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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

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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 4

D1-mGlu5 heteromer creates an atypical D1 receptor–mediated intracellular Ca2+ release.

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D1-mGlu5 heteromer creates an atypical D1 receptor–mediated intracellula...
(A) HEK cell line stably expressing GcAMP6 calcium indicator and Glo cAMP-sensor, cotransfected with mGlu5 and D1 receptors. (B–E) Ca2+ release and cAMP production were measured in cells transfected with mGlu5, D1, or mGlu5 plus D1 receptors. Values represent mean ± SEM of 3 or 4 independent experiments. Data are expressed as a percentage of the maximal Quisq- or SKF-induced effect. (B and C) Ca2+ release dose-response curve induced by (B) D1 agonist (SKF81297) and (C) mGlu5 agonist Quisq. (D and E) cAMP production dose response curve induced by (D) D1 agonist SKF81297 and (E) mGlu5 agonist Quisq. (F–H) Synergistic activation of Ca2+ release induced by D1 and mGlu5 receptors. Cells were transfected with D1 (F), mGlu5 (G), or both receptors (H). Ca2+ release is here expressed as a percentage of basal levels in each transfection condition. Values represent mean ± SEM of 2 to 4 independent experiments.

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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