Is calcineurin a peroxide-specific sensor in T-lymphocytes?

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Abstract
Calcineurin activity in T-lymphocytes has been shown to be sensitive to H2O2. In this report, we investigate the effects of H2O2 and other physiological oxidants on calcineurin activity both in vivo and in vitro. Intracellular calcineurin activity, as determined by NF-AT phosphorylation state and activity, is inhibited by H2O2 but is insensitive to superoxide and NaOCl. Similarly, treatment of T-lymphocytes with NaOCl and paraquat does not drastically alter the activity of calcineurin in crude cell lysate, while H2O2 causes significant inhibition. Sensitivity to H2O2 and NaOCl in vivo correlates with the half-life of each species in cell medium. The intracellular redox potential is unaffected by H2O2 (100 µM) or NaOCl (600 µM), indicating that H2O2 inhibits calcineurin via a direct mechanism that does not involve a change in the cytosolic redox potential. In contrast, calcineurin activity in cell lysate is inhibited by all three oxidants. H2O2 inactivation of calcineurin is rapid, with inactivation occurring in ≤10 s. H2O2 inactivation of calcineurin is reversible in T-lymphocyte lysate using dithiothreitol (DTT) alone, while in rat brain lysate, reversibility requires both DTT and Fe(II), implicating that the enzyme may exist in different metal/redox-sensitive states in different tissues. Electronic supplementary material to this paper, namely Fig. S1 showing the effect of paraquat and NaOCl on NF-AT phosphorylation, can be obtained by using the Springer Link server located at http://dx.doi.org/10.1007/s00775-002-0367-x.

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