Zhang, Shetuan - Queen's University - Department of Biomedical and Molecular Sciences

个人简介

Ion channel function and cardiac arrhythmias Electrical signals generated by ion channels control many biological processes including rhythmic heartbeat. We are studying cardiac ion channel functions and their roles in cardiac arrhythmias and sudden cardiac death. We currently focus on voltage-gated potassium channels encoded by the human Ether-a-go-go-Related Gene (hERG). Mutations in hERG and certain common medications can impair hERG function and cause Long QT Syndrome (LQTS), a cardiac electrical disorder associated with life-threatening arrhythmias and sudden death. We employ molecular biology and electrophysiology techniques in cell lines and animal models to study hERG expression and function under physiological and pathophysiological conditions. Our work has revealed that extracellular potassium is required for the function and expression of hERG channels, and a reduction of serum potassium concentration, clinically known as hypokalemia, can cause LQTS through reducing hERG expression. Current projects include drug-hERG interactions, molecular pathways regulating hERG expression levels, and mechanisms through which LQTS-causing mutations decrease hERG activity.

研究领域

Molecular Mechanisms of Ion Channel Function in Health and Heart Disease HERG is a potassium channel important for cardiac repolarization. Mutations in HERG and drugs can impair HERG function and cause arrhythmias and sudden death. Our research addresses the cellular and molecular mechanisms of cardiac arrhythmias by studying a variety of ion channels with a focus on HERG. Current projects include: 1. The structural basis of K+ channel activity The project focuses on understanding which parts of the channel protein are involved in the channel's opening and closing. We are also interested in other components that interact with the channel to control its function. These components include K+ channel beta subunits (minK - related peptides), protein kinases, and ions (e.g. K+) which permeate through the channels. 2. Mechanisms of drug-HERG channel interaction Many drugs can block HERG channels and potentially lead to lethal cardiac arrhythmias, which represent a major concern in cardiovascular drug safety. We are interested in the mechanisms of drug-HERG channel interactions. Such knowledge is useful for the prevention and treatment of cardiac arrhythmias. 3. The role of potassium channels in cell physiology The project concerns the role of potassium channels in the overall electrical activities of cardiac cells by manipulating K+ channel expression levels in primary culture of cardiac myocytes and in animal models. The project aims to provide fundamental insights into the pathogenesis of cardiac arrhythmias and to explore innovative anti-arrhythmic therapies.

近期论文

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Lamothe SM, Guo J, Li W, Yang T, Zhang S. The Human Ether-a-go-go-Related Gene (hERG) Potassium Channel Represents an Unusual Target for Protease-mediated Damage. J Biol Chem. 291:20387-20401, 2016. PMID: 27502273 Zhao Y, Wang T, Guo J, Yang T, Li W, Koichopolos J, Lamothe SM, Kang Y, Ma A, Zhang S. Febrile temperature facilitates hERG/IKr degradation through an altered K+ dependence. Heart Rhythm. 13:2004-2011, 2016. PMID: 27321242 Lamothe SM, Zhang S. Ubiquitination of Ion Channels and Transporters. Book Chapter: Prog Mol Biol Transl Sci. 141:161-223, 2016. PMID: 27378758 Hogan-Cann A, Li W, Guo J, Yang T, Zhang S. Proteolytic cleavage in the S1-S2 linker of the Kv1.5 channel does not affect channel function. Biochim Biophys Acta. Jun;1858(6):1082-1090, 2016. PMID: 26874203 Kang Y, Guo J, Yang T, Li W, Zhang S. Regulation of the human ether-a-go-go-related gene (hERG) potassium channel by Nedd4 family interacting proteins (Ndfips). Biochem J. 472(1):71-82, 2015. PMID: 26363003 Chen J, Guo J, Yang T, Li W, Lamothe SM, Kang Y, Szendrey JA, Zhang S. Rab11-dependent Recycling of the Human Ether-a-go-go-Related Gene (hERG) Channel. J Biol Chem. 290:21101-21113, 2015. PMID: 26152716 Wang T, Hogan-Cann A, Kang Y, Cui Z, Guo J, Yang T, Lamothe SM, Li W, Ma A, Fisher JT, Zhang S. Muscarinic Receptor Activation Increases hERG Channel Expression through Phosphorylation of Ubiquitin Ligase Nedd4-2. Mol Pharmacol. 85:877-886, 2014. PMID: 24688054 Cui Z and Zhang S. Regulation of the Human Ether-a-go-go-Related Gene (hERG) Channel by Rab4 Through Neural Precursor Cell-expressed Developmentally Downregulated Protein 4-2 (Nedd4-2). J Biol Chem. 288:21876-21886, 2013. PMID: 23792956 Lamothe S and Zhang S. The Serum- and Glucocorticoid-Inducible Kinase SGK1 and SGK3 Regulate hERG Channel Expression via Ubiquitin Ligase Nedd4-2 and GTPase Rab11. J Biol Chem. 288:15075-15084, 2013. PMID: 23589291 Guo J, Wang T, Li X, Shallow H, Yang T, Li W, Xu J, Fridman MD, Yang X and Zhang S. Cell surface expression of hERG channels is regulated by caveolin-3 via Nedd4-2. J Biol Chem. 287:33132-33141, 2012. PMID: 22879586 Guo J, Wang T, Yang T, Xu J, Li W, Fridman MD, Fisher JT and Zhang S. Interaction between the cardiac rapidly (IKr) and slowly (IKs) activating delayed rectifier potassium channels revealed by low K+-induced endocytic degradation. J Biol Chem. 286:34664-34674, 2011. PMID: 21844197 Guo J, Li X, Shallow H, Xu J, Yang T, Massaeli H, Li W, Sun T, Pierce G and Zhang S. Involvement of caveolin in probucol-induced reduction in hERG plasma-membrane expression. Mol Pharmacol. 79:806-813, 2011. PMID: 21278233 Sun T, Guo J, Shallow H, Yang T, Xu J, Li W, Hanson C, Wu JG, Li X, Massaeli H and Zhang S. The role of monoubiquitination in endocytic degradation of Human Ether-a-go-go-Related Gene (hERG) channels under low K+ conditions. J Biol Chem. 286:6751–6759, 2011. PMID: 21177251