Myotoxin a reduces the threshold for calcium-induced calcium release in skeletal muscle

Abstract

M. L. Yudkowsky, J. Beech and J. E. Fletcher. Myotoxin a reduces the threshold for calcium-induced calcium release in skeletal muscle. Toxicon 32, 273–278, 1994.—Myotoxin a, isolated from the venom of the prairie rattlesnake Crotalus viridis viridis, induces necrosis in skeletal muscle. In isolated organelles, it has been reported that myotoxin a reduces Ca 2+ uptake into the sarcoplasmic reticulum. The effects of the toxin on Ca 2+ regulation were examined in heavy sarcoplasmic reticulum fractions from human and equine skeletal muscle. Ca 2+ uptake and release (the threshold of Ca 2+-induced Ca 2+ release) were examined by dual wavelength spectrophotometry. The toxin lowered the threshold of Ca 2+-induced Ca 2+ release in a dose-dependent manner (1–10 μM) and this effect was antagonized by ruthenium red, a Ca 2+ release channel blocker. Ca 2+ uptake into equine heavy sarcoplasmic reticulum was not decreased by myotoxin a (10 μM) when Ca 2+ release was blocked by ruthenium red. [ 3H]Ryanodine binding to equine heavy sarcoplasmic reticulum was converted from a relatively low affinity state to a higher affinity state by myotoxin a. These results suggest that the dominant effect of myotoxin a is to increase the Ca 2+ sensitivity for the opening of the calcium release channel (ryanodine receptor). Myotoxin a may prove to be a useful tool to probe the modulation of calcium release in sarcoplasmic reticulum fractions.