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

Research output: Contribution to journalArticle

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 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.

Details

Authors
  • 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
Organisations
External organisations
  • University of Montpellier
  • UCB Pharma
  • Istituto Neurologico Mediterraneo Neuromed
  • Sapienza University of Rome
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Neurosciences
Original languageEnglish
Pages (from-to)1168-1184
JournalJournal of Clinical Investigation
Volume130
Issue number3
Publication statusPublished - 2020 Mar 2
Publication categoryResearch
Peer-reviewedYes