New mechanism contributing to drug-induced arrhythmia: rescue of a misprocessed LQT3 mutant.
BACKGROUND
The cardiac sodium channel (SCN5A) mutation L1825P has been identified in a patient with drug-induced torsade de pointes precipitated by the IKr blocker cisapride. Although L1825P generates late sodium current typical of SCN5A-linked long-QT syndrome (LQT3) in vitro, the patient reported had a normal QT interval before administration of the drug. To address this discrepancy, we tested the hypothesis that this mutant channel is not processed normally.


RESULTS
CHO cells transfected with L1825P displayed significantly reduced peak INa (209+/-36 versus 23+/-3 pA/pF, P<0.05). Confocal imaging and cell-counting studies using epitope-tagged constructs demonstrated that cell surface expression of the mutant was only approximately 9% of wild-type. Incubating transfected cells with cisapride partially rescued misprocessing to 30% of wild-type. As a result, "late" sodium current increased with cisapride from 1.2+/-0.11 to 5.04+/-0.77 pA/pF (P<0.05).


CONCLUSIONS
L1825P fails to generate QT prolongation because it does not reach the cell surface. Moreover, the data suggest that cisapride caused torsade de pointes not only by blocking IKr but also by rescuing cell surface expression of the mutant channel, further exaggerating the LQT3 phenotype. This not only represents a new mechanism in the drug-induced long-QT syndrome but also strongly supports the concept that variable cell surface expression contributes to clinical variability in the LQT3 phenotype.
Liu
Kai
K
Departments of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Yang
Tao
T
Viswanathan
Prakash C
PC
Roden
Dan M
DM
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D016466:CHO Cells; D020117:Cisapride / Q000009:adverse effects*; D006224:Cricetinae; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D008133:Long QT Syndrome / Q000235:genetics / Q000503:physiopathology*; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D009124:Muscle Proteins / Q000235:genetics* / Q000502:physiology; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D010641:Phenotype; D017366:Serotonin Receptor Agonists / Q000009:adverse effects*; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics* / Q000502:physiology; D013268:Stimulation, Chemical; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000235:genetics / Q000503:physiopathology; D014162:Transfection
D008565:Membrane Proteins; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D017366:Serotonin Receptor Agonists; D015222:Sodium Channels; D012964:Sodium; D020117:Cisapride