Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 130, Issue 3, Pages 1168-1184Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI126361
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Funding
- European Research Council (ERC) under the European Union's Horizon 2020 Research and Innovation program [646788]
- Agence Nationale de la Recherche [ANR-13-JSV4-0005-01, ANR-17-CE11-0046]
- Region Languedoc-Roussillon (Chercheur d'Avenir)
- Swedish Research Council
- Multidisciplinary Research on Parkinson's Disease (Multipark)
- Swedish Brain Foundation
- Swedish Governmental Funds for Clinical Research
- Basal Ganglia Disorders Linnaeus Consortium (BAGADILICO)
- Agence Nationale de la Recherche (ANR) [ANR-13-JSV4-0005] Funding Source: Agence Nationale de la Recherche (ANR)
- European Research Council (ERC) [646788] Funding Source: European Research Council (ERC)
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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 (mGlus) 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 unregulated 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.
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