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Peroxynitrite enhances astrocytic volume‐sensitive excitatory amino acid release via a src tyrosine kinase‐dependent mechanism
Author(s) -
Haskew Renée E.,
Mongin Alexander A.,
Kimelberg Harold K.
Publication year - 2002
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2002.01037.x
Subject(s) - peroxynitrite , chemistry , superoxide , proto oncogene tyrosine protein kinase src , nitric oxide , tyrosine , peroxynitrous acid , tyrosine kinase , biochemistry , tyrosine phosphorylation , chelerythrine , sodium nitroprusside , microbiology and biotechnology , kinase , signal transduction , biology , protein kinase c , enzyme , organic chemistry
Volume‐regulated anion channels (VRACs) are critically important for cell volume homeostasis, and under pathological conditions contribute to neuronal damage via excitatory amino (EAA) release. The precise mechanisms by which brain VRACs are activated and/or modulated remain elusive. In the present work we explored the possible involvement of nitric oxide (NO) and NO‐related reactive species in the regulation of VRAC activity and EAA release, using primary astrocyte cultures. The NO donors sodium nitroprusside and spermine NONOate did not affect volume‐activated d ‐[ 3 H]aspartate release. In contrast, the peroxynitrite (ONOO – ) donor 3‐morpholinosydnomine hydrochloride (SIN‐1) increased volume‐dependent EAA release by approx. 80–110% under identical conditions. Inhibition of ONOO – formation with superoxide dismutase completely abolished the effects of SIN‐1. Both the volume‐ and SIN‐1‐induced EAA release were sensitive to the VRAC blockers NPPB and ATP. Further pharmacological analysis ruled out the involvement of cGMP‐dependent reactions and modification of sulfhydryl groups in the SIN‐1‐inducedmodulation of EAA release. The src family tyrosine kinase inhibitor 4‐amino‐5‐(4‐chlorophenyl)‐7‐(t‐butyl)pyrazolo [3,4‐d]pyrimidine (PP2), but not its inactive analog PP3, abolished the effects of SIN‐1. A broader spectrum tyrosine kinase inhibitor tyrphostin A51, also completely eliminated the SIN‐1‐induced EAA release. Our data suggest that ONOO – up‐regulates VRAC activity via a src tyrosine kinase‐dependent mechanism. This modulation may contribute to EAA‐mediated neuronal damage in ischemia and other pathological conditions favoring cell swelling and ONOO – production.