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 7

mGlu5 and D1 receptors interact to induce PLC signaling and ERK1/2 activation in the DA-denervated striatum.

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mGlu5 and D1 receptors interact to induce PLC signaling and ERK1/2 activ...
(A) InsP hydrolysis in intact (Int.) and lesioned (Les.) rat striatal slices. SKF38393 and DHPG synergistically activated PLC in the DA-denervated striatum. n = 4–13 tubes per treatment. Treatment: F(4,70) = 14.33, P < 0.001; side: F(1,70) = 9.40, P < 0.01; interaction: F(4,70) = 2.81, P < 0.05. Bonferroni’s test: *P < 0.05 and ***P < 0.001 vs. baseline of same group; ###P < 0.001 vs. all other treatments within same group (Les.); &&&P < 0.001 vs. same treatment of opposite group (Int.). (B) Sample areas for counting pERK1/2-positive cells in DM and VL striata (rat and mouse). (C–F) U73122 (U73) attenuates L-DOPA– (C and D) and SKF38393-induced pERK1/2 (E and F) in DA-denervated rat striatum (n = 5 per condition). (D and F) pERK1/2-immunostained rat striatal sections. Scale bar: 200 μm. C-DM: treatment: F(1,16) = 14.64, P < 0.01; side: F(1,16) = 106.6, P < 0.001; interaction: F(1,16) = 17.13, P < 0.001. C-VL: treatment: F(1,16) = 12.57, P < 0.01; side: F(1.16) = 146.1, P < 0.001; interaction: F(1,16) = 12.36, P < 0.01. E-DM: treatment: F(1,16) = 10.67, P < 0.01; side: F(1,16) = 212.7, P < 0.001; interaction: F(1,16) = 10.21, P < 0.01. E-VL: treatment: F(1,16) = 9.99, P < 0.01; side: F(1,16) = 65.29, P < 0.001; interaction: F(1,16) = 9.82, P < 0.01). Bonferroni’s test: **P < 0.01 and ***P < 0.001 vs. L-DOPA/SKF38393 + vehicle of Les. side; #P < 0.05, ##P < 0.01, and ###P < 0.001 vs. L-DOPA/SKF38393 + vehicle/U73122 of Int. side. (G and H) U73122 attenuates D1-dependent pERK1/2 in DA-denervated striata from WT but not mGlu5KO-D1 mice (KO) (n = 6–8 mice per condition). (H) pERK1/2 immunostainings. Scale bar: 200 μm. G-DM: treatment: F(3,25) = 18.63, P < 0.001. G-VL: treatment: F(3,25) = 20.36, P < 0.001. Bonferroni’s test: ***P < 0.001 vs. WT: SKF38393 + vehicle.