Publications

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Ion channel proteins regulate complex patterns of cellular electrical activity and ionic signaling. Certain K+ channels play an important role in immunological biodefense mechanisms of adaptive and innate immunity. Most ion channel proteins are oligomeric complexes with the conductive pore located at the central subunit interface. The long-term activity of many K+ channel proteins is dependent on the concentration of extracellular K+; however, the mechanism is unclear. Thus, this project focused on mechanisms underlying structural stability of tetrameric K+ channels. Using KcsA of Streptomyces lividans as a model K+ channel of known structure, the molecular basis of tetramer stability was investigated by: 1. Bioinformatic analysis of the tetramer interface. 2. Effect of two local anesthetics (lidocaine, tetracaine) on tetramer stability. 3. Molecular simulation of drug docking to the ion conduction pore. The results provide new insights regarding the structural stability of K+ channels and its possible role in cell physiology.

In many respects tetrodotoxin (TTX) is the quintessential natural toxin. It is unequivocally toxic to mammals with LD50 values for mice in the range of 10 μg/kg (intraperitoneal), 16 μg/kg (subcutaneous), and 332 μg/kg (oral) (Kao, 1966). Its biothreat status is recognized by its listing as a " Select Agent" by the US Department of Health and Human Services which includes regulated agents " determined to have the potential to pose a severe threat to both human and animal health" (http://www.selectagents.gov/). It has a well-defined cellular target (i.e., NaV channels) and pharmacological mode of action (i.e., block of nerve and muscle action potentials), and it is an indispensable chemical tool in neuroscience. It is widely distributed in marine and terrestrial ecosystems where it plays a role in the chemical ecology of predator-prey relationships and drives evolutionary selection of TTX-resistance (Hanifin, 2010; Williams, 2010; Zimmer and Ferrer, 2007). Lastly, TTX has acquired a certain mystique in scientific lore attributable to many fascinating aspects of its natural history and molecular interactions as presented in selected summary below. Additional information may be found in other excellent reviews (Fozzard and Lipkind, 2010; Kao, 1966; Lee and Ruben, 2008; Narahashi, 2001, 2008). © 2012.

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