Shetuan Zhang Lab

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.

Davis J, Cornwell JD, Campagna N, Guo J, Li W, Yang T, Wang T, Zhang S. Rescue of expression and function of long QT syndrome-causing mutant hERG channels by enhancing channel stability in the plasma membrane. J Biol Chem. 2024 Aug;300(8):107526. doi: 10.1016/j.jbc.2024.107526.
PMID: 38960041

Chakraborty A, Paynter A, Szendrey M, Cornwell JD, Li W, Guo J, Yang T, Du Y, Wang T, Zhang S. Ubiquitination is involved in PKC-mediated degradation of cell surface Kv1.5 channels. J Biol Chem. 2024 Jul;300(7):107483. doi: 10.1016/j.jbc.2024.107483.
PMID: 38897569

El Sherbini A, Liblik K, Lee J, Baranchuk A, Zhang S, El-Diasty M. Opioids-induced inhibition of HERG ion channels and sudden cardiac death, a systematic review of current literature. Trends Cardiovasc Med. 2024 Jul;34(5):279-285. doi: 10.1016/j.tcm.2023.03.006.
PMID: 37015297

Gelman I, Sharma N, Mckeeman O, Lee P, Campagna N, Tomei N, Baranchuk A, Zhang S, El-Diasty M. The ion channel basis of pharmacological effects of amiodarone on myocardial electrophysiological properties, a comprehensive review. Biomed Pharmacother. 2024 May:174:116513. doi: 10.1016/j.biopha.2024.116513.
PMID: 38565056

Liblik K, Zucker J, Baranchuk A, Fernandez AL, Zhang S, El-Diasty M. The role of pericardial fluid biomarkers in predicting post-operative atrial fibrillation, a comprehensive review of current literature. Trends Cardiovasc Med. 2024 May;34(4):244-247. doi: 10.1016/j.tcm.2023.02.009.
PMID: 36863643

Campagna N, Wall E, Lee K, Guo J, Li W, Yang T, Baranchuk A, El-Diasty M, Zhang S. Differential Effects of Remdesivir and Lumacaftor on Homomeric and Heteromeric hERG Channels. Mol Pharmacol. 2023 Oct;104(4):164-173. doi: 10.1124/molpharm.123.000708.
PMID: 37419691

Du Y, Wang T, Guo J, Li W, Yang T, Szendrey M, Zhang S. Activation of protein kinase C induces endocytic degradation of Kv1.5 channels. J Biol Chem. 2021 Jan-Jun:296:100514. doi: 10.1016/j.jbc.2021.100514.
PMID: 33676894

Szendrey M, Guo J, Li W, Yang T, Zhang S. COVID-19 Drugs Chloroquine and Hydroxychloroquine, but Not Azithromycin and Remdesivir, Block hERG Potassium Channels. J Pharmacol Exp Ther. 2021 May;377(2):265-272. doi: 10.1124/jpet.120.000484.
PMID: 33674391

Tschirhart JN, Zhang S. Fentanyl-Induced Block of hERG Channels Is Exacerbated by Hypoxia, Hypokalemia, Alkalosis, and the Presence of hERG1b. Mol Pharmacol. 2020 Oct;98(4):508-517. doi: 10.1124/mol.119.119271.
PMID: 32321735

Milton AO, Wang T, Li W, Guo J, Zhang S. Mechanical stretch increases Kv1.5 current through an interaction between the S1-S2 linker and N-terminus of the channel. J Biol Chem. 2020 Apr 3;295(14):4723-4732. doi: 10.1074/jbc.RA119.011302.
PMID: 32122972

Sutherland-Deveen ME, Wang T, Lamothe SM, Tschirhart JN, Guo J, Li W, Yang T, Du Y, Zhang S. Differential regulation of hERG current and expression by activation of protein kinase C. Mol Pharmacol. 2019 Jul;96(1):1-12. doi: 10.1124/mol.118.115188.
PMID: 31015282

Tschirhart JN, Li W, Guo J, Zhang S. Blockade of the human ether a-go-go related gene (hERG) potassium channel by fentanyl. Mol Pharmacol. 2019 Apr;95(4):386-397. doi: 10.1124/mol.118.114751.
PMID: 30665971

Szendrey J, Lamothe SM, Vanner S, Guo J, Yang T, Li W, Davis J, Joneja M, Baranchuk A, Zhang S. Anti-Ro52 antibody acts on the S5-pore linker of hERG to chronically reduce channel expression. Cardiovasc Res. 2019 Aug 1;115(10):1500-1511. doi: 10.1093/cvr/cvy310
PMID: 30544220

Lamothe SM, Hogan-Cann AE, Li W, Guo J, Yang T, Tschirhart JN, Zhang S. The N terminus and transmembrane segment S1 of Kv1.5 can coassemble with the rest of the channel independent of the S1-S2 linkage. J Biol Chem. 2018 Oct 5;293(40):15347-15358. doi: 10.1074/jbc.RA118.004065.
PMID: 30121572

