Abstract
Long QT syndrome variant 3 (LQT-3) is a channelopathy in which mutations in SCN5A, the gene coding for the primary heart Na + channel alpha subunit, disrupt inactivation to elevate the risk of mutation carriers for arrhythmias that are thought to be calcium (Ca 2+)-dependent. Spontaneous arrhythmogenic diastolic activity has been reported in myocytes isolated from mice harboring the well-characterized ΔKPQ LQT-3 mutation but the link to altered Ca 2+ cycling related to mutant Na + channel activity has not previously been demonstrated. Here we have investigated the relationship between elevated sarcoplasmic reticulum (SR) Ca 2+ load and induction of spontaneous diastolic inward current (I TI) in myocytes expressing ΔKPQ Na + channels, and tested the sensitivity of both to the antianginal compound ranolazine. We combined whole-cell patch clamp measurements, imaging of intracellular Ca 2+, and measurement of SR Ca 2+ content using a caffeine dump methodology. We compared the Ca 2+ content of ΔKPQ +/− myocytes displaying I TI to those without spontaneous diastolic activity and found that I TI induction correlates with higher sarcoplasmic reticulum (SR) Ca 2+. Both spontaneous diastolic I TI and underlying Ca 2+ waves are inhibited by ranolazine at concentrations that preferentially target I NaL during prolonged depolarization. Furthermore, ranolazine I TI inhibition is accompanied by a small but significant decrease in SR Ca 2+ content. Our results provide the first direct evidence that induction of diastolic transient inward current (I TI) in ΔKPQ +/− myocytes occurs under conditions of elevated SR Ca 2+ load.
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