Browsing by Author "Ko, Jum-Suk"

Now showing 1 - 2 of 2

Ondansetron blocks wild-type and p.F503L variant small conductance C2+-activated K+ channels
(2018-08-01)
Ko, Jum-Suk
;
Guo, Shuai
;
Hassel, Jonathan
;
Celestino-Soper, Patricia
;
Lynnes, Ty C.
Apamin-sensitive small-conductance Ca2+ activated K+ (SK) current (I-KAS) is encoded by Ca2+ -activated K+ channel subfamily N (KCNN) genes. I-KAS importantly contributes to cardiac repolarization in conditions associated with reduced repolarization reserve. To test the hypothesis that I-KAS 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 (WI) and variant KCNN channels. and determined if the 5-HT3 receptor antagonist ondansetron blocks I-KAS. 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 KCNEI and ankyrin 2, respectively. Patch-clamp experiments revealed that the p.F503L KCNN2 valiant heterologously expressed in human embryonic kidney (HEK)-293 cells augmented Ca2+ sensitivity, increasing I KAS 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 WI and p.F503L SK2 channels expressed in HEK-293 cells as well as native SK channels in ventricular cardiomyocytes. Ondansetron-induced I-KAS inhibition was also demonstrated in Langendorff-perfused murine hearts. In conclusion, the heterozygous p.F5031. KCNN2 variant increases Ca2+ sensitivity and I-KAS density in transfected HEK-293 cells. Ondansetron at therapeutic (i.e., nanomolar) concentrations is a potent I-KAS 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 druginduced long QT syndrome.
Small-Conductance Calcium-Activated Potassium Current Is Activated During Hypokalemia and Masks Short-Term Cardiac Memory Induced by Ventricular Pacing
(2015-10-13)
Chan, Yi-Hsin
;
Tsai, Wei-Chung
;
Ko, Jum-Suk
;
Yin, Dechun
;
Chang, Po-Cheng
Background-Hypokalemia increases the vulnerability to ventricular fibrillation. We hypothesize that the apamin-sensitive small-conductance calcium-activated potassium current (I-KAS) is activated during hypokalemia and that I-KAS blockade is proarrhythmic. Methods and Results-Optical mapping was performed in 23 Langendorff-perfused rabbit ventricles with atrioventricular block and either right or left ventricular pacing during normokalemia or hypokalemia. Apamin prolonged the action potential duration (APD) measured to 80% repolarization (APD(80)) by 26 milliseconds (95% confidence interval [CI], 14-37) during normokalemia and by 54 milliseconds (95% CI, 40-68) during hypokalemia (P=0.01) at a 1000-millisecond pacing cycle length. In hypokalemic ventricles, apamin increased the maximal slope of APD restitution, the pacing cycle length threshold of APD alternans, the pacing cycle length for wave-break induction, and the area of spatially discordant APD alternans. Apamin significantly facilitated the induction of sustained ventricular fibrillation (from 3 of 9 hearts to 9 of 9 hearts; P=0.009). Short-term cardiac memory was assessed by the slope of APD(80) versus activation time. The slope increased from 0.01 (95% CI, -0.09 to 0.12) at baseline to 0.34 (95% CI, 0.23-0.44) after apamin (P<0.001) during right ventricular pacing and from 0.07 (95% CI, -0.05 to 0.20) to 0.54 (95% CI, 0.06-1.03) after apamin infusion (P=0.045) during left ventricular pacing. Patch-clamp studies confirmed increased I-KAS in isolated rabbit ventricular myocytes during hypokalemia (P=0.038). Conclusions-Hypokalemia activates I-KAS to shorten APD and maintain repolarization reserve at late activation sites during ventricular pacing. I-KAS blockade prominently lengthens the APD at late activation sites and facilitates ventricular fibrillation induction.