenosine A2A receptor (A2AR) cell surface expression and function in vivo. In addition, we showed that GPR37 and A2AR do oligomerize in the striatum. Thus, a close proximity of GPR37 and A2AR at the postsynaptic level of striatal synapses was observed by double-labelling post-embedding immunogold detection. Indeed, the direct receptor-receptor interaction was further substantiated by proximity ligation in situ assay. Interestingly, GPR37 deletion promoted striatal A2AR cell surface expression that correlated well with an increased A2AR agonist-mediated cAMP accumulation, both in primary striatal neurons and nerve terminals. Furthermore, GPR37−/− mice showed enhanced A2AR agonist-induced catalepsy and an increased response to A2AR antagonist-mediated locomotor activity. Overall, these results revealed a key role for GPR37 controlling A2AR biology in the striatum, which may be relevant for PD management.

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“…TJMs were defined as rapid vertical deflections of the lower jaw that resembled chewing but were not directed at any particular stimulus ( Salamone et al, 1998 ). Each individual deflection of the jaw was recorded using a mechanical hand counter by a trained observer, who was blind to the experimental condition of the rat being observed ( Gandía et al, 2015 ).…”

Section: Methodsmentioning

confidence: 99%

PBF509, an Adenosine A2A Receptor Antagonist With Efficacy in Rodent Models of Movement Disorders

et al. 2018

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Adenosine A2A receptor (A2AR) antagonists have emerged as complementary non-dopaminergic drugs to alleviate Parkinson’s disease (PD) symptomatology. Here, we characterize a novel non-xhantine non-furan A2AR antagonist, PBF509, as a potential pro-dopaminergic drug for PD management. First, PBF509 was shown to be a highly potent ligand at the human A2AR, since it antagonized A2AR agonist-mediated cAMP accumulation and impedance responses with KB values of 72.8 ± 17.4 and 8.2 ± 4.2 nM, respectively. Notably, these results validated our new A2AR-based label-free assay as a robust and sensitive approach to characterize A2AR ligands. Next, we evaluated the efficacy of PBF509 reversing motor impairments in several rat models of movement disorders, including catalepsy, tremor, and hemiparkinsonism. Thus, PBF509 (orally) antagonized haloperidol-mediated catalepsy, reduced pilocarpine-induced tremulous jaw movements and potentiated the number of contralateral rotations induced by L-3,4-dihydroxyphenylalanine (L-DOPA) in unilaterally 6-OHDA-lesioned rats. Moreover, PBF509 (3 mg/kg) inhibited L-DOPA-induced dyskinesia (LID), showing not only its efficacy on reversing parkinsonian motor impairments but also acting as antidyskinetic agent. Overall, here we describe a new orally selective A2AR antagonist with potential utility for PD treatment, and for some of the side effects associated to the current pharmacotherapy (i.e., dyskinesia).

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Adenosine A2A receptor-mediated control of pilocarpine-induced tremulous jaw movements is Parkinson's disease-associated GPR37 receptor-dependent

Cited by 17 publications

References 25 publications

Drug Discovery Opportunities at the Endothelin B Receptor-Related Orphan G Protein-Coupled Receptors, GPR37 and GPR37L1

Drug Discovery Opportunities at the Endothelin B Receptor-Related Orphan G Protein-Coupled Receptors, GPR37 and GPR37L1

The Parkinson’s disease-associated GPR37 receptor interacts with striatal adenosine A2A receptor controlling its cell surface expression and function in vivo

PBF509, an Adenosine A2A Receptor Antagonist With Efficacy in Rodent Models of Movement Disorders

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