title: Escitalopram block of hERG potassium channels.
abstract: Escitalopram, a selective serotonin reuptake inhibitor, is the pharmacologically active S-enantiomer of the racemic mixture of RS-citalopram and is widely used in the treatment of depression. The effects of escitalopram and citalopram on the human ether-a-go-go-related gene (hERG) channels expressed in human embryonic kidney cells were investigated using voltage-clamp and Western blot analyses. Both drugs blocked hERG currents in a concentration-dependent manner with an IC50 value of 2.6 μM for escitalopram and an IC50 value of 3.2 μM for citalopram. The blocking of hERG by escitalopram was voltage-dependent, with a steep increase across the voltage range of channel activation. However, voltage independence was observed over the full range of activation. The blocking by escitalopram was frequency dependent. A rapid application of escitalopram induced a rapid and reversible blocking of the tail current of hERG. The extent of the blocking by escitalopram during the depolarizing pulse was less than that during the repolarizing pulse, suggesting that escitalopram has a high affinity for the open state of the hERG channel, with a relatively lower affinity for the inactivated state. Both escitalopram and citalopram produced a reduction of hERG channel protein trafficking to the plasma membrane but did not affect the short-term internalization of the hERG channel. These results suggest that escitalopram blocked hERG currents at a supratherapeutic concentration and that it did so by preferentially binding to both the open and the inactivated states of the channels and by inhibiting the trafficking of hERG channel protein to the plasma membrane.
authors.affiliation: Department of Physiology, Cell Death and Disease Research Center, College of Medicine, The Catholic University of Korea, 224 Banpo-daero, Seocho-gu, Seoul, 137-701, Korea.
authors.forename: Yun Ju
authors.initials: YJ
authors.lastname: Chae
authors.forename: Ji Hyun
authors.initials: JH
authors.lastname: Jeon
authors.forename: Hong Joon
authors.initials: HJ
authors.lastname: Lee
authors.forename: In-Beom
authors.initials: IB
authors.lastname: Kim
authors.forename: Jin-Sung
authors.initials: JS
authors.lastname: Choi
authors.forename: Ki-Wug
authors.initials: KW
authors.lastname: Sung
authors.forename: Sang June
authors.initials: SJ
authors.lastname: Hahn
mesh_terms: D015283:Citalopram / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D026902:Potassium Channel Blockers / Q000494:pharmacology*
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D026902:Potassium Channel Blockers; D015283:Citalopram
references.citation: J Biol Chem. 2011 Sep 30;286(39):34413-25
references.pmid: 21832094
references.citation: Pol J Pharmacol Pharm. 1984 Nov-Dec;36(6):675-82
references.pmid: 6598490
references.citation: CNS Drugs. 2003;17(5):343-62
references.pmid: 12665392
references.citation: PLoS One. 2013;8(3):e59673
references.pmid: 23527248
references.citation: Ann Cardiol Angeiol (Paris). 2011 Jun;60(3):165-8
references.pmid: 21295285
references.citation: J Pharmacol Exp Ther. 2001 Sep;298(3):1108-19
references.pmid: 11504808
references.citation: CNS Drugs. 2010 Sep;24(9):769-96
references.pmid: 20806989
references.citation: Br J Pharmacol. 2003 Jul;139(5):887-98
references.pmid: 12839862
references.citation: Basic Clin Pharmacol Toxicol. 2006 Aug;99(2):91-5
references.pmid: 16918708
references.citation: FEBS Lett. 2002 Feb 13;512(1-3):59-66
references.pmid: 11852052
references.citation: Gen Pharmacol. 2000 Jan;34(1):17-23
references.pmid: 10793264
references.citation: J Pharmacol Exp Ther. 1996 Feb;276(2):637-46
references.pmid: 8632331
references.citation: Proc Natl Acad Sci U S A. 2000 Oct 24;97(22):12329-33
references.pmid: 11005845
references.citation: J Pharmacol Exp Ther. 2008 Mar;324(3):977-84
references.pmid: 18048694
references.citation: Br J Pharmacol. 2006 Nov;149(5):481-9
references.pmid: 16967046
references.citation: Can J Cardiol. 2008 Jul;24(7):e38-40
references.pmid: 18612505
references.citation: Am J Physiol Cell Physiol. 2009 Apr;296(4):C701-10
references.pmid: 19244476
references.citation: Trends Pharmacol Sci. 2001 May;22(5):240-6
references.pmid: 11339975
references.citation: Clin Neuropharmacol. 2001 May-Jun;24(3):158-62
references.pmid: 11391127
references.citation: Physiol Rev. 2012 Jul;92(3):1393-478
references.pmid: 22988594
references.citation: Gen Hosp Psychiatry. 2012 Mar-Apr;34(2):210.e13-5
references.pmid: 22133983
references.citation: J Pharmacol Exp Ther. 2002 Feb;300(2):543-8
references.pmid: 11805215
references.citation: Proc Natl Acad Sci U S A. 2000 Oct 24;97(22):11683-4
references.pmid: 11050193
references.citation: Br J Pharmacol. 2005 Mar;144(6):840-8
references.pmid: 15778703
references.citation: Acta Pharmacol Sin. 2010 Apr;31(4):429-35
references.pmid: 20228830
references.citation: Curr Med Chem Cardiovasc Hematol Agents. 2003 Oct;1(3):273-87
references.pmid: 15326917
references.citation: Ann Pharmacother. 2000 Jun;34(6):761-71
references.pmid: 10860138
references.citation: Biochem Pharmacol. 2003 Dec 1;66(11):2125-32
references.pmid: 14609737
references.citation: Br J Pharmacol. 2002 Jul;136(5):717-29
references.pmid: 12086981
references.citation: J Emerg Med. 2003 Aug;25(2):163-6
references.pmid: 12902002
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 1982;6(3):277-95
references.pmid: 6128769
references.citation: Curr Pharm Des. 2004;10(20):2463-75
references.pmid: 15320756
references.citation: J Clin Psychiatry. 2000 Dec;61(12):896-908
references.pmid: 11206593