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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Research Article Neuroscience

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 2

D1 and mGlu5 receptors form heteromers in neurons.

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D1 and mGlu5 receptors form heteromers in neurons. (A–C) BRET imaging be...
(A–C) BRET imaging between mGlu5-Nluc and D1-Venus was measured in soma, dendrites, and spines of hippocampal neurons. (A) Single-cell BRET imaging in neurons expressing either mGlu5-Nluc and D1-Venus (top) or mGlu5-Nluc with DsRed as transfection reporter (bottom). Cells were identified by green or red fluorescence (left). Em480 and Em535 images were recorded, and the 535 nm/480 nm pseudo-colored ratio images were processed. Square areas are shown at a higher magnification in the insets, which are 3 μm × 3 μm. Cells are representative of 19 to 21 cells. Scale bar: 10 μm. (B) Quantification of the BRET signal intensity in soma from mGlu5-Nluc and D1-Venus transfected neurons compared with the basal BRET measured in neurons expressing mGlu5-Nluc alone (left). Box and whiskers plots of 19 to 20 measurements in the soma of neurons. ****P < 0.0001, Mann-Whitney U test. (C) netBRET between mGlu5-Nluc and D1-Venus in soma, dendrites, and spines. The average basal BRET in respective compartment has been subtracted from BRET measurements. Box and whiskers plots of n = 23 measurements in soma, n = 21 in dendrites, n = 11 in spines from neurons expressing mGlu5-Nluc and D1-Venus. #P < 0.05, Kruskal-Wallis test.