Mutations in AKAP5 Disrupt Dendritic Signaling Complexes and Lead to Electrophysiological and Behavioral Phenotypes in Mice

Hdl Handle:
http://hdl.handle.net/10675.2/583
Title:
Mutations in AKAP5 Disrupt Dendritic Signaling Complexes and Lead to Electrophysiological and Behavioral Phenotypes in Mice
Authors:
Weisenhaus, Michael; Allen, Margaret L.; Yang, Linghai; Lu, Yuan; Nichols, C. Blake; Su, Thomas; Hell, Johannes W. ( 0000-0001-7960-7531 ) ; McKnight, G. Stanley
Abstract:
AKAP5 (also referred to as AKAP150 in rodents and AKAP79 in humans) is a scaffolding protein that is highly expressed in neurons and targets a variety of signaling molecules to dendritic membranes. AKAP5 interacts with PKA holoenzymes containing RIIa or RIIb as well as calcineurin (PP2B), PKC, calmodulin, adenylyl cyclase type V/VI, L-type calcium channels, and b-adrenergic receptors. AKAP5 has also been shown to interact with members of the MAGUK family of PSD-scaffolding proteins including PSD95 and SAP97 and target signaling molecules to receptors and ion channels in the postsynaptic density (PSD). We created two lines of AKAP5 mutant mice: a knockout of AKAP5 (KO) and a mutant that lacks the PKA binding domain of AKAP5 (D36). We find that PKA is delocalized in both the hippocampus and striatum of KO and D36 mice indicating that other neural AKAPs cannot compensate for the loss of PKA binding to AKAP5. In AKAP5 mutant mice, a significant fraction of PKA becomes localized to dendritic shafts and this correlates with increased binding to microtubule associated protein-2 (MAP2). Electrophysiological and behavioral analysis demonstrated more severe deficits in both synaptic plasticity and operant learning in the D36 mice compared with the complete KO animals. Our results indicate that the targeting of calcineurin or other binding partners of AKAP5 in the absence of the balancing kinase, PKA, leads to a disruption of synaptic plasticity and results in learning and memory defects.
Editors:
Mei, Lin
Citation:
PLoS One. 2010 Apr 23; 5(4):e10325
Issue Date:
23-Apr-2010
URI:
http://hdl.handle.net/10675.2/583
DOI:
10.1371/journal.pone.0010325
PubMed ID:
20428246
PubMed Central ID:
PMC2859064
Type:
Article
ISSN:
1932-6203
Appears in Collections:
Department of Neurology: Faculty Research and Presentations

Full metadata record

DC FieldValue Language
dc.contributor.authorWeisenhaus, Michaelen_US
dc.contributor.authorAllen, Margaret L.en_US
dc.contributor.authorYang, Linghaien_US
dc.contributor.authorLu, Yuanen_US
dc.contributor.authorNichols, C. Blakeen_US
dc.contributor.authorSu, Thomasen_US
dc.contributor.authorHell, Johannes W.en_US
dc.contributor.authorMcKnight, G. Stanleyen_US
dc.contributor.editorMei, Lin-
dc.date.accessioned2012-10-26T16:26:47Z-
dc.date.available2012-10-26T16:26:47Z-
dc.date.issued2010-04-23en_US
dc.identifier.citationPLoS One. 2010 Apr 23; 5(4):e10325en_US
dc.identifier.issn1932-6203en_US
dc.identifier.pmid20428246en_US
dc.identifier.doi10.1371/journal.pone.0010325en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/583-
dc.description.abstractAKAP5 (also referred to as AKAP150 in rodents and AKAP79 in humans) is a scaffolding protein that is highly expressed in neurons and targets a variety of signaling molecules to dendritic membranes. AKAP5 interacts with PKA holoenzymes containing RIIa or RIIb as well as calcineurin (PP2B), PKC, calmodulin, adenylyl cyclase type V/VI, L-type calcium channels, and b-adrenergic receptors. AKAP5 has also been shown to interact with members of the MAGUK family of PSD-scaffolding proteins including PSD95 and SAP97 and target signaling molecules to receptors and ion channels in the postsynaptic density (PSD). We created two lines of AKAP5 mutant mice: a knockout of AKAP5 (KO) and a mutant that lacks the PKA binding domain of AKAP5 (D36). We find that PKA is delocalized in both the hippocampus and striatum of KO and D36 mice indicating that other neural AKAPs cannot compensate for the loss of PKA binding to AKAP5. In AKAP5 mutant mice, a significant fraction of PKA becomes localized to dendritic shafts and this correlates with increased binding to microtubule associated protein-2 (MAP2). Electrophysiological and behavioral analysis demonstrated more severe deficits in both synaptic plasticity and operant learning in the D36 mice compared with the complete KO animals. Our results indicate that the targeting of calcineurin or other binding partners of AKAP5 in the absence of the balancing kinase, PKA, leads to a disruption of synaptic plasticity and results in learning and memory defects.en_US
dc.rightsWeisenhaus 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.subjectCell Biology/Cell Signalingen_US
dc.subjectCell Biology/Neuronal and Glial Cell Biologyen_US
dc.subjectNeuroscience/Animal Cognitionen_US
dc.subjectNeuroscience/Neuronal Signaling Mechanismsen_US
dc.titleMutations in AKAP5 Disrupt Dendritic Signaling Complexes and Lead to Electrophysiological and Behavioral Phenotypes in Miceen_US
dc.typeArticleen_US
dc.identifier.pmcidPMC2859064en_US
dc.contributor.corporatenameDepartment of Neurology-
dc.contributor.corporatenameCollege of Graduate Studies-

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