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 8

MTEP and U73122 improve D1 receptor–dependent dyskinesias in WT mice, but have no effect in mGluR5KD-D1 mice.

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MTEP and U73122 improve D1 receptor–dependent dyskinesias in WT mice, bu...
(A and B) L-DOPA–induced AIMs in WT mice. (A) Time course of AIMs (n = 11; repeated-measures [RM] 2-way ANOVA, treatment: F(2,20) = 13.6, P < 0.001; time: F(9,90) = 45.87, P < 0.001; interaction: F(18,180) = 4.49, P < 0.001). (B) Peak AIMs (n = 11; Friedman test (Fr) = 16.55, P < 0.001). (C and D) SKF38393-induced AIMs in WT. (C) Time course of AIMs (n = 11; RM 2-way ANOVA, treatment: F(2,20) = 17.28, P < 0.001; time: F(8,80) = 23, P < 0.001; interaction: F(16,160) = 5.05, P < 0.001). (D) Peak AIMs (n = 11; Fr = 11.45, P < 0.01). (E and F) Quinpirole-induced AIMs in WT. (E) Time course of AIMs (n = 11; RM 2-way ANOVA, treatment: F(2,20) = 1.48, P = 0.25; time: F(8,80) = 148.6, P < 0.001; interaction: F(16,160) = 2.16, P < 0.01). (F) Peak AIMs (n = 11; Fr = 4.97, P > 0.05). (G and H) L-DOPA–induced AIMs in mGluR5KD-D1 mice. (G) Time course of AIMs (n = 10; RM 2-way ANOVA, treatment: F(2,18) = 3.92, P = 0.31; time: F(9,81) = 20.56, P < 0.001; interaction: F(18,162) = 2.04, P < 0.05). (H) Peak AIMs (n = 10; Fr = 7.4, P < 0.05). (I and J) SKF38393-induced AIMs in mGluR5KD-D1 mice. (I) Time course of AIMs (n = 10; RM 2-way ANOVA, treatment: F(2,18) = 5.42, P < 0.05; time: F(8,72) = 17.33, P < 0.001; interaction: F(16,144) = 3.23, P < 0.001). (J) Peak AIMs (n = 10; Fr = 5, P > 0.05). (K and L) Quinpirole-induced AIMs in mGluR5KD-D1 mice. (K) Time course of AIMs (n = 10; RM 2-way ANOVA, treatment: F(2,18) = 2.51, P = 0.12; time: F(8,72) = 178.8, P < 0.001; interaction: F(16,144) = 2.98, P < 0.001). (L) Peak AIMs (n = 10; Fr = 1.4, P > 0.05). Bonferroni’s test or Dunn’s test (for peak AIMs): *P < 0.05, **P < 0.01 and ***P < 0.001 vs. DA receptor agonist + vehicle; #P < 0.05 and ###P < 0.001 vs. DA receptor agonist + MTEP.