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Dopamine-Induced Changes in Gα(olf) Protein Levels in Striatonigral and Striatopallidal Medium Spiny Neurons Underlie the Genesis of l-DOPA-Induced Dyskinesia in Parkinsonian Mice
The dopamine precursor, l-3,4-dihydroxyphenylalanine (l-DOPA), exerts powerful therapeutic effects but eventually generates l-DOPA-induced dyskinesia (LID) in patients with Parkinson’s disease (PD). LID has a close link with deregulation of striatal dopamine/cAMP signaling, which is integrated by me...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2017
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5300978/ https://www.ncbi.nlm.nih.gov/pubmed/28239340 http://dx.doi.org/10.3389/fncel.2017.00026 |
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author | Morigaki, Ryoma Okita, Shinya Goto, Satoshi |
author_facet | Morigaki, Ryoma Okita, Shinya Goto, Satoshi |
author_sort | Morigaki, Ryoma |
collection | PubMed |
description | The dopamine precursor, l-3,4-dihydroxyphenylalanine (l-DOPA), exerts powerful therapeutic effects but eventually generates l-DOPA-induced dyskinesia (LID) in patients with Parkinson’s disease (PD). LID has a close link with deregulation of striatal dopamine/cAMP signaling, which is integrated by medium spiny neurons (MSNs). Olfactory type G-protein α subunit (Gα(olf)), a stimulatory GTP-binding protein encoded by the GNAL gene, is highly concentrated in the striatum, where it positively couples with dopamine D(1) (D(1)R) receptor and adenosine A(2A) receptor (A(2A)R) to increase intracellular cAMP levels in MSNs. In the striatum, D(1)Rs are mainly expressed in the MSNs that form the striatonigral pathway, while D(2)Rs and A(2A)Rs are expressed in the MSNs that form the striatopallidal pathway. Here, we examined the association between striatal Gα(olf) protein levels and the development of LID. We used a hemi-parkinsonian mouse model with nigrostriatal lesions induced by 6-hydroxydopamine (6-OHDA). Using quantitative immunohistochemistry (IHC) and a dual-antigen recognition in situ proximity ligation assay (PLA), we here found that in the dopamine-depleted striatum, there appeared increased and decreased levels of Gα(olf) protein in striatonigral and striatopallidal MSNs, respectively, after a daily pulsatile administration of l-DOPA. This leads to increased responsiveness to dopamine stimulation in both striatonigral and striatopallidal MSNs. Because Gα(olf) protein levels serve as a determinant of cAMP signal-dependent activity in striatal MSNs, we suggest that l-DOPA-induced changes in striatal Gα(olf) levels in the dopamine-depleted striatum could be a key event in generating LID. |
format | Online Article Text |
id | pubmed-5300978 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-53009782017-02-24 Dopamine-Induced Changes in Gα(olf) Protein Levels in Striatonigral and Striatopallidal Medium Spiny Neurons Underlie the Genesis of l-DOPA-Induced Dyskinesia in Parkinsonian Mice Morigaki, Ryoma Okita, Shinya Goto, Satoshi Front Cell Neurosci Neuroscience The dopamine precursor, l-3,4-dihydroxyphenylalanine (l-DOPA), exerts powerful therapeutic effects but eventually generates l-DOPA-induced dyskinesia (LID) in patients with Parkinson’s disease (PD). LID has a close link with deregulation of striatal dopamine/cAMP signaling, which is integrated by medium spiny neurons (MSNs). Olfactory type G-protein α subunit (Gα(olf)), a stimulatory GTP-binding protein encoded by the GNAL gene, is highly concentrated in the striatum, where it positively couples with dopamine D(1) (D(1)R) receptor and adenosine A(2A) receptor (A(2A)R) to increase intracellular cAMP levels in MSNs. In the striatum, D(1)Rs are mainly expressed in the MSNs that form the striatonigral pathway, while D(2)Rs and A(2A)Rs are expressed in the MSNs that form the striatopallidal pathway. Here, we examined the association between striatal Gα(olf) protein levels and the development of LID. We used a hemi-parkinsonian mouse model with nigrostriatal lesions induced by 6-hydroxydopamine (6-OHDA). Using quantitative immunohistochemistry (IHC) and a dual-antigen recognition in situ proximity ligation assay (PLA), we here found that in the dopamine-depleted striatum, there appeared increased and decreased levels of Gα(olf) protein in striatonigral and striatopallidal MSNs, respectively, after a daily pulsatile administration of l-DOPA. This leads to increased responsiveness to dopamine stimulation in both striatonigral and striatopallidal MSNs. Because Gα(olf) protein levels serve as a determinant of cAMP signal-dependent activity in striatal MSNs, we suggest that l-DOPA-induced changes in striatal Gα(olf) levels in the dopamine-depleted striatum could be a key event in generating LID. Frontiers Media S.A. 2017-02-10 /pmc/articles/PMC5300978/ /pubmed/28239340 http://dx.doi.org/10.3389/fncel.2017.00026 Text en Copyright © 2017 Morigaki, Okita and Goto. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution and reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Neuroscience Morigaki, Ryoma Okita, Shinya Goto, Satoshi Dopamine-Induced Changes in Gα(olf) Protein Levels in Striatonigral and Striatopallidal Medium Spiny Neurons Underlie the Genesis of l-DOPA-Induced Dyskinesia in Parkinsonian Mice |
title | Dopamine-Induced Changes in Gα(olf) Protein Levels in Striatonigral and Striatopallidal Medium Spiny Neurons Underlie the Genesis of l-DOPA-Induced Dyskinesia in Parkinsonian Mice |
title_full | Dopamine-Induced Changes in Gα(olf) Protein Levels in Striatonigral and Striatopallidal Medium Spiny Neurons Underlie the Genesis of l-DOPA-Induced Dyskinesia in Parkinsonian Mice |
title_fullStr | Dopamine-Induced Changes in Gα(olf) Protein Levels in Striatonigral and Striatopallidal Medium Spiny Neurons Underlie the Genesis of l-DOPA-Induced Dyskinesia in Parkinsonian Mice |
title_full_unstemmed | Dopamine-Induced Changes in Gα(olf) Protein Levels in Striatonigral and Striatopallidal Medium Spiny Neurons Underlie the Genesis of l-DOPA-Induced Dyskinesia in Parkinsonian Mice |
title_short | Dopamine-Induced Changes in Gα(olf) Protein Levels in Striatonigral and Striatopallidal Medium Spiny Neurons Underlie the Genesis of l-DOPA-Induced Dyskinesia in Parkinsonian Mice |
title_sort | dopamine-induced changes in gα(olf) protein levels in striatonigral and striatopallidal medium spiny neurons underlie the genesis of l-dopa-induced dyskinesia in parkinsonian mice |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5300978/ https://www.ncbi.nlm.nih.gov/pubmed/28239340 http://dx.doi.org/10.3389/fncel.2017.00026 |
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