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Mechanisms of Dopamine D1 Receptor-Mediated ERK1/2 Activation in the Parkinsonian Striatum and Their Modulation by Metabotropic Glutamate Receptor Type 5
- Source :
- The Journal of neuroscience : the official journal of the Society for Neuroscience; 34(13), pp 4728-4740 (2014)
- Publication Year :
- 2014
- Publisher :
- Society for Neuroscience, 2014.
-
Abstract
- In animal models of Parkinson′s disease, striatal overactivation of ERK1/2 via dopamine (DA) D1 receptors is the hallmark of a supersensitive molecular response associated with dyskinetic behaviors. Here we investigate the pathways involved in D1 receptor-dependent ERK1/2 activation using acute striatal slices from rodents with unilateral 6-hydroxydopamine (6-OHDA) lesions. Application of the dopamine D1-like receptor agonist SKF38393 induced ERK1/2 phosphorylation and downstream signaling in the DA-denervated but not the intact striatum. This response was mediated through a canonical D1R/PKA/MEK1/2 pathway and independent of ionotropic glutamate receptors but blocked by antagonists of L-type calcium channels. Coapplication of an antagonist of metabotropic glutamate receptor type 5 (mGluR5) or its downstream signaling molecules (PLC, PKC, IP3receptors) markedly attenuated SKF38393-induced ERK1/2 activation. The role of striatal mGluR5 in D1-dependent ERK1/2 activation was confirmedin vivoin 6-OHDA-lesioned animals treated systemically with SKF38393. In one experiment, local infusion of the mGluR5 antagonist MTEP in the DA-denervated rat striatum attenuated the activation of ERK1/2 signaling by SKF38393. In another experiment, 6-OHDA lesions were applied to transgenic mice with a cell-specific knockdown of mGluR5 in D1 receptor-expressing neurons. These mice showed a blunted striatal ERK1/2 activation in response to SFK38393 treatment. Our results reveal that D1-dependent ERK1/2 activation in the DA-denervated striatum depends on a complex interaction between PKA- and Ca2+-dependent signaling pathways that is critically modulated by striatal mGluR5.
- Subjects :
- Agonist
Tyrosine 3-Monooxygenase
Pyridines
medicine.drug_class
Receptor, Metabotropic Glutamate 5
Mice, Transgenic
Striatum
In Vitro Techniques
Pharmacology
Rats, Sprague-Dawley
Mice
Adrenergic Agents
Dopamine receptor D1
Dopamine
medicine
Animals
Oxidopamine
Metabotropic glutamate receptor 5
Chemistry
Receptors, Dopamine D1
General Neuroscience
Neurosciences
Glutamate receptor
Excitatory Postsynaptic Potentials
Parkinson Disease
Articles
Corpus Striatum
Rats
Mice, Inbred C57BL
Disease Models, Animal
Thiazoles
MTEP
nervous system
Metabotropic glutamate receptor
Dopamine Agonists
Female
Excitatory Amino Acid Antagonists
Neuroscience
medicine.drug
Subjects
Details
- ISSN :
- 15292401 and 02706474
- Volume :
- 34
- Database :
- OpenAIRE
- Journal :
- The Journal of Neuroscience
- Accession number :
- edsair.doi.dedup.....9355f756b13258470d4c744b95d94165