Snake a-Neurotoxins and the Nicotinic Acetylcholine Receptor

Abstract

α-Neurotoxins from snake venoms act on postsynaptic nicotinic acetylcholine receptors at the neuromuscular junction to produce clinically significant skeletal muscle paralysis following envenomation. From the seminal discovery almost 50 years ago of α-bungarotoxin, the prototypical α-neurotoxin, our knowledge of the composition of snake venoms, snake envenomation and its treatment, physiology of the neuromuscular junction, structure and function of nicotinic acetylcholine receptors, protein-protein interactions, and pathophysiological mechanisms that underpin diseases like myasthenia gravis has grown exponentially. The potential for the discovery of therapeutic lead compounds from snake venoms has also been advanced. This review looks back at the historical milestones of this research; highlights the challenges of nomenclature pertaining to the increasing number of novel toxins; provides an overview of nicotinic acetylcholine receptors and their subtypes; discusses the classification of snake α-neurotoxins; describes the three-finger protein fold that is the characteristic scaffold of most snake α-neurotoxins, while noting the unique exceptions; details the pharmacology of snake α-neurotoxins including their mechanisms of neuromuscular blockade, reversibility of blockade, and differential binding affinities for the two different acetylcholine-binding sites on the muscle nicotinic receptor; and lastly, delivers an updated and in-depth analysis of the structure-function relationships of the α-neurotoxin–nicotinic acetylcholine receptor interaction, including information gleaned from mutational, computer modeling, and structural studies of complexes formed between α-neurotoxins and receptor components or homologues. These new facets in toxinology have significantly broadened the scope of α-neurotoxins in scientific discovery as well as their therapeutic potential.