Visit our Expo - Redox and Inflammation signaling 2012

Session XII : Cell death and neurodegenerative diseases Poster XII, 7
Protein domain interactions as a target for inhibition of excitotoxic p38 stress-activated
protein kinase activation and neuronal cell death: the PSD95–nNOS interface./
Jiong Cao, Lotta E. Parviainen, Anu M.J. Mäki-Hokkonen, Jenni I. Viholainen and
Michael J. Courtney/
Molecular Signalling Lab, A. I. Virtanen Institute, University of Kuopio, Kuopio FIN
70211, Finland. E-mail : courtney@messi.uku.fi /
The stress-activated protein kinase p38 and nitric oxide (NO) are proposed downstream
mediators of excitotoxicity, a mechanism of neuronal cell death common to both acute
conditions such as cerebral ischaemia and chronic neurodegenerative diseases. The
postsynaptic density protein PSD95 can recruit a wide range of effectors, such as the calciumdependent
neuronal NO synthase (nNOS), to the calcium-permeable channel of the NMDA
subtype of glutamate receptor. Depletion and displacement of PSD95 from NMDA receptors
reportedly inhibits excitotoxicity, but the multifunctional nature of the PSD95 interactome
makes it hard to deduce from this the precise mechanism of neuroprotection provided by
targeting PSD95. The possibility that selective uncoupling of nNOS from PSD95 might be
neuroprotective has not been previously explored. The relationship between excitotoxic
stress–generated NO and activation of p38, and the significance of the PSD95–nNOS
interaction to p38 activation also remain unclear. We find that NOS inhibitors reduce both
glutamate-induced p38 activation and the resulting neuronal death, whereas NO donor has
effects consistent with NO as an upstream regulator of p38 in glutamate-induced cell death.
Experiments using a panel of decoy constructs targeting interactions between NMDA
receptors, PSD95 and nNOS suggest that the PSD95–nNOS interaction and subsequent NO
production are critical for glutamate-induced p38 activation and the ensuing cell death, and
demonstrate that the PSD95–nNOS interface provides a genuine possibility for design of
neuroprotective drugs with increased selectivity.
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