Complex Physiological Phenotypes: Structural Variation in the Muscle Voltage-Gated Sodium Channel Imparts Resistance to Lethal Scorpion Toxins

Abstract

SUMMARYExtreme environments drive the evolution of adaptations that underlie tolerance to painful stimuli. However, painful stimuli provide valuable warnings to animals about conditions that could damage tissues or cause death. Thus, reduced pain sensitivity should evolve as part of a phenotype that includes physiological resistance to lethal stimuli. Interactions between Arizona (AZ) bark scorpions and southern grasshopper mice provide an ideal system to investigate complex physiological phenotypes across multiple levels of biological organization. Grasshopper mice prey on AZ bark scorpions, despite the painful and deadly toxins associated with their sting. Adaptation of the pain receptor Nav1.8 imparts grasshopper mice with resistance to painful toxins, but mechanisms underlying resistance to lethal toxins, necessary for survival, remain unknown. The pathophysiological effects of bark scorpion venom include respiratory failure from impaired muscle contraction. Two classes of venom proteins, alpha and beta toxins, enhance activation and delay inactivation in the voltage-gated sodium channel (Nav1.4) that regulates muscle contraction. We show that grasshopper mice soleus muscle is resistant to bark scorpion venom, and that Nav1.4 is resistant to alpha- and beta-toxin effects on channel activation and inactivation. Reduced sensitivity to b-toxin effects on activation is due, in part, to molecular variation at two distinct locations within the channel. Computational models of Nav1.4 revealed that amino acid substitutions alter the biochemical properties of the channel near toxin binding sites. Elucidating the structure-activity relationships in physiologically critical proteins will advance efforts to determine the rules that govern how genotypes interact with the environment to yield complex physiological phenotypes.