Homer1a-Dependent Crosstalk Between NMDA and Metabotropic Glutamate Receptors in Mouse Neurons

Hdl Handle:
http://hdl.handle.net/10675.2/579
Title:
Homer1a-Dependent Crosstalk Between NMDA and Metabotropic Glutamate Receptors in Mouse Neurons
Authors:
Bertaso, Federica; Roussignol, Gautier; Worley, Paul; Bockaert, Joël ( 0000-0001-8226-9529 ) ; Fagni, Laurent; Ango, Fabrice
Abstract:
null; Background: A large number of evidences suggest that group-I metabotropic glutamate receptors (mGluR1a, 1b, 1c, 5a, 5b) can modulate NMDA receptor activity. Interestingly, a physical link exists between these receptors through a Homer-Shank multi-protein scaffold that can be disrupted by the immediate early gene, Homer1a. Whether such a versatile link supports functional crosstalk between the receptors is unknown.; Methodology/Principal Findings: Here we used biochemical, electrophysiological and molecular biological approaches in cultured mouse cerebellar neurons to investigate this issue. We found that Homer1a or dominant negative Shank3 mutants that disrupt the physical link between the receptors allow inhibition of NMDA current by group-I mGluR agonist. This effect is antagonized by pertussis toxin, but not thapsigargin, suggesting the involvement of a G protein, but not intracellular calcium stores. Also, this effect is voltage-sensitive, being present at negative, but not positive membrane potentials. In the presence of DHPG, an apparent NMDA â tail currentâ was evoked by large pulse depolarization, only in neurons transfected with Homer1a. Co-immunoprecipitation experiments showed interaction between G-protein bc subunits and NMDA receptor in the presence of Homer1a and group-I mGluR agonist.; Conclusions/Significance: Altogether these results suggest a direct inhibition of NMDA receptor-channel by Gbetagamma subunits, following disruption of the Homer-Shank3 complex by the immediate early gene Homer1a. This study provides a new molecular mechanism by which group-I mGluRs could dynamically regulate NMDA receptor function.
Editors:
Mei, Lin
Citation:
PLoS One. 2010 Mar 18; 5(3):e9755
Issue Date:
18-Mar-2010
URI:
http://hdl.handle.net/10675.2/579
DOI:
10.1371/journal.pone.0009755
PubMed ID:
20305784
PubMed Central ID:
PMC2841198
Type:
Article
ISSN:
1932-6203
Appears in Collections:
Department of Neurology: Faculty Research and Presentations

Full metadata record

DC FieldValue Language
dc.contributor.authorBertaso, Federicaen_US
dc.contributor.authorRoussignol, Gautieren_US
dc.contributor.authorWorley, Paulen_US
dc.contributor.authorBockaert, Joëlen_US
dc.contributor.authorFagni, Laurenten_US
dc.contributor.authorAngo, Fabriceen_US
dc.contributor.editorMei, Lin-
dc.date.accessioned2012-10-26T16:26:47Z-
dc.date.available2012-10-26T16:26:47Z-
dc.date.issued2010-03-18en_US
dc.identifier.citationPLoS One. 2010 Mar 18; 5(3):e9755en_US
dc.identifier.issn1932-6203en_US
dc.identifier.pmid20305784en_US
dc.identifier.doi10.1371/journal.pone.0009755en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/579-
dc.description.abstractnullen_US
dc.description.abstractBackground: A large number of evidences suggest that group-I metabotropic glutamate receptors (mGluR1a, 1b, 1c, 5a, 5b) can modulate NMDA receptor activity. Interestingly, a physical link exists between these receptors through a Homer-Shank multi-protein scaffold that can be disrupted by the immediate early gene, Homer1a. Whether such a versatile link supports functional crosstalk between the receptors is unknown.en_US
dc.description.abstractMethodology/Principal Findings: Here we used biochemical, electrophysiological and molecular biological approaches in cultured mouse cerebellar neurons to investigate this issue. We found that Homer1a or dominant negative Shank3 mutants that disrupt the physical link between the receptors allow inhibition of NMDA current by group-I mGluR agonist. This effect is antagonized by pertussis toxin, but not thapsigargin, suggesting the involvement of a G protein, but not intracellular calcium stores. Also, this effect is voltage-sensitive, being present at negative, but not positive membrane potentials. In the presence of DHPG, an apparent NMDA â tail currentâ was evoked by large pulse depolarization, only in neurons transfected with Homer1a. Co-immunoprecipitation experiments showed interaction between G-protein bc subunits and NMDA receptor in the presence of Homer1a and group-I mGluR agonist.en_US
dc.description.abstractConclusions/Significance: Altogether these results suggest a direct inhibition of NMDA receptor-channel by Gbetagamma subunits, following disruption of the Homer-Shank3 complex by the immediate early gene Homer1a. This study provides a new molecular mechanism by which group-I mGluRs could dynamically regulate NMDA receptor function.en_US
dc.rightsBertaso et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_US
dc.subjectResearch Articleen_US
dc.subjectNeuroscienceen_US
dc.subjectNeuroscience/Neurobiology of Disease and Regenerationen_US
dc.subjectNeuroscience/Neuronal Signaling Mechanismsen_US
dc.titleHomer1a-Dependent Crosstalk Between NMDA and Metabotropic Glutamate Receptors in Mouse Neuronsen_US
dc.typeArticleen_US
dc.identifier.pmcidPMC2841198en_US
dc.contributor.corporatenameDepartment of Neurology-
dc.contributor.corporatenameCollege of Graduate Studies-

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