Modulation of protein kinases and protein phosphatases by reactive oxygen species: implications for hippocampal synaptic plasticity.

1. Reactive oxygen species are known for their role in neurotoxicity. However, recent studies indicate that reactive oxygen species also play a role in cell function under physiological conditions. 2. Both superoxide and hydrogen peroxide alter the activity of various protein kinases and protein phosphatases, some of which are involved in hippocampal synaptic plasticity. Specifically, the activity of protein kinase C, extracellular-regulated kinase 2, and a protein tyrosine kinase(s) is increased in the presence of these reactive oxygen species, whereas the activity of protein phosphatases 2A and 2B, and a protein tyrosine phosphatase(s) is decreased. 3. Protein kinase C, extracellular-regulated kinase 2, and protein tyrosine kinases critically participate in the induction and/or early expression of long-term potentiation at glutamatergic synapses in hippocampus. Protein phosphatases 2A and 2B participate in the induction and/or early expression of long-term depression at these synapses. 4. Treatment of hippocampal slices with scavengers of either superoxide or hydrogen peroxide prevents the full expression of long-term potentiation. Long-term potentiation in hippocampus also is attenuated in transgenic mice that overexpress Cu/Zn superoxide dismutase. 5. The link between reactive oxygen species and long-term potentiation may be the activating effect on protein kinases. The inhibiting effect of reactive oxygen species on protein phosphatases may also contribute to long-term potentiation. 6. The authors hypothesize that reactive oxygen species play a critical role in hippocampal long-term potentiation by favoring the activation of a protein kinase over a protein phosphatase signaling cascade.