Gαolf Mutation Allows Parsing the Role of cAMP-Dependent and Extracellular Signal-Regulated Kinase-Dependent Signaling in L-3,4-Dihydroxyphenylalanine-Induced Dyskinesia.
Identifieur interne : 000489 ( Hal/Curation ); précédent : 000488; suivant : 000490Gαolf Mutation Allows Parsing the Role of cAMP-Dependent and Extracellular Signal-Regulated Kinase-Dependent Signaling in L-3,4-Dihydroxyphenylalanine-Induced Dyskinesia.
Auteurs : Cristina Alcacer [France] ; Emanuela Santini [États-Unis] ; Emmanuel Valjent [France] ; Florence Gaven [France] ; Jean-Antoine Girault [France] ; Denis Hervé [France]Source :
- Journal of Neuroscience [ 0270-6474 ] ; 2012-04-25.
Abstract
Although l-3,4-dihydroxyphenylalanine (l-DOPA) remains the reference treatment of Parkinson's disease, its long-term beneficial effects are hindered by l-DOPA-induced dyskinesia (LID). In the dopamine (DA)-denervated striatum, l-DOPA activates DA D(1) receptor (D(1)R) signaling, including cAMP-dependent protein kinase A (PKA) and extracellular signal-regulated kinase (ERK), two responses associated with LID. However, the cause of PKA and ERK activation, their respective contribution to LID, and their relationship are not known. In striatal neurons, D(1)R activates adenylyl-cyclase through Gα(olf), a protein upregulated after lesion of DA neurons in rats and in patients. We report here that increased Gα(olf) levels in hemiparkinsonian mice are correlated with LID after chronic l-DOPA treatment. To determine the role of this upregulation, we performed unilateral lesion in mice lacking one allele of the Gnal gene coding for Gα(olf) (Gnal(+/-)). Despite an increase in the lesioned striatum, Gα(olf) levels remained below those of unlesioned wild-type mice. In Gnal(+/-) mice, the lesion-induced l-DOPA stimulation of cAMP/PKA-mediated phosphorylation of GluA1 Ser845 and DARPP-32 (32 kDa DA- and cAMP-regulated phosphoprotein) Thr34 was dramatically reduced, whereas ERK activation was preserved. LID occurrence was similar in Gnal(+/+) and Gnal(+/-) mice after a 10-d l-DOPA (20 mg/kg) treatment. Thus, in lesioned animals, Gα(olf) upregulation is critical for the activation by l-DOPA of D(1)R-stimulated cAMP/PKA but not ERK signaling. Although the cAMP/PKA pathway appears to be required for LID development, our results indicate that its activation is unlikely to be the main source of LID. In contrast, the persistence of l-DOPA-induced ERK activation in Gnal(+/-) mice supports its causal role in LID development.
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DOI: 10.1523/JNEUROSCI.0837-12.2012
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Paris 6</orgName> <orgName type="acronym">UPMC</orgName> <desc> <address> <addrLine>4 place Jussieu - 75005 Paris</addrLine> <country key="FR"></country> </address> <ref type="url">http://www.upmc.fr/</ref> </desc></org></tutelle><tutelle name="U839" active="#struct-303623" type="direct"><org type="institution" xml:id="struct-303623" status="VALID"> <idno type="IdRef">026388278</idno> <orgName>Institut National de la Santé et de la Recherche Médicale</orgName> <orgName type="acronym">INSERM</orgName> <desc> <address> <addrLine>101, rue de Tolbiac, 75013 Paris </addrLine> <country key="FR"></country> </address> <ref type="url">http://www.inserm.fr</ref> </desc></org></tutelle></tutelles></hal:affiliation><country>France</country></affiliation></author><author><name sortKey="Girault, Jean Antoine" sort="Girault, Jean Antoine" uniqKey="Girault J" first="Jean-Antoine" last="Girault">Jean-Antoine Girault</name><affiliation wicri:level="1"><hal:affiliation type="laboratory" xml:id="struct-27461" status="VALID"><idno type="RNSR">200716490Y</idno><orgName>Institut du Fer à Moulin</orgName><desc><address><addrLine>17, rue du fer à moulin 75005 PARIS</addrLine><country key="FR"></country></address></desc><listRelation><relation active="#struct-93591" type="direct"></relation><relation name="U839" active="#struct-303623" type="direct"></relation></listRelation><tutelles><tutelle active="#struct-93591" type="direct"><org type="institution" xml:id="struct-93591" status="VALID"> <orgName>Université Pierre et Marie Curie - Paris 6</orgName> <orgName type="acronym">UPMC</orgName> <desc> <address> <addrLine>4 place Jussieu - 75005 Paris</addrLine> <country