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D1-mGlu5 heteromers mediate noncanonical dopamine signaling in Parkinson's disease.
The Journal of Clinical Investigation ( IF 12.282 ) Pub Date : 2020-02-10 , DOI: 10.1172/jci126361
Irene Sebastianutto,Elise Goyet,Laura Andreoli,Joan Font-Ingles,David Moreno-Delgado,Nathalie Bouquier,Céline Jahannault-Talignani,Enora Moutin,Luisa Di Menna,Natallia Maslava,Jean-Philippe Pin,Laurent Fagni,Ferdinando Nicoletti,Fabrice Ango,M Angela Cenci,Julie Perroy

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.
更新日期:2020-03-19

 

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