Inward rectifying potassium (Kir) channels regulate excitability in many tissues, and multiple diseases result from mutations of Kir channel genes. The long-term goal of this project is to understand the molecular details of Kir channel function. Previously, we discovered that soluble cytoplasmic polyamines cause inward rectification and demonstrated their mechanism and sites of action in the channel. We have developed novel systems for large-scale purification of bacterial and human Kir channels, and have succeeded in functional analysis of these recombinant channel proteins in reconstituted membrane systems. Together with ideas generated by recent crystal structures of both pro- and eukaryotic Kir channels, our novel approaches to biochemical and functional analysis of these channels allow us to develop and address exciting new questions and hypotheses regarding the fundamental basis of Kir channel activity. We will determine the molecular mechanisms by which lipids regulate gating in model Kir channels, and the dynamic structural changes that accompany gating, by combinations of biochemical and electrophysiological recordings.

Public Health Relevance

Inward rectifier potassium channels control excitability in many tissues and defects in these channels in humans lead to multiple diseases, including cardiac arrhythmias, diabetes, vascular dysfunction, epilepsy and other disorders of cell excitability. The novel approaches that we have uniquely developed put us in position to bring previously unobtainable insights to the molecular mechanisms of the functioning of these channels. As such, the work will provide fundamental information for developing rational therapies to treat human diseases resulting from channel dysfunction.

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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Krull, Holly
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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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