D1-mGlu5 heteromers mediate noncanonical dopamine signaling in Parkinson’s disease
Irene Sebastianutto, … , M. Angela Cenci, Julie Perroy
Irene Sebastianutto, … , M. Angela Cenci, Julie Perroy
Published February 10, 2020
Citation Information: J Clin Invest. 2020;130(3):1168-1184. https://doi.org/10.1172/JCI126361.
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D1-mGlu5 heteromers mediate noncanonical dopamine signaling in Parkinson’s disease

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.

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

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Figure 6

Endogenous D1-mGlu5 clusters are increased in the DA-denervated striatum.

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Endogenous D1-mGlu5 clusters are increased in the DA-denervated striatum...
Protein ligation assay (PLA) experiments were performed on intact (A and B) and DA-denervated (C–H, lesioned) striata of WT mice (A–F, WT, n = 7 per treatment condition) and mice with a selective KO of mGluR5 in D1 receptor–expressing neurons (mGluR5KO-D1; n = 7) (G and H). DA-denervated mice received daily s.c. injection of either L-DOPA (6 mg/kg) (E and F) or vehicle (saline, C and D, G and H) for 3 weeks. All L-DOPA–treated mice developed dyskinesia. (A–H) PLA were obtained with primary antibodies directed against mGlu5 and D1. Plus and minus probes that correspond to secondary antibodies allow rolling-circle amplification and detection of the amplicons by a fluorescence labeled probe (red dots). Nuclei were counterstained with DAPI. Scale bar: 10 μm. (I) Box and whiskers plots of the number of PLA signals (reds dots) per presized zone from WT and KO striatal sections in indicated conditions. Six ROI were analyzed per striatum to measure a mean value per animal. *P < 0.05; ***P < 0.001, Mann-Whitney U test.