The proposed study will examine the mechanisms underlying inward rectification in cloned potassium channels, utilizing a combination of molecular biological and electrophysiological techniques. In previous experiments, novel inward rectifying potassium (Kir) channels were cloned and characterized, and polyamines (spermine, spermidine and putrescine) were identified as soluble factors responsible for intrinsic rectification. Based on background and preliminary data, the hypothesis is developed that polyamines cause intrinsic rectification by voltage-dependent block of the Kir channel pore. In order to extend preliminary data and examine the above hypothesis, four experimental series are proposed to address the following questions: (1) What are the polyamine structural requirements for Kir channel blockade? (2) What pore structures are involved in polyamine block of potassium channels? (3) What does the Kir pore look like to permeating ions and water? (4) Can a theoretical basis be developed for understanding ion channel block by polyamines? The results of the proposed experiments, answering the above questions, will provide detailed insight into the fundamental mechanism of inward rectification, a critical determinant of the functional diversity of potassium channels. Inward rectification is essential for regulation of cell excitability and potassium homeostasis in cardiac, brain and other tissues. The work will therefore provide information that may ultimately underlie the development of rational therapies for the treatment of cardiac arrhythmias, epilepsy and other disorders of cell excitability.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG2-RAP (01))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Schools of Medicine
Saint Louis
United States
Zip Code
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
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
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
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

Showing the most recent 10 out of 74 publications