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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM063190-01A2
Application #
6547020
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Schwab, John M
Project Start
2002-06-01
Project End
2006-05-31
Budget Start
2002-06-01
Budget End
2003-05-31
Support Year
1
Fiscal Year
2002
Total Cost
$305,235
Indirect Cost
Name
Washington University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Daschbach, Megan M; Negin, Saeedeh; You, Lei et al. (2012) Aggregation and supramolecular membrane interactions that influence anion transport in tryptophan-containing synthetic peptides. Chemistry 18:7608-23
Wang, Wei; Li, Ruiqiong; Gokel, George W (2009) Membrane-length amphiphiles exhibiting structural simplicity and ion channel activity. Chemistry 15:10543-53
You, Lei; Ferdani, Riccardo; Li, Ruiqiong et al. (2008) Carboxylate anion diminishes chloride transport through a synthetic, self-assembled transmembrane pore. Chemistry 14:382-96
Elliott, Elizabeth K; Daschbach, Megan M; Gokel, George W (2008) Aggregation behavior and dynamics of synthetic amphiphiles that self-assemble to anion transporters. Chemistry 14:5871-9
You, Lei; Gokel, George W (2008) Fluorescent, synthetic amphiphilic heptapeptide anion transporters: evidence for self-assembly and membrane localization in liposomes. Chemistry 14:5861-70
You, Lei; Li, Ruiqiong; Gokel, George W (2008) Anion transport properties of amine and amide-sidechained peptides are affected by charge and phospholipid composition. Org Biomol Chem 6:2914-23
Yamnitz, Carl R; Gokel, George W (2007) Synthetic, biologically active amphiphilic peptides. Chem Biodivers 4:1395-412
Gokel, George W; Carasel, I Alexandru (2007) Biologically active, synthetic ion transporters. Chem Soc Rev 36:378-89
Ferdani, Riccardo; Gokel, George W (2006) Planar bilayer studies reveal multiple conductance states for synthetic anion transporters. Org Biomol Chem 4:3746-50
Pajewski, Robert; Garcia-Medina, Raquel; Brody, Steven L et al. (2006) A synthetic, chloride-selective channel that alters chloride transport in epithelial cells. Chem Commun (Camb) :329-31

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