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Am J Physiol Heart Circ Physiol. 2018 Aug 1;315(2):H375-H388. doi: 10.1152/ajpheart.00479.2017. Epub 2018 Apr 20.

Ondansetron blocks wild-type and p.F503L variant small-conductance Ca2+-activated K+ channels.

Author information

1
The Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine , Indianapolis, Indiana.
2
Wonkwang University School of Medicine and Hospital, Iksan, South Korea.
3
Department of Medical and Molecular Genetics, Indiana University School of Medicine , Indianapolis, Indiana.
4
Department of Pharmacy Practice, College of Pharmacy, Purdue University , West Lafayette, Indiana.
5
Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine , Indianapolis, Indiana.
6
Regenstrief Institute , Indianapolis, Indiana.
7
Department of Biostatistics, Department of Medicine, Indiana University School of Medicine , Indianapolis, Indiana.
8
Institute of Biomedical Engineering, National Chiao-Tung University, Hsin-Chu, Taiwan.
9
Department of Pediatrics, Riley Heart Research Center, Indiana University School of Medicine , Indianapolis, Indiana.

Abstract

Apamin-sensitive small-conductance Ca2+-activated K+ (SK) current ( IKAS) is encoded by Ca2+-activated K+ channel subfamily N ( KCNN) genes. IKAS importantly contributes to cardiac repolarization in conditions associated with reduced repolarization reserve. To test the hypothesis that IKAS inhibition contributes to drug-induced long QT syndrome (diLQTS), we screened for KCNN variants among patients with diLQTS, determined the properties of heterologously expressed wild-type (WT) and variant KCNN channels, and determined if the 5-HT3 receptor antagonist ondansetron blocks IKAS. We searched 2,306,335 records in the Indiana Network for Patient Care and found 11 patients with diLQTS who had DNA available in the Indiana Biobank. DNA sequencing discovered a heterozygous KCNN2 variant (p.F503L) in a 52-yr-old woman presenting with corrected QT interval prolongation at baseline (473 ms) and further corrected QT interval lengthening (601 ms) after oral administration of ondansetron. That patient was also heterozygous for the p.S38G and p.P2835S variants of the QT-controlling genes KCNE1 and ankyrin 2, respectively. Patch-clamp experiments revealed that the p.F503L KCNN2 variant heterologously expressed in human embryonic kidney (HEK)-293 cells augmented Ca2+ sensitivity, increasing IKAS density. The fraction of total F503L-KCNN2 protein retained in the membrane was higher than that of WT KCNN2 protein. Ondansetron at nanomolar concentrations inhibited WT and p.F503L SK2 channels expressed in HEK-293 cells as well as native SK channels in ventricular cardiomyocytes. Ondansetron-induced IKAS inhibition was also demonstrated in Langendorff-perfused murine hearts. In conclusion, the heterozygous p.F503L KCNN2 variant increases Ca2+ sensitivity and IKAS density in transfected HEK-293 cells. Ondansetron at therapeutic (i.e., nanomolar) concentrations is a potent IKAS blocker. NEW & NOTEWORTHY We showed that ondansetron, a 5-HT3 receptor antagonist, blocks small-conductance Ca2+-activated K+ (SK) current. Ondansetron may be useful in controlling arrhythmias in which increased SK current is a likely contributor. However, its SK-blocking effects may also facilitate the development of drug-induced long QT syndrome.

KEYWORDS:

Ca2+-activated K+ channel subfamily N variants; drug-induced long QT syndrome; ondansetron; small-conductance Ca2+-activated K+ channel

PMID:
29677462
PMCID:
PMC6139629
[Available on 2019-08-01]
DOI:
10.1152/ajpheart.00479.2017

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