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.
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.
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. pii: mol.118.115188. doi: 10.1124/mol.118.115188. 2019 Apr 23. [Epub ahead of print]
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. doi: 10.1093/cvr/cvy310. 2018 Dec 13. [Epub ahead of print]
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. 293:15347-15358, 2018.
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. 32:1933-1943, 2018.
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. 31:5068-5077, 2017.
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. 92:162-174, 2017.
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.
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. 13:2004-2011, 2016.
Lamothe SM, Zhang S. Ubiquitination of Ion Channels and Transporters. Book Chapter: Prog Mol Biol Transl Sci. 141:161-223, 2016.
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;1858:1082-1090, 2016.
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. 472:71-82, 2015.
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.
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.
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.
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.
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.
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.
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.
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.
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. 285:27259-27264, 2010.
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. 106:1072-1082, 2010.
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. 119:2745-2757, 2009.
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. 321:911-920, 2007.
Gang H and Zhang S. Na+ permeation and block of hERG potassium channels. J Gen Physiol. 128:55-71, 2006.
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. 317:865-874, 2006.
Zhang S. Isolation and characterization of IKr in cardiac myocytes by Cs+ permeation. Am J Physiol Heart Circ Physiol. 290:H1038-H1049, 2006.
Lin J, Guo J, Gang H, Wojciechowski P, Wigle JT, Zhang S. Intracellular K+ is required for the inactivation-induced high-affinity binding of cisapride to HERG channels. Mol Pharmacol. 68:855-865, 2005.
Zhang S, Eduljee C, Kwan DC, Kehl SJ, Fedida D. Constitutive inactivation of the hKv1.5 mutant channel, H463G, in K+-free solutions at physiological pH. Cell Biochem Biophys. 43:221-230, 2005.
Zhang S, Kehl SJ, Fedida D. Modulation of human ether-a-go-go-related K+ (HERG) channel inactivation by Cs+ and K+. J Physiol. 548:691-702, 2003.
Zhang S, Kurata HT, Kehl SJ, Fedida D. Rapid induction of P/C-type inactivation is the mechanism for acid-induced K+ current inhibition. J Gen Physiol. 121:215-225, 2003.
Zhang S, Rajamani S, Chen Y, Gong Q, Rong Y, Zhou Z, Ruoho A, January CT. Cocaine blocks HERG, but not KvLQT1+minK, potassium channels. Mol Pharmacol. 59:1069-1076, 2001.
Zhang S, Kehl SJ, Fedida D. Modulation of Kv1.5 potassium channel gating by extracellular zinc. Biophys J. 81:125-136, 2001.
Zhang S, Kwan DCH, Fedida D, Kehl SJ. External K+ relieves the block but not the gating shift caused by Zn2+ in human Kv1.5 channels. J Physiol. 532:349-358, 2001.
Zhang S, Zhou Z, Gong Q, Makielski JC, January CT. Mechanism of block and identification of the verapamil binding domain to HERG potassium channels. Circ Res. 84:989-998, 1999.
Zhang S, Hirano Y, Hiraoka M. Arginine vasopressin-induced potentiation of unitary L-type Ca2+ channel current in guinea pig ventricular myocytes. Circ Res. 76:592-599, 1995.