D1-mGlu5 heteromers mediate noncanonical dopamine signaling in Parkinson’s disease
(2020) In Journal of Clinical Investigation 130(3). p.1168-1184- 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... (More)
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.
(Less)
- author
- organization
- publishing date
- 2020-03-02
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Clinical Investigation
- volume
- 130
- issue
- 3
- pages
- 1168 - 1184
- publisher
- The American Society for Clinical Investigation
- external identifiers
-
- scopus:85081140397
- pmid:32039920
- ISSN
- 0021-9738
- DOI
- 10.1172/JCI126361
- language
- English
- LU publication?
- yes
- id
- 52b87891-65e1-43fb-b017-0ff4b457eeb7
- date added to LUP
- 2020-04-23 22:33:10
- date last changed
- 2024-09-18 21:38:18
@article{52b87891-65e1-43fb-b017-0ff4b457eeb7, abstract = {{<p>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.</p>}}, author = {{Sebastianutto, Irene and Goyet, Elise and Andreoli, Laura and Font-Ingles, Joan and Moreno-Delgado, David and Bouquier, Nathalie and Jahannault-Talignani, Céline and Moutin, Enora and Di Menna, Luisa and Maslava, Natallia and Pin, Jean Philippe and Fagni, Laurent and Nicoletti, Ferdinando and Ango, Fabrice and Cenci, M. Angela and Perroy, Julie}}, issn = {{0021-9738}}, language = {{eng}}, month = {{03}}, number = {{3}}, pages = {{1168--1184}}, publisher = {{The American Society for Clinical Investigation}}, series = {{Journal of Clinical Investigation}}, title = {{D1-mGlu5 heteromers mediate noncanonical dopamine signaling in Parkinson’s disease}}, url = {{http://dx.doi.org/10.1172/JCI126361}}, doi = {{10.1172/JCI126361}}, volume = {{130}}, year = {{2020}}, }