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

J Clin Invest. 2020 Mar 2;130(3):1168-1184. doi: 10.1172/JCI126361.

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.

Keywords: G-protein coupled receptors; Movement disorders; Neuroscience; Parkinson’s disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Corpus Striatum / metabolism*
  • Corpus Striatum / pathology
  • HEK293 Cells
  • Humans
  • MAP Kinase Signaling System*
  • Mice
  • Mice, Knockout
  • Multiprotein Complexes / agonists
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism
  • Neurons / metabolism*
  • Neurons / pathology
  • Parkinson Disease, Secondary / drug therapy
  • Parkinson Disease, Secondary / genetics
  • Parkinson Disease, Secondary / metabolism*
  • Parkinson Disease, Secondary / pathology
  • Rats
  • Receptor, Metabotropic Glutamate 5 / genetics
  • Receptor, Metabotropic Glutamate 5 / metabolism*
  • Receptors, Dopamine D1 / agonists
  • Receptors, Dopamine D1 / genetics
  • Receptors, Dopamine D1 / metabolism*

Substances

  • Grm5 protein, mouse
  • Grm5 protein, rat
  • Multiprotein Complexes
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Dopamine D1

Grants and funding

To JP