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D1-mGlu5 heteromers mediate noncanonical dopamine signaling in Parkinson's disease.

ABSTRACT: Dopamine receptor D1 modulates glutamatergic transmission in cortico-basal ganglia circuits and represents a major target of L-DOPA therapy in Parkinson's disease. Here we show that D1 and metabotropic glutamate type 5 (mGlu5) receptors can form previously unknown heteromeric entities with distinctive functional properties. Interacting with Gq proteins, cell-surface D1-mGlu5 heteromers exacerbated PLC signaling and intracellular calcium release in response to either glutamate or dopamine. In rodent models of Parkinson's disease, D1-mGlu5 nanocomplexes were strongly upregulated in the dopamine-denervated striatum, resulting in a synergistic activation of PLC signaling by D1 and mGlu5 receptor agonists. In turn, D1-mGlu5-dependent PLC signaling was causally linked with excessive activation of extracellular signal-regulated kinases in striatal neurons, leading to dyskinesia in animals treated with L-DOPA or D1 receptor agonists. The discovery of D1-mGlu5 functional heteromers mediating maladaptive molecular and motor responses in the dopamine-denervated striatum may prompt the development of new therapeutic principles for Parkinson's disease.

SUBMITTER: Sebastianutto I

PROVIDER: S-EPMC7269571 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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D1-mGlu5 heteromers mediate noncanonical dopamine signaling in Parkinson's disease.

Sebastianutto Irene I Goyet Elise E Andreoli Laura L Font-Ingles Joan J Moreno-Delgado David D Bouquier Nathalie N Jahannault-Talignani Céline C Moutin Enora E Di Menna Luisa L Maslava Natallia N Pin Jean-Philippe JP Fagni Laurent L Nicoletti Ferdinando F Ango Fabrice F Cenci M Angela MA Perroy Julie J

The Journal of clinical investigation 20200301 3

Dopamine receptor D1 modulates glutamatergic transmission in cortico-basal ganglia circuits and represents a major target of L-DOPA therapy in Parkinson's disease. Here we show that D1 and metabotropic glutamate type 5 (mGlu5) receptors can form previously unknown heteromeric entities with distinctive functional properties. Interacting with Gq proteins, cell-surface D1-mGlu5 heteromers exacerbated PLC signaling and intracellular calcium release in response to either glutamate or dopamine. In rod ...[more]

PMID: 32039920

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Project description:IntroductionThere is a need for new therapies in Parkinson's disease that may help to address known limitations of current options. PF-06649751 is a novel, highly selective dopamine D1/D5 agonist targeted for Parkinson's disease treatment.MethodsThe safety, pharmacokinetics, and pharmacodynamics of PF-06649751 were assessed in single ascending dose and multiple ascending dose clinical trials in patients with Parkinson's disease. The single ascending dose study (N = 18) was a double-blind, placebo-controlled study with a three-way crossover design consisting of three treatment periods separated by 7-day study drug washout periods. PF-06649751 doses were 0.75 mg, 1.5 mg, 3 mg, 6 mg, and 9 mg. In the open-label multiple ascending dose study, eligible subjects received once-daily doses of PF-06649751 (N = 45) over 21 days, with up-titration to 5 mg, 15 mg, and 25 mg once daily. Pharmacodynamics were assessed by measuring change from baseline in the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III at different time points post dose.ResultsPF-06649751 was safe and well tolerated across studies and in all cohorts. Peak plasma concentrations were attained 1-4 h post dose across both studies, and exposure increased with increasing dose. PF-06649751 demonstrated sustained pharmacodynamic effects compared with placebo, with mean reductions from baseline in the MDS-UPDRS Part III up to 12 h post dose at 9 mg single dose. MDS-UPDRS Part III changes in the open-label multiple dose study on day 22 also demonstrated sustained pharmacodynamic activity.ConclusionsPF-06649751 represents a novel therapeutic candidate for Parkinson's disease with an initial safety, tolerability, and pharmacokinetic profile and potential for efficacy that merits further study in larger clinical trials.Trial registrationThese studies are registered at www.clinicaltrials.gov as NCT02373072, NCT02224664.FundingPfizer.

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D1-mGlu5 heteromers mediate noncanonical dopamine signaling in Parkinson's disease.

Publications

D1-mGlu5 heteromers mediate noncanonical dopamine signaling in Parkinson's disease.

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