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Tetrodotoxin (TTX) binds to voltage-gated sodium (NaV) channels, blocking the initiation of action potentials and the activity of nerve and muscle fibers. Some salamanders use TTX as an anti-predator defense. These salamanders are resistant to TTX because they express TTX-resistant NaV channels in their nerves and muscles. In vertebrates, NaV channels are encoded by a multi-gene family. Different members of this gene family possess different functional properties and are expressed in different neuromuscular tissues. Cardiac muscle and the cardiac muscle channel (NaV 1.5) of amphibians and many reptiles is TTX-sensitive while NaV 1.5 in mammals (and some reptiles) is TTX-resistant. TTX-resistant channels (NaV 1.4) have also been identified in the skeletal muscle of salamanders that possess TTX and snakes that eat TTX-bearing prey. TTX-resistance of NaV 1.5 of mammals and reptiles results from changes in domain I of the channel, but TTX-resistance in NaV 1.4 from salamanders and snakes results from amino acid substitutions in domains 3 and 4 suggesting that functional requirements play an important role in channel evolution. Cardiac muscle of TTX-bearing salamanders (amphibians) is TTX-resistant, but the molecular basis of resistance unknown. The goals of my project are to answer two questions: 1) Is NaV 1.5 of TTX-bearing salamanders TTX-resistant? 2) Do the changes in Nav 1.5 of salamanders occur in domain I of the protein or do they occur in domains 3 and 4? Completing the goals of this project will improve our understanding of the dynamics of molecular evolution and the physiology of NaV channels.