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Block of the human ether-a-go-go-related gene (hERG) K+ channel by the antidepressant desipramine.
Biochem Biophys Res Commun. 2010 Apr 09; 394(3):536-41.BB

Abstract

Desipramine is a tricyclic antidepressant for psychiatric disorders that can induce QT prolongation, which may lead to torsades de pointes. Since blockade of cardiac human ether-a-go-go-related gene (hERG) channels is an important cause of acquired long QT syndrome, we investigated the acute effects of desipramine on hERG channels to determine the electrophysiological basis for its pro-arrhythmic potential. We examined the effects of desipramine on the hERG channels expressed in Xenopus oocytes using two-microelectrode voltage-clamp techniques. Desipramine-induced concentration-dependent decreases in the current amplitude at the end of the voltage steps and hERG tail currents. The IC(50) for desipramine needed to block the hERG current in Xenopus oocytes decreased progressively relative to the degree of depolarization. Desipramine affected the channels in the activated and inactivated states but not in the closed states. The S6 domain mutations, Tyr-652 located in the S6 domain of the hERG channel reduced the potency of the channel block by desipramine more than a mutation of Phe-656 in the same region. These results suggest that desipramine is a blocker of the hERG channels, providing a molecular mechanism for the arrhythmogenic side effects during the clinical administration of desipramine.

Authors+Show Affiliations

Department of Physiology, Institute of Bioscience and Biotechnology, School of Medicine, Kangwon National University, Hyoja-Dong, Chuncheon 200-701, Republic of Korea.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20211602

Citation

Hong, Hee-Kyung, et al. "Block of the Human Ether-a-go-go-related Gene (hERG) K+ Channel By the Antidepressant Desipramine." Biochemical and Biophysical Research Communications, vol. 394, no. 3, 2010, pp. 536-41.
Hong HK, Park MH, Lee BH, et al. Block of the human ether-a-go-go-related gene (hERG) K+ channel by the antidepressant desipramine. Biochem Biophys Res Commun. 2010;394(3):536-41.
Hong, H. K., Park, M. H., Lee, B. H., & Jo, S. H. (2010). Block of the human ether-a-go-go-related gene (hERG) K+ channel by the antidepressant desipramine. Biochemical and Biophysical Research Communications, 394(3), 536-41. https://doi.org/10.1016/j.bbrc.2010.03.010
Hong HK, et al. Block of the Human Ether-a-go-go-related Gene (hERG) K+ Channel By the Antidepressant Desipramine. Biochem Biophys Res Commun. 2010 Apr 9;394(3):536-41. PubMed PMID: 20211602.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Block of the human ether-a-go-go-related gene (hERG) K+ channel by the antidepressant desipramine. AU - Hong,Hee-Kyung, AU - Park,Mi-Hyeong, AU - Lee,Byung Hoon, AU - Jo,Su-Hyun, Y1 - 2010/03/06/ PY - 2010/02/24/received PY - 2010/03/02/accepted PY - 2010/3/10/entrez PY - 2010/3/10/pubmed PY - 2010/5/5/medline SP - 536 EP - 41 JF - Biochemical and biophysical research communications JO - Biochem Biophys Res Commun VL - 394 IS - 3 N2 - Desipramine is a tricyclic antidepressant for psychiatric disorders that can induce QT prolongation, which may lead to torsades de pointes. Since blockade of cardiac human ether-a-go-go-related gene (hERG) channels is an important cause of acquired long QT syndrome, we investigated the acute effects of desipramine on hERG channels to determine the electrophysiological basis for its pro-arrhythmic potential. We examined the effects of desipramine on the hERG channels expressed in Xenopus oocytes using two-microelectrode voltage-clamp techniques. Desipramine-induced concentration-dependent decreases in the current amplitude at the end of the voltage steps and hERG tail currents. The IC(50) for desipramine needed to block the hERG current in Xenopus oocytes decreased progressively relative to the degree of depolarization. Desipramine affected the channels in the activated and inactivated states but not in the closed states. The S6 domain mutations, Tyr-652 located in the S6 domain of the hERG channel reduced the potency of the channel block by desipramine more than a mutation of Phe-656 in the same region. These results suggest that desipramine is a blocker of the hERG channels, providing a molecular mechanism for the arrhythmogenic side effects during the clinical administration of desipramine. SN - 1090-2104 UR - https://www.unboundmedicine.com/medline/citation/20211602/Block_of_the_human_ether_a_go_go_related_gene__hERG__K+_channel_by_the_antidepressant_desipramine_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-291X(10)00433-X DB - PRIME DP - Unbound Medicine ER -