key="FR"></country> </address> <ref type="url">http://www.upmc.fr/</ref> </desc></org></tutelle><tutelle name="U839" active="#struct-303623" type="direct"><org type="institution" xml:id="struct-303623" status="VALID"> <idno type="IdRef">026388278</idno> <orgName>Institut National de la Santé et de la Recherche Médicale</orgName> <orgName type="acronym">INSERM</orgName> <desc> <address> <addrLine>101, rue de Tolbiac, 75013 Paris </addrLine> <country key="FR"></country> </address> <ref type="url">http://www.inserm.fr</ref> </desc></org></tutelle></tutelles></hal:affiliation><country>France</country></affiliation></author><author><name sortKey="Herve, Denis" sort="Herve, Denis" uniqKey="Herve D" first="Denis" last="Hervé">Denis Hervé</name><affiliation wicri:level="1"><hal:affiliation type="laboratory" xml:id="struct-27461" status="VALID"><idno type="RNSR">200716490Y</idno><orgName>Institut du Fer à Moulin</orgName><desc><address><addrLine>17, rue du fer à moulin 75005 PARIS</addrLine><country key="FR"></country></address></desc><listRelation><relation active="#struct-93591" type="direct"></relation><relation name="U839" active="#struct-303623" type="direct"></relation></listRelation><tutelles><tutelle active="#struct-93591" type="direct"><org type="institution" xml:id="struct-93591" status="VALID"> <orgName>Université Pierre et Marie Curie - Paris 6</orgName> <orgName type="acronym">UPMC</orgName> <desc> <address> <addrLine>4 place Jussieu - 75005 Paris</addrLine> <country key="FR"></country> </address> <ref type="url">http://www.upmc.fr/</ref> </desc></org></tutelle><tutelle name="U839" active="#struct-303623" type="direct"><org type="institution" xml:id="struct-303623" status="VALID"> <idno type="IdRef">026388278</idno> <orgName>Institut National de la Santé et de la Recherche Médicale</orgName> <orgName type="acronym">INSERM</orgName> <desc> <address> <addrLine>101, rue de Tolbiac, 75013 Paris </addrLine> <country key="FR"></country> </address> <ref type="url">http://www.inserm.fr</ref> </desc></org></tutelle></tutelles></hal:affiliation><country>France</country></affiliation></author></analytic><idno type="DOI">10.1523/JNEUROSCI.0837-12.2012</idno><series><title level="j">Journal of Neuroscience</title><idno type="ISSN">0270-6474</idno><imprint><date type="datePub">2012-04-25</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Although l-3,4-dihydroxyphenylalanine (l-DOPA) remains the reference treatment of Parkinson's disease, its long-term beneficial effects are hindered by l-DOPA-induced dyskinesia (LID). In the dopamine (DA)-denervated striatum, l-DOPA activates DA D(1) receptor (D(1)R) signaling, including cAMP-dependent protein kinase A (PKA) and extracellular signal-regulated kinase (ERK), two responses associated with LID. However, the cause of PKA and ERK activation, their respective contribution to LID, and their relationship are not known. In striatal neurons, D(1)R activates adenylyl-cyclase through Gα(olf), a protein upregulated after lesion of DA neurons in rats and in patients. We report here that increased Gα(olf) levels in hemiparkinsonian mice are correlated with LID after chronic l-DOPA treatment. To determine the role of this upregulation, we performed unilateral lesion in mice lacking one allele of the Gnal gene coding for Gα(olf) (Gnal(+/-)). Despite an increase in the lesioned striatum, Gα(olf) levels remained below those of unlesioned wild-type mice. In Gnal(+/-) mice, the lesion-induced l-DOPA stimulation of cAMP/PKA-mediated phosphorylation of GluA1 Ser845 and DARPP-32 (32 kDa DA- and cAMP-regulated phosphoprotein) Thr34 was dramatically reduced, whereas ERK activation was preserved. LID occurrence was similar in Gnal(+/+) and Gnal(+/-) mice after a 10-d l-DOPA (20 mg/kg) treatment. Thus, in lesioned animals, Gα(olf) upregulation is critical for the activation by l-DOPA of D(1)R-stimulated cAMP/PKA but not ERK signaling. Although the cAMP/PKA pathway appears to be required for LID development, our results indicate that its activation is unlikely to be the main source of LID. In contrast, the persistence of l-DOPA-induced ERK activation in Gnal(+/-) mice supports its causal role in LID development.