G2C::PSD-95 SH3 domain peptide interactors

SH3 domain of PSD-95 mediates inflammatory pain through PI3 kinase recruitment

Margaret I. Arbuckle^1*, Noboru H. Komiyama^2*, Ada Delaney^1*, Marcelo Coba², Emer M. Garry¹, Roberta Rosie¹, Andrew Allchorne¹, Lynsey H. Forsyth¹, Matthew Bence¹, Holly J. Carlisle³, Thomas J. O'Dell³, Rory Mitchell¹, Susan M. Fleetwood-Walker^1† and Seth G.N. Grant^2†

Author email: sg3@sanger.ac.uk   * - These authors contributed equally to this work; † - These authors supervised the project

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

Mutation of the tryptophan 470 residue of PSD-95 to leucine in the polyproline binding site of the SH3 domain blocks interaction with PI3 kinase (Pik3c2α) and inflammatory pain.

Sensitisation 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 PSD-95 using mice carrying a single amino acid substitution in the polyproline binding site. Testing multiple forms of plasticity we found sensitisation to inflammation was specifically attenuated. The inflammatory response required recruitment of phosphoinositide 3-kinase-C2α to the SH3 binding site of PSD-95. In wild-type mice, wortmannin or peptide competition attenuated the sensitisation. These results show different types of behavioural plasticity are mediated by specific domains of PSD-95 and suggest novel therapeutic avenues for inflammatory pain.

Supplementary Table 1.

List of 290 peptide sequences binding the SH3 domain of PSD-95, on Jerini SH3-domain profiler^tm. Shown are Gene Symbol, HGNC ID, Peptide Sequence, mean intensity of triplicates (Mean Intensity), standard deviation (SD), and UniProt Acc.