| Autor: |
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 |
| Rok vydání: |
2018 |
| Předmět: |
|
| Zdroj: |
J Clin Invest |
| ISSN: |
1558-8238 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
|
