Ondansetron blocks wild-type and p.F503l variant small-conductance Ca2+-activated K+ channels

Jum Suk Ko, Shuai Guo, Jonathan Hassel, Patricia Celestino-Soper, Ty C. Lynnes, James E. Tisdale, James J. Zheng, Stanley E. Taylor, Tatiana Foroud, Michael Murray, Richard Kovacs, Xiaochun Li, Shien-Fong Lin, Zhenhui Chen, Matteo Vatta, Peng-Sheng Chen, Michael Rubart-von der Lohe

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)H375-H388
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume315
Issue number2
DOIs
StatePublished - Aug 1 2018

Fingerprint

Calcium-Activated Potassium Channels
Ondansetron
Long QT Syndrome
Serotonin 5-HT3 Receptor Antagonists
Receptors, Serotonin, 5-HT3
Kidney
Pharmaceutical Preparations
Ankyrins
Apamin
DNA Sequence Analysis
Cardiac Myocytes
Genes
Oral Administration
Cardiac Arrhythmias
Patient Care
Proteins
Membranes
DNA

Keywords

  • Ca-activated K channel subfamily N variants
  • Drug-induced long QT syndrome
  • Ondansetron
  • Small-conductance Ca-activated K channel

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Ondansetron blocks wild-type and p.F503l variant small-conductance Ca2+-activated K+ channels. / Ko, Jum Suk; Guo, Shuai; Hassel, Jonathan; Celestino-Soper, Patricia; Lynnes, Ty C.; Tisdale, James E.; Zheng, James J.; Taylor, Stanley E.; Foroud, Tatiana; Murray, Michael; Kovacs, Richard; Li, Xiaochun; Lin, Shien-Fong; Chen, Zhenhui; Vatta, Matteo; Chen, Peng-Sheng; Rubart-von der Lohe, Michael.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 315, No. 2, 01.08.2018, p. H375-H388.

Research output: Contribution to journalArticle

Ko, Jum Suk ; Guo, Shuai ; Hassel, Jonathan ; Celestino-Soper, Patricia ; Lynnes, Ty C. ; Tisdale, James E. ; Zheng, James J. ; Taylor, Stanley E. ; Foroud, Tatiana ; Murray, Michael ; Kovacs, Richard ; Li, Xiaochun ; Lin, Shien-Fong ; Chen, Zhenhui ; Vatta, Matteo ; Chen, Peng-Sheng ; Rubart-von der Lohe, Michael. / Ondansetron blocks wild-type and p.F503l variant small-conductance Ca2+-activated K+ channels. In: American Journal of Physiology - Heart and Circulatory Physiology. 2018 ; Vol. 315, No. 2. pp. H375-H388.
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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.",
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T1 - Ondansetron blocks wild-type and p.F503l variant small-conductance Ca2+-activated K+ channels

AU - Ko, Jum Suk

AU - Guo, Shuai

AU - Hassel, Jonathan

AU - Celestino-Soper, Patricia

AU - Lynnes, Ty C.

AU - Tisdale, James E.

AU - Zheng, James J.

AU - Taylor, Stanley E.

AU - Foroud, Tatiana

AU - Murray, Michael

AU - Kovacs, Richard

AU - Li, Xiaochun

AU - Lin, Shien-Fong

AU - Chen, Zhenhui

AU - Vatta, Matteo

AU - Chen, Peng-Sheng

AU - Rubart-von der Lohe, Michael

PY - 2018/8/1

Y1 - 2018/8/1

N2 - 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.

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