Ion channels regulate excitability in many tissues, and multiple diseases result from mutations of ion channel genes. This project is focused on one class of potassium channels, the inward rectifying (Kir) channels. To date, it has been determined that soluble cytoplasmic polyamines cause inward rectification in strong inward rectifiers, together with the location of polyamine block and gating within the channel. Extensive preliminary data now lead us to novel hypotheses regarding the molecular details of channel permeation, block, and gating. These hypotheses will be critically examined in the proposed experiments, utilizing a unique model system consisting of recombinant bacterial Kir channel homolog, amenable to a combination of physical, biochemical and electrophysiological techniques, together with molecular modeling to define the physical basis of Kir channel function.
Relevance. Kir channels are critical for the function of many tissues and organs. Mutations of Kir channels can cause cardiac arrhythmias, epilepsies, diabetes and other disorders of cell excitability. In understanding how these Kir channels operate, how they can be blocked and gated, this work will provide fundamental information that will explain how Kir channels function and thereby provide for the development of rational therapies for treatment of these diseases.
|Zubcevic, Lejla; Bavro, Vassiliy N; Muniz, Joao R C et al. (2014) Control of KirBac3.1 potassium channel gating at the interface between cytoplasmic domains. J Biol Chem 289:143-51|
|Sala-Rabanal, Monica; Li, Dan C; Dake, Gregory R et al. (2013) Polyamine transport by the polyspecific organic cation transporters OCT1, OCT2, and OCT3. Mol Pharm 10:1450-8|
|Kurata, Harley T; Akrouh, Alejandro; Li, Jenny B W et al. (2013) Scanning the topography of polyamine blocker binding in an inwardly rectifying potassium channel. J Biol Chem 288:6591-601|
|D'Avanzo, Nazzareno; McCusker, Emily C; Powl, Andrew M et al. (2013) Differential lipid dependence of the function of bacterial sodium channels. PLoS One 8:e61216|
|D'Avanzo, Nazzareno; Lee, Sun-Joo; Cheng, Wayland W L et al. (2013) Energetics and location of phosphoinositide binding in human Kir2.1 channels. J Biol Chem 288:16726-37|
|Wang, Shizhen; Lee, Sun-Joo; Heyman, Sarah et al. (2012) Structural rearrangements underlying ligand-gating in Kir channels. Nat Commun 3:617|
|Cheng, Wayland W L; McCoy, Jason G; Thompson, Ameer N et al. (2011) Mechanism for selectivity-inactivation coupling in KcsA potassium channels. Proc Natl Acad Sci U S A 108:5272-7|
|D'Avanzo, Nazzareno; Hyrc, Krzysztof; Enkvetchakul, Decha et al. (2011) Enantioselective protein-sterol interactions mediate regulation of both prokaryotic and eukaryotic inward rectifier K+ channels by cholesterol. PLoS One 6:e19393|
|Cheng, Wayland W L; D'Avanzo, Nazzareno; Doyle, Declan A et al. (2011) Dual-mode phospholipid regulation of human inward rectifying potassium channels. Biophys J 100:620-8|
|McCusker, Emily C; D'Avanzo, Nazzareno; Nichols, Colin G et al. (2011) Simplified bacterial "pore" channel provides insight into the assembly, stability, and structure of sodium channels. J Biol Chem 286:16386-91|
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