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D1-mGlu5 heteromers mediate noncanonical dopamine signaling in Parkinson’s disease

Sebastianutto, Irene LU ; Goyet, Elise ; Andreoli, Laura LU ; Font-Ingles, Joan ; Moreno-Delgado, David ; Bouquier, Nathalie ; Jahannault-Talignani, Céline ; Moutin, Enora ; Di Menna, Luisa and Maslava, Natallia LU , et al. (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.

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organization
publishing date
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
2024-06-26 14:00:29
@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}},
}