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Cardiac glycosides as novel inhibitors of human ether-a-go-go-related gene channel trafficking.
J Pharmacol Exp Ther. 2007 Feb; 320(2):525-34.JP

Abstract

Direct block of the cardiac potassium channel human ether-a-go-go-related gene (hERG) by a large, structurally diverse group of therapeutic compounds causes drug-induced QT prolongation and torsades de pointes arrhythmias. In addition, several therapeutic compounds have been identified more recently that prolong the QT interval by inhibition of hERG trafficking to the cell surface. We used a surface expression assay to identify novel compounds that interfere with hERG trafficking and found that cardiac glycosides are potent inhibitors of hERG expression at the cell surface. Further investigation of digitoxin, ouabain, and digoxin revealed that all three cardiac glycosides reduced expression of the fully glycosylated cell surface form of hERG on Western blots, indicating that channel exit from the endoplasmic reticulum is blocked. Likewise, hERG currents were reduced with nanomolar affinity on long-term exposure. hERG trafficking inhibition was initiated by cardiac glycosides through direct block of Na(+)/K(+) pumps and not via off-target interactions with hERG or another closely associated protein in its processing or export pathway. In isolated guinea pig myocytes, long-term exposure to 30 nM of the clinically used drugs digoxin or digitoxin reduced hERG/rapidly activating delayed rectifier K(+) current (I(Kr)) currents by approximately 50%, whereas three other cardiac membrane currents--inward rectifier current, slowly activating delayed rectifier K(+) current, and calcium current--were not affected. Importantly, 100 nM digitoxin prolonged action potential duration on long-term exposure consistent with a reduction in hERG/I(Kr) channel number. Thus, cardiac glycosides are able to delay cardiac repolarization at nanomolar concentrations via hERG trafficking inhibition, and this may contribute to the complex electrocardiographic changes seen with compounds such as digitoxin.

Authors+Show Affiliations

Rammelkamp Center for Education and Research, Case Western Reserve University, Cleveland, OH 44109, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

17095614

Citation

Wang, Lu, et al. "Cardiac Glycosides as Novel Inhibitors of Human Ether-a-go-go-related Gene Channel Trafficking." The Journal of Pharmacology and Experimental Therapeutics, vol. 320, no. 2, 2007, pp. 525-34.
Wang L, Wible BA, Wan X, et al. Cardiac glycosides as novel inhibitors of human ether-a-go-go-related gene channel trafficking. J Pharmacol Exp Ther. 2007;320(2):525-34.
Wang, L., Wible, B. A., Wan, X., & Ficker, E. (2007). Cardiac glycosides as novel inhibitors of human ether-a-go-go-related gene channel trafficking. The Journal of Pharmacology and Experimental Therapeutics, 320(2), 525-34.
Wang L, et al. Cardiac Glycosides as Novel Inhibitors of Human Ether-a-go-go-related Gene Channel Trafficking. J Pharmacol Exp Ther. 2007;320(2):525-34. PubMed PMID: 17095614.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cardiac glycosides as novel inhibitors of human ether-a-go-go-related gene channel trafficking. AU - Wang,Lu, AU - Wible,Barbara A, AU - Wan,Xiaoping, AU - Ficker,Eckhard, Y1 - 2006/11/09/ PY - 2006/11/11/pubmed PY - 2007/3/14/medline PY - 2006/11/11/entrez SP - 525 EP - 34 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 320 IS - 2 N2 - Direct block of the cardiac potassium channel human ether-a-go-go-related gene (hERG) by a large, structurally diverse group of therapeutic compounds causes drug-induced QT prolongation and torsades de pointes arrhythmias. In addition, several therapeutic compounds have been identified more recently that prolong the QT interval by inhibition of hERG trafficking to the cell surface. We used a surface expression assay to identify novel compounds that interfere with hERG trafficking and found that cardiac glycosides are potent inhibitors of hERG expression at the cell surface. Further investigation of digitoxin, ouabain, and digoxin revealed that all three cardiac glycosides reduced expression of the fully glycosylated cell surface form of hERG on Western blots, indicating that channel exit from the endoplasmic reticulum is blocked. Likewise, hERG currents were reduced with nanomolar affinity on long-term exposure. hERG trafficking inhibition was initiated by cardiac glycosides through direct block of Na(+)/K(+) pumps and not via off-target interactions with hERG or another closely associated protein in its processing or export pathway. In isolated guinea pig myocytes, long-term exposure to 30 nM of the clinically used drugs digoxin or digitoxin reduced hERG/rapidly activating delayed rectifier K(+) current (I(Kr)) currents by approximately 50%, whereas three other cardiac membrane currents--inward rectifier current, slowly activating delayed rectifier K(+) current, and calcium current--were not affected. Importantly, 100 nM digitoxin prolonged action potential duration on long-term exposure consistent with a reduction in hERG/I(Kr) channel number. Thus, cardiac glycosides are able to delay cardiac repolarization at nanomolar concentrations via hERG trafficking inhibition, and this may contribute to the complex electrocardiographic changes seen with compounds such as digitoxin. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/17095614/Cardiac_glycosides_as_novel_inhibitors_of_human_ether_a_go_go_related_gene_channel_trafficking_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=17095614 DB - PRIME DP - Unbound Medicine ER -