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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL054171-16
Application #
8197416
Study Section
Biophysics of Neural Systems Study Section (BPNS)
Program Officer
Wang, Lan-Hsiang
Project Start
1995-05-01
Project End
2013-08-14
Budget Start
2011-12-01
Budget End
2013-08-14
Support Year
16
Fiscal Year
2012
Total Cost
$266,000
Indirect Cost
$91,000
Name
Washington University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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 23:31-6
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
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
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
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
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
Fürst, Oliver; Nichols, Colin G; Lamoureux, Guillaume et al. (2014) Identification of a cholesterol-binding pocket in inward rectifier K(+) (Kir) channels. Biophys J 107:2786-96
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
Lee, Sun-Joo; Wang, Shizhen; Borschel, William et al. (2013) Secondary anionic phospholipid binding site and gating mechanism in Kir2.1 inward rectifier channels. Nat Commun 4:2786
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

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