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 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.
Arbuckle
Margaret I
MI
Centre for Neuroregeneration, The University of Edinburgh, Institute of Immunology and Infection, Ashworth Buildings, Kings Buildings, Edinburgh EH9 3JT, UK.
Komiyama
Noboru H
NH
Delaney
Ada
A
Coba
Marcelo
M
Garry
Emer M
EM
Rosie
Roberta
R
Allchorne
Andrew J
AJ
Forsyth
Lynsey H
LH
Bence
Matthew
M
Carlisle
Holly J
HJ
O'Dell
Thomas J
TJ
Mitchell
Rory
R
Fleetwood-Walker
Susan M
SM
Grant
Seth G N
SG
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
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
J Neurosci. 2008 Apr 16;28(16):4261-70
18417706
Hum Mol Genet. 2005 Oct 15;14 Spec No. 2:R225-34
16150739
Biochem J. 2006 Mar 15;394(Pt 3):581-92
16336212
Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2854-9
12591944
FEBS Lett. 1994 Mar 14;341(1):79-85
7511113
Nat Neurosci. 2000 Jul;3(7):661-9
10862698
EMBO J. 1995 Mar 1;14(5):963-75
7534229
J Neurosci. 2002 Nov 15;22(22):9721-32
12427827
J Pharmacol Exp Ther. 1997 Feb;280(2):829-38
9023297
Nature. 1992 Oct 29;359(6398):851-5
1279434
Nat Struct Biol. 1994 Aug;1(8):546-51
7664083
Nature. 1998 Dec 3;396(6710):433-9
9853749
Nat Struct Biol. 1994 Apr;1(4):221-5
7656049
Mol Syst Biol. 2009;5:269
19455133
Neuron. 2004 Feb 19;41(4):625-38
14980210
Nat Neurosci. 2008 Jul;11(7):799-806
18536710
J Cell Sci. 2003 Aug 1;116(Pt 15):3037-40
12829733
J Mol Biol. 1995 May 12;248(4):856-66
7752246
Curr Biol. 1995 Apr 1;5(4):364-7
7542990
Curr Biol. 2003 Feb 18;13(4):321-8
12593798
Nucleic Acids Res. 2009 Jan;37(Database issue):D846-51
18984621
EMBO J. 1993 Jul;12(7):2617-24
7687536
J Neurosci. 2007 Mar 7;27(10):2673-82
17344405