Channel or """"""""porin"""""""" molecules reside in cellular membranes and regulate the flow of cations, anions, water, and other molecular species through the bilayer. While a great deal is known about what channels do (transport rates, kinetic and open-close behavior, ion selectivity), the chemical mechanisms that underlie these processes remain largely obscure. It is clear that channels are critical for cellular regulation and various diseases result from their malfunction. The amino acid sequences of many channel proteins have been analyzed and various domains within the structures have been identified. Recently, crystal structures for the potassium-selective KcsA channel, a mechanosensitive channel, and of a water-transporting pore have also provided important new insight into the three-dimensional arrangement of the proteins. Important mechanistic insights have accompanied these structural developments. Not withstanding these recent advances, functional understanding of channel behavior remains a profound and important challenge. Of all channel types known in nature, perhaps the least is known about anion channels. We have now succeeded in developing a structurally simple, chemically accessible, modular anion channel we believe will be an important tool for understanding anion channel function. We propose here to develop and study our novel, modular, synthetic chloride-conducting channel using a broad range of techniques applied to natural ion and molecular channels. The biomedical importance of chloride channels became apparent when studies on the pathogenesis of cystic fibrosis demonstrated the CFTR, the cystic fibrosis transport regulator, was a chloride ion channel as well as a regulator of other transport systems. The mutations in this protein that result in systic fibrosis produce the commonest fatal genetic disease of Caucasion humans.
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