Abstract
Abstract 14372: The Acquired Long QT-Causing Drugs Haloperidol and Terfenadine Cause Defects in HERG Trafficking
Circulation (New York, N.Y.), Vol.144(S_1), p.A14372
11/16/2021
DOI: 10.1161/circ.144.suppl_1.14372
Abstract
Byline: Abagail McKernan, Univ of Iowa, Iowa City, IA; Haider Mehdi; Alexander Greiner; Jin-Young Yoon; Diana Colgan; Jason Dierdorff; Barry London Background: Mutations in Kv11.1 (HERG) cause inherited long QT syndrome (LQTS) type 2 by disrupting channel function or membrane trafficking. Acquired LQTS is caused by drug binding to HERG and directly blocking the channel pore, reducing IKr and prolonging QTc in persons with decreased repolarization reserve. Alternatively, these drugs could bind to HERG and interfere with trafficking, reducing the number of HERG channels at the membrane. Objective: We sought to understand the effects of known acquired LQTS-causing drugs from various classes (terfenadine, haloperidol, ondansetron, fluconazole, azithromycin) on HERG trafficking. Methods: HEK293 cells stably expressing HERG (HERG-HEK293) were cultured in varying concentrations of selected drugs for 24 hours. Differences in trafficking were identified by immunoblot using the terminally-glycosylated HERG at 155 kD and the immature core-glycosylated HERG at 135 kD. Both the mutant HERG-G601S and HERG-HEK293 cells treated for 24 hours with arsenic trioxide (As2O3) served as trafficking-deficient controls. Results: HERG-HEK293 cells treated with haloperidol (>50 ðM) demonstrated a decrease in the size of the terminally glycosylated band, appearing at 140-145 kD in comparison to the fully glycosylated 155 kD (Fig. 1A). HERG-HEK293 cells treated with terfenadine (>15 ðM) demonstrated a deficiency in terminal glycosylation (Fig. 1B). Ondansetron, fluconazole, and azithromycin treatments at 1, 10, and 100 ðM demonstrated no effect on the fully glycosylated band. Conclusions: These data suggest terfenadine and haloperidol interfere with HERG trafficking, resulting in less mature HERG at the membrane. Together, these data provide insight into a non-pore blocking mechanism that may underlie some cases of acquired LQTS.
Details
- Title: Subtitle
- Abstract 14372: The Acquired Long QT-Causing Drugs Haloperidol and Terfenadine Cause Defects in HERG Trafficking
- Creators
- Abagail McKernanHaider MehdiAlexander GreinerJin-Young YoonDiana ColganJason DierdorffBarry London
- Resource Type
- Abstract
- Publication Details
- Circulation (New York, N.Y.), Vol.144(S_1), p.A14372
- Publisher
- Lippincott Williams & Wilkins, WK Health
- DOI
- 10.1161/circ.144.suppl_1.14372
- ISSN
- 0009-7322
- eISSN
- 1524-4539
- Language
- English
- Date published
- 11/16/2021
- Description audience
- Professional
- Academic Unit
- Internal Medicine; Molecular Physiology and Biophysics; Cardiovascular Medicine
- Record Identifier
- 9984303004802771
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