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Clomipramine block of the hERG K+ channel: accessibility to F656 and Y652.
Eur J Pharmacol. 2008 Sep 11; 592(1-3):19-25.EJ

Abstract

Clomipramine 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 clomipramine on hERG channels to determine the electrophysiological basis for its proarrhythmic potential. We examined the effects of clomipramine on the hERG channels expressed in Xenopus oocytes and HEK293 cells using two-microelectrode voltage-clamp and patch-clamp techniques. Clomipramine induced a concentration-dependent decrease in the current amplitude at the end of the voltage steps and hERG tail currents. The IC50 for clomipramine needed to block the hERG current in Xenopus oocytes decreased progressively relative to the degree of depolarization. The fractional electrical distance was estimated to be delta=0.83. The IC50 for the clomipramine-induced blockade of the hERG currents in HEK293 cells at 36 degrees C was 0.13 microM at +20 mV. Clomipramine affected the channels in the activated and inactivated states but not in the closed states. The clomipramine-induced blockade of hERG was found to be use-dependent, exhibiting a more rapid onset and a greater steady-state block at the higher frequencies of activation. The S6 domain mutations, Y652A and F656A partially attenuated (Y652A) or abolished (F656A) the hERG-current blockade. These results suggest that clomipramine is a blocker of the hERG channels, providing a molecular mechanism for the arrhythmogenic side effects during the clinical administration of clomipramine.

Authors+Show Affiliations

Department of Physiology, Institute of Bioscience and Biotechnology, Kangwon National University College of Medicine, Chuncheon 200-701, Korea. suhyunjo@kangwon.ac.krNo affiliation info availableNo affiliation info availableNo 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

18634780

Citation

Jo, Su-Hyun, et al. "Clomipramine Block of the hERG K+ Channel: Accessibility to F656 and Y652." European Journal of Pharmacology, vol. 592, no. 1-3, 2008, pp. 19-25.
Jo SH, Hong HK, Chong SH, et al. Clomipramine block of the hERG K+ channel: accessibility to F656 and Y652. Eur J Pharmacol. 2008;592(1-3):19-25.
Jo, S. H., Hong, H. K., Chong, S. H., Won, K. H., Jung, S. J., & Choe, H. (2008). Clomipramine block of the hERG K+ channel: accessibility to F656 and Y652. European Journal of Pharmacology, 592(1-3), 19-25. https://doi.org/10.1016/j.ejphar.2008.06.094
Jo SH, et al. Clomipramine Block of the hERG K+ Channel: Accessibility to F656 and Y652. Eur J Pharmacol. 2008 Sep 11;592(1-3):19-25. PubMed PMID: 18634780.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Clomipramine block of the hERG K+ channel: accessibility to F656 and Y652. AU - Jo,Su-Hyun, AU - Hong,Hee-Kyung, AU - Chong,Seon Ha, AU - Won,Kwang Hee, AU - Jung,Sung Jun, AU - Choe,Han, Y1 - 2008/07/02/ PY - 2007/12/26/received PY - 2008/06/19/revised PY - 2008/06/27/accepted PY - 2008/7/19/pubmed PY - 2008/10/25/medline PY - 2008/7/19/entrez SP - 19 EP - 25 JF - European journal of pharmacology JO - Eur. J. Pharmacol. VL - 592 IS - 1-3 N2 - Clomipramine 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 clomipramine on hERG channels to determine the electrophysiological basis for its proarrhythmic potential. We examined the effects of clomipramine on the hERG channels expressed in Xenopus oocytes and HEK293 cells using two-microelectrode voltage-clamp and patch-clamp techniques. Clomipramine induced a concentration-dependent decrease in the current amplitude at the end of the voltage steps and hERG tail currents. The IC50 for clomipramine needed to block the hERG current in Xenopus oocytes decreased progressively relative to the degree of depolarization. The fractional electrical distance was estimated to be delta=0.83. The IC50 for the clomipramine-induced blockade of the hERG currents in HEK293 cells at 36 degrees C was 0.13 microM at +20 mV. Clomipramine affected the channels in the activated and inactivated states but not in the closed states. The clomipramine-induced blockade of hERG was found to be use-dependent, exhibiting a more rapid onset and a greater steady-state block at the higher frequencies of activation. The S6 domain mutations, Y652A and F656A partially attenuated (Y652A) or abolished (F656A) the hERG-current blockade. These results suggest that clomipramine is a blocker of the hERG channels, providing a molecular mechanism for the arrhythmogenic side effects during the clinical administration of clomipramine. SN - 0014-2999 UR - https://www.unboundmedicine.com/medline/citation/18634780/Clomipramine_block_of_the_hERG_K+_channel:_accessibility_to_F656_and_Y652_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(08)00708-5 DB - PRIME DP - Unbound Medicine ER -