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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Biophysics of Neural Systems Study Section (BPNS)
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Wang, Lan-Hsiang
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Washington University
Anatomy/Cell Biology
Schools of Medicine
Saint Louis
United States
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Wang, Shizhen; Borschel, William F; Heyman, Sarah et al. (2017) Conformational changes at cytoplasmic intersubunit interactions control Kir channel gating. J Biol Chem 292:10087-10096
Sala-Rabanal, Monica; Yurtsever, Zeynep; Berry, Kayla N et al. (2017) Modulation of TMEM16A channel activity by the von Willebrand factor type A (VWA) domain of the calcium-activated chloride channel regulator 1 (CLCA1). J Biol Chem 292:9164-9174
Borschel, William F; Wang, Shizhen; Lee, Sunjoo et al. (2017) Control of Kir channel gating by cytoplasmic domain interface interactions. J Gen Physiol 149:561-576
Wang, Shizhen; Vafabakhsh, Reza; Borschel, William F et al. (2016) Structural dynamics of potassium-channel gating revealed by single-molecule FRET. Nat Struct Mol Biol 23:31-36
Méndez-González, Miguel P; Kucheryavykh, Yuriy V; Zayas-Santiago, Astrid et al. (2016) Novel KCNJ10 Gene Variations Compromise Function of Inwardly Rectifying Potassium Channel 4.1. J Biol Chem 291:7716-26
Lee, Sun-Joo; Ren, Feifei; Zangerl-Plessl, Eva-Maria et al. (2016) Structural basis of control of inward rectifier Kir2 channel gating by bulk anionic phospholipids. J Gen Physiol 148:227-37
Linder, Tobias; Wang, Shizhen; Zangerl-Plessl, Eva-Maria et al. (2015) Molecular Dynamics Simulations of KirBac1.1 Mutants Reveal Global Gating Changes of Kir Channels. J Chem Inf Model 55:814-22
Li, Dan C; Nichols, Colin G; Sala-Rabanal, Monica (2015) Role of a Hydrophobic Pocket in Polyamine Interactions with the Polyspecific Organic Cation Transporter OCT3. J Biol Chem 290:27633-43
Sala-Rabanal, Monica; Yurtsever, Zeynep; Nichols, Colin G et al. (2015) Secreted CLCA1 modulates TMEM16A to activate Ca(2+)-dependent chloride currents in human cells. Elife 4:
Zubcevic, Lejla; Wang, Shizhen; Bavro, Vassiliy N et al. (2015) Modular Design of the Selectivity Filter Pore Loop in a Novel Family of Prokaryotic 'Inward Rectifier' (NirBac) channels. Sci Rep 5:15305

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