Mechanisms of dopamine D1 receptor-mediated ERK1/2 activation in the parkinsonian striatum and their modulation by metabotropic glutamate receptor type 5

Tim Fieblinger; Irene Sebastianutto; Cristina Alcacer; Zisis Bimpisidis; Natallia Maslava; Sabina Sandberg; David Engblom; M Angela Cenci

doi:10.1523/JNEUROSCI.2702-13.2014

Mechanisms of dopamine D1 receptor-mediated ERK1/2 activation in the parkinsonian striatum and their modulation by metabotropic glutamate receptor type 5

Standard

Mechanisms of dopamine D1 receptor-mediated ERK1/2 activation in the parkinsonian striatum and their modulation by metabotropic glutamate receptor type 5. / Fieblinger, Tim; Sebastianutto, Irene; Alcacer, Cristina; Bimpisidis, Zisis; Maslava, Natallia; Sandberg, Sabina; Engblom, David; Cenci, M Angela.

in: J NEUROSCI, Jahrgang 34, Nr. 13, 26.03.2014, S. 4728-40.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Fieblinger, T, Sebastianutto, I, Alcacer, C, Bimpisidis, Z, Maslava, N, Sandberg, S, Engblom, D & Cenci, MA 2014, 'Mechanisms of dopamine D1 receptor-mediated ERK1/2 activation in the parkinsonian striatum and their modulation by metabotropic glutamate receptor type 5', J NEUROSCI, Jg. 34, Nr. 13, S. 4728-40. https://doi.org/10.1523/JNEUROSCI.2702-13.2014

APA

Fieblinger, T., Sebastianutto, I., Alcacer, C., Bimpisidis, Z., Maslava, N., Sandberg, S., Engblom, D., & Cenci, M. A. (2014). Mechanisms of dopamine D1 receptor-mediated ERK1/2 activation in the parkinsonian striatum and their modulation by metabotropic glutamate receptor type 5. J NEUROSCI, 34(13), 4728-40. https://doi.org/10.1523/JNEUROSCI.2702-13.2014

Vancouver

Fieblinger T, Sebastianutto I, Alcacer C, Bimpisidis Z, Maslava N, Sandberg S et al. Mechanisms of dopamine D1 receptor-mediated ERK1/2 activation in the parkinsonian striatum and their modulation by metabotropic glutamate receptor type 5. J NEUROSCI. 2014 Mär 26;34(13):4728-40. https://doi.org/10.1523/JNEUROSCI.2702-13.2014

Bibtex

@article{3b86bbafd65d41159d4c722355215be2,

title = "Mechanisms of dopamine D1 receptor-mediated ERK1/2 activation in the parkinsonian striatum and their modulation by metabotropic glutamate receptor type 5",

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, IP3 receptors) markedly attenuated SKF38393-induced ERK1/2 activation. The role of striatal mGluR5 in D1-dependent ERK1/2 activation was confirmed in vivo in 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 Ca(2+)-dependent signaling pathways that is critically modulated by striatal mGluR5. ",

keywords = "Adrenergic Agents/toxicity, Animals, Corpus Striatum/drug effects, Disease Models, Animal, Dopamine Agonists/pharmacology, Excitatory Amino Acid Antagonists/toxicity, Excitatory Postsynaptic Potentials/drug effects, Female, In Vitro Techniques, Mice, Mice, Inbred C57BL, Mice, Transgenic, Oxidopamine/toxicity, Parkinson Disease/etiology, Pyridines/toxicity, Rats, Rats, Sprague-Dawley, Receptor, Metabotropic Glutamate 5/genetics, Receptors, Dopamine D1/genetics, Thiazoles/toxicity, Tyrosine 3-Monooxygenase/metabolism",

author = "Tim Fieblinger and Irene Sebastianutto and Cristina Alcacer and Zisis Bimpisidis and Natallia Maslava and Sabina Sandberg and David Engblom and Cenci, {M Angela}",

year = "2014",

month = mar,

day = "26",

doi = "10.1523/JNEUROSCI.2702-13.2014",

language = "English",

volume = "34",

pages = "4728--40",

journal = "J NEUROSCI",

issn = "0270-6474",

publisher = "Society for Neuroscience",

number = "13",

}

RIS

TY - JOUR

T1 - Mechanisms of dopamine D1 receptor-mediated ERK1/2 activation in the parkinsonian striatum and their modulation by metabotropic glutamate receptor type 5

AU - Fieblinger, Tim

AU - Sebastianutto, Irene

AU - Alcacer, Cristina

AU - Bimpisidis, Zisis

AU - Maslava, Natallia

AU - Sandberg, Sabina

AU - Engblom, David

AU - Cenci, M Angela

PY - 2014/3/26

Y1 - 2014/3/26

N2 - 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, IP3 receptors) markedly attenuated SKF38393-induced ERK1/2 activation. The role of striatal mGluR5 in D1-dependent ERK1/2 activation was confirmed in vivo in 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 Ca(2+)-dependent signaling pathways that is critically modulated by striatal mGluR5.

AB - 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, IP3 receptors) markedly attenuated SKF38393-induced ERK1/2 activation. The role of striatal mGluR5 in D1-dependent ERK1/2 activation was confirmed in vivo in 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 Ca(2+)-dependent signaling pathways that is critically modulated by striatal mGluR5.

KW - Adrenergic Agents/toxicity

KW - Animals

KW - Corpus Striatum/drug effects

KW - Disease Models, Animal

KW - Dopamine Agonists/pharmacology

KW - Excitatory Amino Acid Antagonists/toxicity

KW - Excitatory Postsynaptic Potentials/drug effects

KW - Female

KW - In Vitro Techniques

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Transgenic

KW - Oxidopamine/toxicity

KW - Parkinson Disease/etiology

KW - Pyridines/toxicity

KW - Rats

KW - Rats, Sprague-Dawley

KW - Receptor, Metabotropic Glutamate 5/genetics

KW - Receptors, Dopamine D1/genetics

KW - Thiazoles/toxicity

KW - Tyrosine 3-Monooxygenase/metabolism

U2 - 10.1523/JNEUROSCI.2702-13.2014

DO - 10.1523/JNEUROSCI.2702-13.2014

M3 - SCORING: Journal article

C2 - 24672017

VL - 34

SP - 4728

EP - 4740

JO - J NEUROSCI

JF - J NEUROSCI

SN - 0270-6474

IS - 13

ER -