Differential modulation of late sodium current by protein kinase A in R1623Q mutant of LQT3

Aims: In the type 3 long QT syndrome (LQT3), shortening of the QT interval by overdrive pacing is used to prevent life-threatening arrhythmias. However, it is unclear whether accelerated heart rate induced by beta-adrenergic agents produces similar effects on the late sodium current (I-Na) to those by overdrive pacing therapy. We analyzed the beta-adrenergic-like effects of protein kinase A and fluoride on I-Na in R1623Q mutant channels. Main methods: cDNA encoding either wild-type (WT) or R1623Q mutant of hNa(v)1.5 was stably transfected into HEK293 cells. I-Na was recorded using a whole-cell patch-clamp technique at 23 degrees C. Key findings: In R1623Q channels. 2 mM pCPT-AMP and 120 mM fluoride significantly delayed macroscopic current decay and increased relative amplitude of the late I-Na in a time-dependent manner. Modulations of peak I-Na gating kinetics (activation, inactivation, recovery from inactivation) by fluoride were similar in WT and R1623Q channels. The effects of fluoride were almost completely abolished by concomitant dialysis with a protein kinase inhibitor. We also compared the effect of pacing with that of beta-adrenergic stimulation by analyzing the frequency-dependence of the late I-Na. Fluoride augmented frequency-dependent reduction of the late I-Na, which was due to preferential delay of recovery of late I-Na. However, the increase in late IN by fluoride at steady-state was more potent than the frequency-dependent reduction of late I-Na. Significance: Different basic mechanisms participate in the QT interval shortening by pacing and beta-adrenergic stimulation in the LQT3. (C) 2009 Elsevier Inc. All rights reserved.