</div></front></TEI><hal api="V3"><titleStmt><title xml:lang="en">Gαolf Mutation Allows Parsing the Role of cAMP-Dependent and Extracellular Signal-Regulated Kinase-Dependent Signaling in L-3,4-Dihydroxyphenylalanine-Induced Dyskinesia.</title><author role="aut"><persName><forename type="first">Cristina</forename><surname>Alcacer</surname></persName><idno type="halauthorid">719260</idno><affiliation ref="#struct-27461"></affiliation></author><author role="aut"><persName><forename type="first">Emanuela</forename><surname>Santini</surname></persName><idno type="halauthorid">646729</idno><affiliation ref="#struct-163619"></affiliation></author><author role="aut"><persName><forename type="first">Emmanuel</forename><surname>Valjent</surname></persName><idno type="halauthorid">108531</idno><affiliation ref="#struct-27461"></affiliation><affiliation ref="#struct-2001"></affiliation></author><author role="aut"><persName><forename type="first">Florence</forename><surname>Gaven</surname></persName><idno type="halauthorid">121802</idno><affiliation ref="#struct-27461"></affiliation><affiliation ref="#struct-2001"></affiliation></author><author role="aut"><persName><forename type="first">Jean-Antoine</forename><surname>Girault</surname></persName><idno type="halauthorid">108534</idno><affiliation ref="#struct-27461"></affiliation></author><author role="crp"><persName><forename type="first">Denis</forename><surname>Hervé</surname></persName><email type="md5">04c87d1024e071022a5b49e3f1b40b7f</email><email type="domain">inserm.fr</email><idno type="halauthorid">719261</idno><affiliation ref="#struct-27461"></affiliation></author><editor role="depositor"><persName><forename>Jean-Antoine</forename><surname>Girault</surname></persName><email type="md5">638e68322f455cde07b50c4931a2ed44</email><email type="domain">inserm.fr</email></editor><funder>The work was supported by Inserm, Universite' Pierre et Marie Curie, and grants from the Fondation pour la Recherche Me'dicale, the Fondation pour la Recherche sur le Cerveau, European Research Council, the Michael Stem Parkinson's Research Foundation, and Agence Nationale de la Recherche Grant ANR09-MNPS-014</funder></titleStmt><editionStmt><edition n="v1" type="current"><date type="whenSubmitted">2012-05-02 13:59:54</date><date type="whenWritten">2012-02-19</date><date type="whenModified">2012-05-02 14:57:35</date><date type="whenReleased">2012-05-02 14:57:35</date><date type="whenProduced">2012-04-25</date><date type="whenEndEmbargoed">2012-05-02</date><ref type="file" target="https://hal.archives-ouvertes.fr/hal-00693318/document"><date notBefore="2012-05-02"></date></ref><ref type="file" subtype="author" n="1" target="https://hal.archives-ouvertes.fr/hal-00693318/file/Alcacer-et-al_final_HAL.pdf"><date notBefore="2012-05-02"></date></ref></edition><respStmt><resp>contributor</resp><name key="172601"><persName><forename>Jean-Antoine</forename><surname>Girault</surname></persName><email type="md5">638e68322f455cde07b50c4931a2ed44</email><email type="domain">inserm.fr</email></name></respStmt></editionStmt><publicationStmt><distributor>CCSD</distributor><idno type="halId">hal-00693318</idno><idno type="halUri">https://hal.archives-ouvertes.fr/hal-00693318</idno><idno type="halBibtex">alcacer:hal-00693318</idno><idno type="halRefHtml">Journal of Neuroscience, Society for Neuroscience, 2012, 32 (17), pp.5900-10. <10.1523/JNEUROSCI.0837-12.2012></idno><idno type="halRef">Journal of Neuroscience, Society for Neuroscience, 2012, 32 (17), pp.5900-10. <10.1523/JNEUROSCI.0837-12.2012></idno></publicationStmt><seriesStmt><idno type="stamp" n="INSERM">INSERM - Institut national de la santé et de la recherche médicale</idno><idno type="stamp" n="CNRS">CNRS - Centre national de la recherche scientifique</idno><idno type="stamp" n="UNIV-MONTP1">Université Montpellier I</idno><idno type="stamp" n="UNIV-MONTP2">Université Montpellier II - Sciences et Techniques du Languedoc</idno><idno type="stamp" n="IGF">Institut de génomique fonctionnelle</idno><idno type="stamp" n="UPMC">Université Pierre et Marie Curie</idno><idno type="stamp" n="IFM" p="UPMC">Institut du Fer à Moulin</idno></seriesStmt><notesStmt><note type="audience" n="2">International</note><note type="popular" n="0">No</note><note type="peer" n="1">Yes</note></notesStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Gαolf Mutation Allows Parsing the Role of cAMP-Dependent and Extracellular Signal-Regulated Kinase-Dependent Signaling in L-3,4-Dihydroxyphenylalanine-Induced Dyskinesia.