Rattlesnake Neurotoxins: Biochemical and Biological Aspects

Abstract

A number of rattlesnake venoms contain potent neurotoxic protein complexes that have phospholipase A₂ activity. Data derived from studies of some of these neurotoxins indicate that neuromuscular transmission is blocked. The primary action appears to be at presynaptic sites, but at high doses interactions with cholinergic receptors reduce postsynaptic responses. The toxin complexes are mixtures of closely related isoforms, each composed of two distinct and separable subunits. The basic protein subunit is a phospholipase which is somewhat toxic whereas the acidic constituent is devoid of toxicity and lacks enzymatic activity. Even though the two subunits have quite different structures, they have considerable sequence similarity, suggesting a common ancestral origin. The acidic subunit enhances the lethal potency of the basic phospholipase component when the two are combined to generate a reconstituted toxin. Evidence suggests the acidic subunit reduces nonspecific binding of the basic phospholipase to membranes, thereby restricting binding of the neurotoxic component to specific sites on toxin sensitive membranes.

This class of toxins has not been used extensively to study subcellular membrane vesicles or cultured cells. Results from some of our studies with isolated rat brain synaptosomes demonstrated that Mojave toxin and the basic subunit isolated from Mojave toxin alter the uptake and release of neurotransmitters. Recent unpublished studies with cultured muscle cells showed marked effects on the fusion process in which primary myoblasts form myotubes. The toxin also reduces the formation of colonies from several clonal myoblast cell lines. The biochemical bases for these observations remain to be determined.