Lamothe SM, Hulbert M, Guo J, Li W, Yang T, Zhang S. Glycosylation stabilizes hERG channels on the plasma membrane by decreasing proteolytic susceptibility. FASEB J. 2018 Apr;32(4):1933-1943. doi: 10.1096/fj.201700832R.
PMID: 32172531

Lamothe SM, Song W, Guo J, Li W, Yang T, Baranchuk A, Graham CH, Zhang S. Hypoxia reduces mature hERG channels through calpain up-regulation. FASEB J. 2017 Nov;31(11):5068-5077. doi: 10.1096/fj.201700255R.
PMID: 28784631

Sangoi MG, Lamothe SM, Guo J, Yang T, Li W, Avery EG, Fisher JT, Zhang S. β-Arrestin-mediated Regulation of the Human Ether-a-go-go-Related Gene (hERG) Potassium Channel. Mol Pharmacol. 2017 Aug;92(2):162-174. doi: 10.1124/mol.116.108035.
PMID: 28495999

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. 2016 Sep 23;291(39):20387-401. doi: 10.1074/jbc.M116.743138.
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/IKrdegradation through an altered K+ dependence. Heart Rhythm. 2016 Oct;13(10):2004-11. doi: 10.1016/j.hrthm.2016.06.019.
PMID: 27321242

Lamothe SM, Zhang S. Ubiquitination of Ion Channels and Transporters. Book Chapter: Prog Mol Biol Transl Sci. 2016:141:161-223. doi: 10.1016/bs.pmbts.2016.02.005.
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. 2016 Jun;1858(6):1082-90. doi: 10.1016/j.bbamem.2016.02.012.
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. 2015 Nov 15;472(1):71-82. doi: 10.1042/BJ20141282.
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. 2015 Aug 21;290(34):21101-21113. doi: 10.1074/jbc.M115.636324.
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. 2014 Jun;85(6):877-86. doi: 10.1124/mol.113.091553.
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. 2013 Jul 26;288(30):21876-86. doi: 10.1074/jbc.M113.461715.
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. 2013 May 24;288(21):15075-84. doi: 10.1074/jbc.M113.453670.
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. 2012 Sep 28;287(40):33132-41. doi: 10.1074/jbc.M112.389643.
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. 2011 Oct 7;286(40):34664-74. doi: 10.1074/jbc.M111.253351.
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. 2011 May;79(5):806-13. doi: 10.1124/mol.110.069419.
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. 2011 Feb 25;286(8):6751-9. doi: 10.1074/jbc.M110.198408.
PMID: 21177251

Massaeli H, Sun T, Li X, Shallow H, Wu J, Xu J, Li W, Hanson C, Guo J, Zhang S.Involvement of caveolin in low K+-induced endocytic degradation of cell-surface human ether-a-go-go-related gene (hERG) channels. J Biol Chem. 2010 Aug 27;285(35):27259-27264. doi: 10.1074/jbc.M110.124909.
PMID: 20605793

Massaeli H, Guo J, Xu J and Zhang S. Extracellular K+ is a prerequisite for the function and plasma membrane stability of HERG channels. Circ Res. 2010 Apr 2;106(6):1072-82. doi: 10.1161/CIRCRESAHA.109.215970.
PMID: 20133899

Guo J, Massaeli H, Xu J, Jia Z, Wigle JT, Mesaeli N and Zhang S. Extracellular K+ concentration controls cell surface density of IKr in rabbit hearts and of the HERG channel in human cell lines. J Clin Invest. 2009 Sep;119(9):2745-57. doi: 10.1172/JCI39027.
PMID: 19726881

Guo J, Massaeli H, Li W, Xu J, Luo T, Shaw J, Kirshenbaum L and Zhang S. Identification of IKr and its trafficking disruption induced by probucol in cultured neonatal rat cardiomyocytes. J Pharmacol Exp Ther. 2007 Jun;321(3):911-20. doi: 10.1124/jpet.107.120931.
PMID: 17377062

Gang H and Zhang S. Na+ permeation and block of hERG potassium channels. J Gen Physiol. 2006 Jul;128(1):55-71. doi: 10.1085/jgp.200609500.
PMID: 16769794

Guo J, Gang H, and Zhang S. Molecular determinants of cocaine block of human ether-a-go-go-related gene potassium channels. J Pharmacol Exp Ther. 2006 May;317(2):865-74. doi: 10.1124/jpet.105.098103.
PMID: 16397089

Zhang S. Isolation and characterization of IKr in cardiac myocytes by Cs+ permeation. Am J Physiol Heart Circ Physiol. 2006 Mar;290(3):H1038-49. doi: 10.1152/ajpheart.00679.2005.
PMID: 16227343

Summer 2024