title: The SH3 domain of postsynaptic density 95 mediates inflammatory pain through phosphatidylinositol-3-kinase recruitment.
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-C2alpha 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.
authors.affiliation: Centre for Neuroregeneration, The University of Edinburgh, Institute of Immunology and Infection, Ashworth Buildings, Kings Buildings, Edinburgh EH9 3JT, UK.
authors.forename: Margaret I
authors.initials: MI
authors.lastname: Arbuckle
authors.forename: Noboru H
authors.initials: NH
authors.lastname: Komiyama
authors.forename: Ada
authors.initials: A
authors.lastname: Delaney
authors.forename: Marcelo
authors.initials: M
authors.lastname: Coba
authors.forename: Emer M
authors.initials: EM
authors.lastname: Garry
authors.forename: Roberta
authors.initials: R
authors.lastname: Rosie
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Allchorne
authors.forename: Lynsey H
authors.initials: LH
authors.lastname: Forsyth
authors.forename: Matthew
authors.initials: M
authors.lastname: Bence
authors.forename: Holly J
authors.initials: HJ
authors.lastname: Carlisle
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: O'Dell
authors.forename: Rory
authors.initials: R
authors.lastname: Mitchell
authors.forename: Susan M
authors.initials: SM
authors.lastname: Fleetwood-Walker
authors.forename: Seth G N
authors.initials: SG
authors.lastname: Grant
mesh_terms: D000818:Animals; D000076122:Disks Large Homolog 4 Protein; D051528:Guanylate Kinases; D006624:Hippocampus / Q000201:enzymology / Q000473:pathology; D066298:In Vitro Techniques; D007249:Inflammation / Q000150:complications* / Q000201:enzymology*; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009473:Neuronal Plasticity; D010146:Pain / Q000150:complications* / Q000201:enzymology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017354:Point Mutation / Q000235:genetics; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013569:Synapses / Q000201:enzymology; D018909:src Homology Domains
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D051528:Guanylate Kinases
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