The SH3 domain of postsynaptic density 95 mediates inflammatory pain through phosphatidylinositol-3-kinase recruitment

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The SH3 domain of postsynaptic density 95 mediates inflammatory pain through phosphatidylinositol-3-kinase recruitment

Sensitization to inflammatory pain is a pathological form of neuronal plasticity that is poorly understood and treated. Here the authors report that the SH3 domain of the scaffold protein PSD-95 binds a lipid signaling enzyme, PI3K-C2a, that mediates inflammatory sensitization. The results show that different types of behavioural plasticity are mediated by specific domains of PSD-95 and suggest that PI3K-C2a is a potential drug target for inflammatory pain.

Abstract

Sensitization to inflammatory pain is a pathological form of neuronal plasticity that is poorly understood and treated. Here we examine the role of the SH3 domain of postsynaptic density 95 (PSD95) by using mice that carry a single amino-acid substitution in the polyproline-binding site. Testing multiple forms of plasticity we found sensitization to inflammation was specifically attenuated. The inflammatory response required recruitment of phosphatidylinositol-3-kinase-C2α to the SH3-binding site of PSD95. In wild-type mice, wortmannin or peptide competition attenuated the sensitization. These results show that different types of behavioural plasticity are mediated by specific domains of PSD95 and suggest novel therapeutic avenues for reducing inflammatory pain.

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Most cited references 20

Record: found
Abstract: found
Article: not found

Proteomic analysis of NMDA receptor-adhesion protein signaling complexes.

H Husi, M Ward, J. Choudhary … (2000)

N-methyl-d-aspartate receptors (NMDAR) mediate long-lasting changes in synapse strength via downstream signaling pathways. We report proteomic characterization with mass spectrometry and immunoblotting of NMDAR multiprotein complexes (NRC) isolated from mouse brain. The NRC comprised 77 proteins organized into receptor, adaptor, signaling, cytoskeletal and novel proteins, of which 30 are implicated from binding studies and another 19 participate in NMDAR signaling. NMDAR and metabotropic glutamate receptor subtypes were linked to cadherins and L1 cell-adhesion molecules in complexes lacking AMPA receptors. These neurotransmitter-adhesion receptor complexes were bound to kinases, phosphatases, GTPase-activating proteins and Ras with effectors including MAPK pathway components. Several proteins were encoded by activity-dependent genes. Genetic or pharmacological interference with 15 NRC proteins impairs learning and with 22 proteins alters synaptic plasticity in rodents. Mutations in three human genes (NF1, Rsk-2, L1) are associated with learning impairments, indicating the NRC also participates in human cognition.

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Record: found
Abstract: found
Article: found

Is Open Access

Targeted tandem affinity purification of PSD-95 recovers core postsynaptic complexes and schizophrenia susceptibility proteins

Esperanza Fernández, Mark O Collins, Rachel Uren … (2009)

The molecular complexity of mammalian proteomes demands new methods for mapping the organization of multiprotein complexes. Here, we combine mouse genetics and proteomics to characterize synapse protein complexes and interaction networks. New tandem affinity purification (TAP) tags were fused to the carboxyl terminus of PSD-95 using gene targeting in mice. Homozygous mice showed no detectable abnormalities in PSD-95 expression, subcellular localization or synaptic electrophysiological function. Analysis of multiprotein complexes purified under native conditions by mass spectrometry defined known and new interactors: 118 proteins comprising crucial functional components of synapses, including glutamate receptors, K+ channels, scaffolding and signaling proteins, were recovered. Network clustering of protein interactions generated five connected clusters, with two clusters containing all the major ionotropic glutamate receptors and one cluster with voltage-dependent K+ channels. Annotation of clusters with human disease associations revealed that multiple disorders map to the network, with a significant correlation of schizophrenia within the glutamate receptor clusters. This targeted TAP tagging strategy is generally applicable to mammalian proteomics and systems biology approaches to disease.

0 comments Cited 104 times – based on 0 reviews      Review now

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Record: found
Abstract: found
Article: not found

Evolutionary expansion and anatomical specialization of synapse proteome complexity.

Nicola J. Armstrong, Seth Grant, Àlex Bayés … (2008)

Understanding the origins and evolution of synapses may provide insight into species diversity and the organization of the brain. Using comparative proteomics and genomics, we examined the evolution of the postsynaptic density (PSD) and membrane-associated guanylate kinase (MAGUK)-associated signaling complexes (MASCs) that underlie learning and memory. PSD and MASC orthologs found in yeast carry out basic cellular functions to regulate protein synthesis and structural plasticity. We observed marked changes in signaling complexity at the yeast-metazoan and invertebrate-vertebrate boundaries, with an expansion of key synaptic components, notably receptors, adhesion/cytoskeletal proteins and scaffold proteins. A proteomic comparison of Drosophila and mouse MASCs revealed species-specific adaptation with greater signaling complexity in mouse. Although synaptic components were conserved amongst diverse vertebrate species, mapping mRNA and protein expression in the mouse brain showed that vertebrate-specific components preferentially contributed to differences between brain regions. We propose that the evolution of synapse complexity around a core proto-synapse has contributed to invertebrate-vertebrate differences and to brain specialization.

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Author and article information

Journal

Journal ID (nlm-ta): EMBO Rep

Title: EMBO Reports

Publisher: Nature Publishing Group

ISSN (Print): 1469-221X

ISSN (Electronic): 1469-3178

Publication date (Print): June 2010

Publication date (Electronic): 14 May 2010

Publication date PMC-release: 14 May 2010

Volume: 11

Issue: 6

Pages: 473-478

Affiliations

[1 ]Centre for Neuroregeneration, The University of Edinburgh, Institute of Immunology and Infection , Ashworth Buildings, Kings Buildings, Edinburgh EH9 3JT, UK

[2 ]The Wellcome Trust Sanger Institute, Genome Campus, Genes to Cognition Programme, Hinxton , Cambridgeshire CB10 1SA, UK

[3 ]Department of Physiology, David Geffen School of Medicine at UCLA , 10833 Le Conte Avenue, Los Angeles, California 90024, USA

Author notes

[a ]Tel: +44 1223 495380, 494908; Fax: +44 1223 494919;E-mail: sg3@ 123456sanger.ac.uk

[*]

These authors contributed equally to this work

[†]

These authors supervised the project

Article

Publisher Item ID: embor201063

DOI: 10.1038/embor.2010.63

PMC ID: 2892321

PubMed ID: 20467438

SO-VID: f425fb7d-1dcd-406b-8d3d-0328afd4b5a3

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits distribution, and reproduction in any medium, provided the original author and source are credited. This license does not permit commercial exploitation or the creation of derivative works without specific permission.

History

Date received : 28 January 2010

Date revision received : 12 March 2010

Date accepted : 01 April 2010

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The SH3 domain of postsynaptic density 95 mediates inflammatory pain through phosphatidylinositol-3-kinase recruitment

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