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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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Autores principales: Morigaki, Ryoma, Okita, Shinya, Goto, Satoshi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2017
Materias:
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.
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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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