Peroxynitrite-induced tyrosine nitration and inhibition of protein kinase C

Lauren T. Knapp, Beatriz I. Kanterewicz, Emma L. Hayes, Eric Klann

Research output: Contribution to journalArticlepeer-review

Abstract

Protein kinase C (PKC) is an important intracellular signaling molecule whose activity is essential for a number of aspects of neuronal function including synaptic plasticity. We investigated the regulation of PKC activity by reactive nitrogen species in order to examine whether such species regulate PKC in neurons. Neither autonomous nor cofactor-dependent PKC activity was altered when either hippocampal homogenates or rat brain purified PKC were incubated briefly with three different nitric oxide donor compounds. However, brief incubation of either hippocampal homogenates or purified PKC with peroxynitrite (ONOO-) inhibited cofactor-dependent PKC activity in a manner that correlated with the nitration of tyrosine residues on PKC, suggesting that this modification was responsible for the inhibition of PKC. Consistent with this idea, reducing agents had no effect on the inhibition of PKC activity caused by ONOO-. Because there are numerous PKC isoforms that differ in the composition of the regulatory domain, we studied the effect of ONOO- on various PKC isoforms. ONOO- inhibited the cofactor-dependent activity of the α, βII, ∈, and ζ isoforms, indicating that inhibition of enzymatic activity by ONOO- was not PKC isoform-specific. We also were able to isolate nitrated PKCα and PKCβII from ONOO--treated hippocampal homogenates via immunoprecipitation. Collectively, our findings support the hypothesis that ONOO- inhibits PKC activity via tyrosine nitration in neurons.

Original languageEnglish (US)
Pages (from-to)764-770
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume286
Issue number4
DOIs
StatePublished - 2001

Keywords

  • Brain
  • Hippocampus
  • Neurodegenerative disease
  • Nitric oxide
  • Protein kinase C
  • Reactive nitrogen species
  • Reactive oxygen species
  • Superoxide

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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