Evolution of Tetrodotoxin Sensitivity

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9410565 Anderson Animals such as sea anemones, jellyfish (Phylum Cnidaria) and flatworms (Phylum Platyhelminthes) are modern-day representatives of organisms in which the nervous system, as we know it, first evolved. As such, they present us with a window into the evolution of the early nervous system and of the various molecules that enable nervous systems to function as they do. An evolutionary approach to neurobiological questions has an added benefit inasmuch as it is possible to identify groups of relatively closely related animals that differ subtly in some aspect of their neurobiology. A case in point concerns the action of tetrodotoxin (TTX) a toxin that blocks sodium channels extremely specifically and with high affinity. Tetrodotoxin blocks sodium currents in flatworms and higher animals, but is completely ineffective in jellyfish. Thus one might ask, what are the structural differences between the flatworm and jellyfish sodium channels that account for this differential sensitivity. Armed with this information, it should be relatively easy to identify the equivalent site on mammalian sodium channels thereby enabling the development of new classes of highly specific, and highly potent anesthetics and channel blockers that target this hitherto unexploited site on this very important class of proteins. The overall aim of the proposed work is to take advantage of this difference in the TTX sensitivity of flatworm and cnidarian sodium channels to identify the requirements for TTX binding to sodium channels. In addition to using molecular cloning techniques to determine the primary structure of sodium channels from a sea anemone, and a flatworm, the PI will use conventional lipid analysis and protein biochemical techniques to determine the lipid environment of the native sodium channels in these groups, and the types of sugar moieties linked to these proteins. The PI will compare these data with equivalent data previously obtained from a jell yfish.