Mitochondria and sarcoplasmic reticulum as model targets for neurotoxic and myotoxic phospholipases A2

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Certain neurotoxins and myotoxins from snake venoms have phospholipase A2 activity (phosphatide 2-acylhydrolase, EC 3.1.1.4), which appears to be necessary for their toxicity. Several of these toxins inhibit the net uptake of Ca2+ into sarcoplasmic reticulum vesicles and brain mitochondria. We have obtained evidence that the ability to inhibit this Ca2+ uptake is a mechanistically relevant correlate of the toxicity of these proteins rather than being just a nonspecific consequence of their phospholipase A2 activity. Two of the toxins, β-bungarotoxin and notexin, had 5% and 50%, respectively, of the phospholipase A2 activity of IVa phospholipase A2(a nontoxic enzyme), but β-bungarotoxin was as effective as IVa in inhibiting Ca2+ uptake into brain mitochondria and notexin was more effective. Each of the myotoxic enzymes substantially inhibited Ca2+ uptake into sarcoplasmic reticulum, notexin being the most effective in this regard. This ability correlated better with their myotoxic potency than with their phospholipase A2 activity. β-Bungarotoxin lost its toxicity but not its measurable phospholipase A2 activity after modification with ethoxyformic anhydride in the presence of dihexanoylphosphatidylcholine. The modified toxin also lost most of its ability to inhibit Ca2+ uptake into sarcoplasmic reticulum and brain mitochondria. Sarcoplasmic reticulum vesicles reconstituted from solubilized sarcoplasmic reticulum retained their sensitivity to notexin.

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