Mechanisms of Dopamine D1 Receptor-Mediated ERK1/2 Activation in the Parkinsonian Striatum and Their Modulation by Metabotropic Glutamate Receptor Type 5.
Fieblinger, Tim LU ; Sebastianutto, Irene LU ; Alcacer, Cristina LU ; Bimpisidis, Zisis LU ; Maslava, Natallia LU ; Sandberg, Sabina ; Engblom, David and Cenci Nilsson, Angela LU
(2014)
In The Journal of Neuroscience : the official journal of the Society for Neuroscience
34(13).
p.4728-4740
- 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... (More)
- 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. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/4379624
- author
- Fieblinger, Tim
LU
; Sebastianutto, Irene
LU
; Alcacer, Cristina
LU
; Bimpisidis, Zisis
LU
; Maslava, Natallia
LU
; Sandberg, Sabina
; Engblom, David
and Cenci Nilsson, Angela
LU
- organization
- publishing date
- 2014
- type
- Contribution to journal
- publication status
- published
- subject
- in
- The Journal of Neuroscience : the official journal of the Society for Neuroscience
- volume
- 34
- issue
- 13
- pages
- 4728 - 4740
- publisher
- Society for Neuroscience
- external identifiers
-
- pmid:24672017
- wos:000333674200028
- scopus:84897585156
- pmid:24672017
- ISSN
- 1529-2401
- DOI
- 10.1523/JNEUROSCI.2702-13.2014
- language
- English
- LU publication?
- yes
- id
- 6e062fe7-288c-43c8-86d0-a7238940f678 (old id 4379624)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/24672017?dopt=Abstract
- date added to LUP
- 2016-04-01 14:45:51
- date last changed
- 2024-10-10 21:03:00
@article{6e062fe7-288c-43c8-86d0-a7238940f678,
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.}},
author = {{Fieblinger, Tim and Sebastianutto, Irene and Alcacer, Cristina and Bimpisidis, Zisis and Maslava, Natallia and Sandberg, Sabina and Engblom, David and Cenci Nilsson, Angela}},
issn = {{1529-2401}},
language = {{eng}},
number = {{13}},
pages = {{4728--4740}},
publisher = {{Society for Neuroscience}},
series = {{The Journal of Neuroscience : the official journal of the Society for Neuroscience}},
title = {{Mechanisms of Dopamine D1 Receptor-Mediated ERK1/2 Activation in the Parkinsonian Striatum and Their Modulation by Metabotropic Glutamate Receptor Type 5.}},
url = {{https://lup.lub.lu.se/search/files/4150669/4646771}},
doi = {{10.1523/JNEUROSCI.2702-13.2014}},
volume = {{34}},
year = {{2014}},
}