Mechanisms underlying complex physiological phenotypes: resistance to venoms that are both painful and lethal involve adaptation of both sensory and neuromuscular systems

Life in extreme environments drives the evolution of sensory adaptations that underlie tolerance to painful stimuli. For example, African naked mole rats living communally in subterranean tunnels are resistant to C02induced acidosis pain, thirteen-lined ground squirrels and Syrian hamsters tolerate noxious cold temperatures during hibernation, and Bactrian camels tolerate noxious heat in desert environments.

While reduced sensitivity to pain is beneficial because it enables animals to live in extreme habitats, pain warns of conditions that could potentially damage tissues or cause death. Thus, resistance to pain is often accompanied by adaptation of additional physiological systems. A grand challenge in the 21st century is to understand how changes in gene structure, function and expression cause changes in proteins that underlie complex phenotypes, particularly complex physiological phenotypes associated with behavior (foraging, habitat or host selection, predation). Model systems where the stimulus and target gene can be identified and manipulated are tractable for sorting out the connection between genes, physiology and behavior. Interactions between scorpion mice and their chemically defended prey provide just such a system.

Predatory scorpion mice hunt AZ bark scorpions whose venom causes burning, stinging pain. Scorpion mice are resistant to venom pain via molecular changes to Nav1.8 that block transmission of pain signals to the brain. By reducing their sensitivity to venom pain, scorpion mice are able to exploit an abundant, nutritious food resource. However, bark scorpion venom is not only painful, it is deadly. Bark scorpion venom kills vulnerable animals through asphyxiation – the diaphragm stops contracting and animals cannot breathe. Thus, while resistance to pain is beneficial for feeding on bark scorpions, resistance to lethal toxins is necessary for survival.  

This project examines the structural and functional changes to Nav1.4 and Nav1.6 expressed in scorpion mice skeletal muscle and motor neuron, respectively, that impart resistance to lethal scorpion venom peptides.

Ribbon and Space filled computational models of scorpion mice (Onychomys torridus) muscle Nav1.4 (domains: I = red, II = blue, III = yellow, IV = cyan; C-terminal = green). Models generated using Rosetta technology, Vladimir Yarav-Yarovoy, U.C. Davis.

Comparison of space-filled and ribbon filled computational models of muscle Nav1.4 Domain I from Human, OA (Onychomys arenicola, Means scorpion mouse) and OT (O. torridus, southern scorpion mouse). Amino acid substitutions change the topography (left, middle) and the charge (right) at corresponding positions in domain I. Models generated by Rosetta technology, Vladimir Yarov-Yarovoy ( A. Rowe, J. Kline & V. Yarov- Yarovoy, unpublished.

Peak Na+ current traces from Rat, Gmouse (O. torridus, southern scorpion  mouse) and Mouse (house mouse) Nav1.4. Na+ current recorded from Xenopus oocytes expressing Nav1.4 cRNA for each species. ( A. Parigi & A. Rowe, unpublished data).