Premium
A new function for an old enzyme: Src protein tyrosine kinase directs excitotoxic neuronal death in stroke (596.3)
Author(s) -
Cheng HeungChin,
Hossain Mohammed,
Roulston Carli,
Ng Dominic,
Williamson Nicholas,
Hoque Ashfaqul,
Hill Andrew
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.596.3
Subject(s) - excitotoxicity , proto oncogene tyrosine protein kinase src , calpain , microbiology and biotechnology , tyrosine kinase , biology , programmed cell death , src family kinase , receptor tyrosine kinase , ionotropic effect , neuroprotection , kinase , glutamate receptor , receptor , signal transduction , neuroscience , biochemistry , apoptosis , enzyme
Excitotoxicity resulting from over‐stimulation of ionotropic glutamate receptors is a major cause of neuronal death in cerebral ischemic stroke. The over‐stimulated receptors exert their neurotoxic effects in part by over‐activation of calpains which induce neuronal death by catalyzing limited proteolysis of specific cellular proteins. Here, we report that in cultured cortical neurons and in vivo in a rat model of focal ischemic stroke, the tyrosine kinase Src is cleaved by calpains at a site in the N‐terminal unique domain. This generates a truncated Src fragment of ~52 kDa localised predominantly in the cytosol. A synthetic cell membrane‐permeable fusion peptide derived from the Src unique domain prevents calpains from cleaving Src in neurons and protects against excitotoxic neuronal death. To explore the role of the truncated Src fragment in neuronal death, we expressed a recombinant truncated Src fragment in cultured neurons, and demonstrated that expression of this fragment, which lacks the unique domain, was sufficient to induce neuronal death. Furthermore, inactivation of the pro‐survival kinase Akt is a key step in its neurotoxic signaling pathway. As Src maintains neuronal survival, our results implicate calpain cleavage as a key step of neuronal death in excitotoxicity, and suggest blockade of calpain cleavage of Src as a potential therapeutic strategy to minimize brain damage in ischemic stroke. Grant Funding Source : NHMRC Australia