Abstract
Calpain is a ubiquitous calcium-dependent cysteine protease, whose cytoskeletal protein substrates suggest that it may be important in neuronal differentiation. Lead (Pb 2+) is known to substitute for Ca 2+ in a variety of intracellular processes, and interferes with the development of hippocampal neurons in vitro. We found that free Pb 2+ at 1 nM does not activate calpain in the absence of Ca 2+. Pb 2+ inhibited the activity of calpain; the degree of calpain inhibition was dependent on an interaction between concentrations of both Ca 2+ and Pb 2+. In the presence of 1 μM free Ca 2+, 10 pM free Pb 2+ reduced calpain activity, but in the presence of 100 μM free Ca 2+, 1 nM free Pb 2+ failed to inhibit calpain. This provides evidence that Pb 2+ competes for the Ca 2+ binding sites on calpain. In the presence of 40 μM free Ca 2+, 1 nM free Pb 2+ significantly reduces V max without altering K m, suggesting that Pb 2+ acts as a noncompetitive inhibitor of calpain. Inhibition of calpain is one mechanism by which Pb 2+ may interfere with neuronal development.
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