Kalirin Binds the NR2B Subunit of the NMDA Receptor, Altering Its Synaptic Localization and Function

Handle URI:
http://hdl.handle.net/10754/555633
Title:
Kalirin Binds the NR2B Subunit of the NMDA Receptor, Altering Its Synaptic Localization and Function
Authors:
Kiraly, D. D.; Lemtiri-Chlieh, Fouad ( 0000-0002-7418-2623 ) ; Levine, E. S.; Mains, R. E.; Eipper, B. A.
Abstract:
The ability of dendritic spines to change size and shape rapidly is critical in modulating synaptic strength; these morphological changes are dependent upon rearrangements of the actin cytoskeleton. Kalirin-7 (Kal7), a Rho guanine nucleotide exchange factor localized to the postsynaptic density (PSD), modulates dendritic spine morphology in vitro and in vivo. Kal7 activates Rac and interacts with several PSD proteins, including PSD-95, DISC-1, AF-6, and Arf6. Mice genetically lacking Kal7 (Kal7KO) exhibit deficient hippocampal long-term potentiation (LTP) as well as behavioral abnormalities in models of addiction and learning. Purified PSDs from Kal7KO mice contain diminished levels of NR2B, an NMDA receptor subunit that plays a critical role in LTP induction. Here we demonstrate that Kal7KO animals have decreased levels of NR2B-dependent NMDA receptor currents in cortical pyramidal neurons as well as a specific deficit in cell surface expression of NR2B. Additionally, we demonstrate that the genotypic differences in conditioned place preference and passive avoidance learning seen in Kal7KO mice are abrogated when animals are treated with an NR2B-specific antagonist during conditioning. Finally, we identify a stable interaction between the pleckstrin homology domain of Kal7 and the juxtamembrane region of NR2B preceding its cytosolic C-terminal domain. Binding of NR2B to a protein that modulates the actin cytoskeleton is important, as NMDA receptors require actin integrity for synaptic localization and function. These studies demonstrate a novel and functionally important interaction between the NR2B subunit of the NMDA receptor and Kalirin, proteins known to be essential for normal synaptic plasticity.
KAUST Department:
Biological and Environmental Sciences and Engineering (BESE) Division
Citation:
Kalirin Binds the NR2B Subunit of the NMDA Receptor, Altering Its Synaptic Localization and Function 2011, 31 (35):12554 Journal of Neuroscience
Publisher:
Society for Neuroscience
Journal:
Journal of Neuroscience
Issue Date:
31-Aug-2011
DOI:
10.1523/JNEUROSCI.3143-11.2011
PubMed ID:
21880917
PubMed Central ID:
PMC3172699
Type:
Article
ISSN:
0270-6474; 1529-2401
Additional Links:
http://www.jneurosci.org/cgi/doi/10.1523/JNEUROSCI.3143-11.2011
Appears in Collections:
Articles; Biological and Environmental Sciences and Engineering (BESE) Division; Biological and Environmental Sciences and Engineering (BESE) Division

Full metadata record

DC FieldValue Language
dc.contributor.authorKiraly, D. D.en
dc.contributor.authorLemtiri-Chlieh, Fouaden
dc.contributor.authorLevine, E. S.en
dc.contributor.authorMains, R. E.en
dc.contributor.authorEipper, B. A.en
dc.date.accessioned2015-05-25T07:57:29Zen
dc.date.available2015-05-25T07:57:29Zen
dc.date.issued2011-08-31en
dc.identifier.citationKalirin Binds the NR2B Subunit of the NMDA Receptor, Altering Its Synaptic Localization and Function 2011, 31 (35):12554 Journal of Neuroscienceen
dc.identifier.issn0270-6474en
dc.identifier.issn1529-2401en
dc.identifier.pmid21880917en
dc.identifier.doi10.1523/JNEUROSCI.3143-11.2011en
dc.identifier.urihttp://hdl.handle.net/10754/555633en
dc.description.abstractThe ability of dendritic spines to change size and shape rapidly is critical in modulating synaptic strength; these morphological changes are dependent upon rearrangements of the actin cytoskeleton. Kalirin-7 (Kal7), a Rho guanine nucleotide exchange factor localized to the postsynaptic density (PSD), modulates dendritic spine morphology in vitro and in vivo. Kal7 activates Rac and interacts with several PSD proteins, including PSD-95, DISC-1, AF-6, and Arf6. Mice genetically lacking Kal7 (Kal7KO) exhibit deficient hippocampal long-term potentiation (LTP) as well as behavioral abnormalities in models of addiction and learning. Purified PSDs from Kal7KO mice contain diminished levels of NR2B, an NMDA receptor subunit that plays a critical role in LTP induction. Here we demonstrate that Kal7KO animals have decreased levels of NR2B-dependent NMDA receptor currents in cortical pyramidal neurons as well as a specific deficit in cell surface expression of NR2B. Additionally, we demonstrate that the genotypic differences in conditioned place preference and passive avoidance learning seen in Kal7KO mice are abrogated when animals are treated with an NR2B-specific antagonist during conditioning. Finally, we identify a stable interaction between the pleckstrin homology domain of Kal7 and the juxtamembrane region of NR2B preceding its cytosolic C-terminal domain. Binding of NR2B to a protein that modulates the actin cytoskeleton is important, as NMDA receptors require actin integrity for synaptic localization and function. These studies demonstrate a novel and functionally important interaction between the NR2B subunit of the NMDA receptor and Kalirin, proteins known to be essential for normal synaptic plasticity.en
dc.publisherSociety for Neuroscienceen
dc.relation.urlhttp://www.jneurosci.org/cgi/doi/10.1523/JNEUROSCI.3143-11.2011en
dc.rightsArchived with thanks to Journal of Neuroscienceen
dc.titleKalirin Binds the NR2B Subunit of the NMDA Receptor, Altering Its Synaptic Localization and Functionen
dc.typeArticleen
dc.contributor.departmentBiological and Environmental Sciences and Engineering (BESE) Divisionen
dc.identifier.journalJournal of Neuroscienceen
dc.identifier.pmcidPMC3172699en
dc.eprint.versionPublisher's Version/PDFen
dc.contributor.institutionDepartment of Neuroscience, University of Connecticut Health Center, Farmington, Connecticut 06030en
kaust.authorLemtiri-Chlieh, Fouaden

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