In hypokalemia or lowered extracellular K+ levels, human cardiac cells can become paradoxically depolarized inconsistent with the Nernst equation for K+. Such paradoxical depolarization has been observed for over thirty years. It is also crucial to the etiology of hypokalemia-induced cardiac arrhythmia. However, its molecular mechanism is not well understood. Ion selectivity of K+ channels is generally considered to be static and not changed in response to physiological stimuli. How K+ channels select K+ over other monovalent cations still remains an unsolved question. Particularly, ion selectivity and the selectivity filter of dimeric two-pore domain K+ channels (K2P) are less understood compared to those in tetrameric K+ channels. Our long-term goal is to understand physiological roles of K+ channels and molecular mechanisms of K+ channel function. The objective of this proposal is to explore functional roles of TWIK-1, the first cloned member of mammalian K2P channels in human cardiomyocytes in hypokalemia, and to characterize dynamic behaviors in ion selectivity and permeability of K2P channels. Based on studies in the past thirty years, the implications that are derived from these studies, and our preliminary studies on cloned TWIK-1 K+ channels, we hypothesize: 1) TWIK-1 K+ channels respond to challenges of lowered extracellular K+ levels and contribute to paradoxical depolarization in human cardiomyocytes in hypokalemia by changing ion selectivity and conducting inward leak Na+ currents; 2) K2P channels can adjust the conformations of the selectivity filter and exhibit dynamic behaviors in ion selectivity and permeability for monovalent cations. By employing standard methods and conventional approaches in the field of ion channels and electrophysiology, we will test these hypotheses in two specific aims: 1) Investigate how TWIK-1 K+ channels regulate the resting potential and action potential of human primary cardiomyocytes in both normal and hypokalemic conditions. 2) Study ion selectivity and permeability of K2P channels for small alkali metal ions and large organic monovalent cations in the absence of intracellular K+. The proposed research will demonstrate physiological roles of TWIK-1 K+ channels in human cardiomyocytes, describe a novel mechanism that regulates cardiac excitability, provide novel insights on the understanding of paradoxical depolarization in the heart in hypokalemia, and shed light on the etiology of hypokalemia-induced cardiac arrhythmias. It will also introduce the concept of dynamic ion selectivity of K+ channels under physiological conditions, provide evidence of a flexible K+ selectivity filter, which supports or supplements well-known hypotheses regarding ion selectivity of K+ channels, and improve the understanding of ion selectivity and the selectivity filter of K2P channels.

Public Health Relevance

Hypokalemia refers to lower-than-normal blood potassium levels, which can cause human cardiac disorders. A phenomenon called 'paradoxical depolarization' is crucial to the pathological mechanism of hypokalemia-induced cardiac disorders. The goal of this project is: 1) to understand the mechanism of such a phenomenon, by studying a gene or a genetic molecule in the human heart, which function is not known; 2) to characterize novel behaviors of twelve genes or molecules in the same family. This research will provide novel insights for hypokalemia-induced cardiac disorders, possibly suggesting new methods for cardio-protection and treatment of cardiac disorders.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Biophysics of Neural Systems Study Section (BPNS)
Program Officer
Nie, Zhongzhen
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
State University of New York at Albany
Schools of Arts and Sciences
United States
Zip Code
Chen, Kuihao; Zuo, Dongchuan; Liu, Zheng et al. (2018) Kir2.1 channels set two levels of resting membrane potential with inward rectification. Pflugers Arch 470:599-611
Chen, Kuihao; Zuo, Dongchuan; Wang, Sho-Ya et al. (2018) Kir2 inward rectification-controlled precise and dynamic balances between Kir2 and HCN currents initiate pacemaking activity. FASEB J 32:3047-3057
Zuo, Dongchuan; Chen, Kuihao; Zhou, Min et al. (2017) Kir2.1 and K2P1 channels reconstitute two levels of resting membrane potential in cardiomyocytes. J Physiol 595:5129-5142
Chen, Haijun; Zuo, Dongchuan; Zhang, Jianing et al. (2014) Classification of 2-pore domain potassium channels based on rectification under quasi-physiological ionic conditions. Channels (Austin) 8:503-8
Chen, Haijun; Chatelain, Franck C; Lesage, Florian (2014) Altered and dynamic ion selectivity of K+ channels in cell development and excitability. Trends Pharmacol Sci 35:461-9
Ma, Liqun; Zhang, Xuexin; Zhou, Min et al. (2012) Acid-sensitive TWIK and TASK two-pore domain potassium channels change ion selectivity and become permeable to sodium in extracellular acidification. J Biol Chem 287:37145-53