</title><author role="aut"><persName><forename type="first">Cristina</forename><surname>Alcacer</surname></persName><idno type="halauthorid">719260</idno><affiliation ref="#struct-27461"></affiliation></author><author role="aut"><persName><forename type="first">Emanuela</forename><surname>Santini</surname></persName><idno type="halauthorid">646729</idno><affiliation ref="#struct-163619"></affiliation></author><author role="aut"><persName><forename type="first">Emmanuel</forename><surname>Valjent</surname></persName><idno type="halauthorid">108531</idno><affiliation ref="#struct-27461"></affiliation><affiliation ref="#struct-2001"></affiliation></author><author role="aut"><persName><forename type="first">Florence</forename><surname>Gaven</surname></persName><idno type="halauthorid">121802</idno><affiliation ref="#struct-27461"></affiliation><affiliation ref="#struct-2001"></affiliation></author><author role="aut"><persName><forename type="first">Jean-Antoine</forename><surname>Girault</surname></persName><idno type="halauthorid">108534</idno><affiliation ref="#struct-27461"></affiliation></author><author role="crp"><persName><forename type="first">Denis</forename><surname>Hervé</surname></persName><email type="md5">04c87d1024e071022a5b49e3f1b40b7f</email><email type="domain">inserm.fr</email><idno type="halauthorid">719261</idno><affiliation ref="#struct-27461"></affiliation></author></analytic><monogr><idno type="halJournalId" status="VALID">6330</idno><idno type="issn">0270-6474</idno><idno type="eissn">1529-2401</idno><title level="j">Journal of Neuroscience</title><imprint><publisher>Society for Neuroscience</publisher><biblScope unit="volume">32</biblScope><biblScope unit="issue">17</biblScope><biblScope unit="pp">5900-10</biblScope><date type="datePub">2012-04-25</date></imprint></monogr><idno type="doi">10.1523/JNEUROSCI.0837-12.2012</idno><idno type="pubmed">22539851</idno></biblStruct></sourceDesc><profileDesc><langUsage><language ident="en">English</language></langUsage><textClass><classCode scheme="halDomain" n="sdv.neu.nb">Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology</classCode><classCode scheme="halTypology" n="ART">Journal articles</classCode></textClass><abstract xml:lang="en">Although l-3,4-dihydroxyphenylalanine (l-DOPA) remains the reference treatment of Parkinson's disease, its long-term beneficial effects are hindered by l-DOPA-induced dyskinesia (LID). In the dopamine (DA)-denervated striatum, l-DOPA activates DA D(1) receptor (D(1)R) signaling, including cAMP-dependent protein kinase A (PKA) and extracellular signal-regulated kinase (ERK), two responses associated with LID. However, the cause of PKA and ERK activation, their respective contribution to LID, and their relationship are not known. In striatal neurons, D(1)R activates adenylyl-cyclase through Gα(olf), a protein upregulated after lesion of DA neurons in rats and in patients. We report here that increased Gα(olf) levels in hemiparkinsonian mice are correlated with LID after chronic l-DOPA treatment. To determine the role of this upregulation, we performed unilateral lesion in mice lacking one allele of the Gnal gene coding for Gα(olf) (Gnal(+/-)). Despite an increase in the lesioned striatum, Gα(olf) levels remained below those of unlesioned wild-type mice. In Gnal(+/-) mice, the lesion-induced l-DOPA stimulation of cAMP/PKA-mediated phosphorylation of GluA1 Ser845 and DARPP-32 (32 kDa DA- and cAMP-regulated phosphoprotein) Thr34 was dramatically reduced, whereas ERK activation was preserved. LID occurrence was similar in Gnal(+/+) and Gnal(+/-) mice after a 10-d l-DOPA (20 mg/kg) treatment. Thus, in lesioned animals, Gα(olf) upregulation is critical for the activation by l-DOPA of D(1)R-stimulated cAMP/PKA but not ERK signaling. Although the cAMP/PKA pathway appears to be required for LID development, our results indicate that its activation is unlikely to be the main source of LID. In contrast, the persistence of l-DOPA-induced ERK activation in Gnal(+/-) mice supports its causal role in LID development.</abstract></profileDesc></hal></record>Pour manipuler ce document sous Unix (Dilib)
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