| First Author | Sebastianutto I | Year | 2020 |
| Journal | J Clin Invest | Volume | 130 |
| Issue | 3 | Pages | 1168-1184 |
| PubMed ID | 32039920 | Mgi Jnum | J:297858 |
| Mgi Id | MGI:6479340 | Doi | 10.1172/JCI126361 |
| Citation | Sebastianutto I, et al. (2020) D1-mGlu5 heteromers mediate noncanonical dopamine signaling in Parkinson's disease. J Clin Invest 130(3):1168-1184 |
| abstractText | 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. |
