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- Title
Long-QT syndrome-related sodium channel mutations probed by the dynamic action potential clamp technique.
- Authors
Berecki, Géza; Zegers, Jan G.; Bhuiyan, Zahurul A.; Verkerk, Arie O.; Wilders, Ronald; Van Ginneken, Antoni C. G.
- Abstract
Long-QT3 syndrome (LQT3) is linked to cardiac sodium channel gene ( SCN5A) mutations. In this study, we used the ‘dynamic action potential clamp’ (dAPC) technique to effectively replace the native sodium current ( INa) of the Priebe–Beuckelmann human ventricular cell model with wild-type (WT) or mutant INa generated in a human embryonic kidney (HEK)-293 cell that is voltage clamped by the free-running action potential of the ventricular cell. We recorded INa from HEK cells expressing either WT or LQT3-associated Y1795C or A1330P SCN5A at 35°C, and let this current generate and shape the action potential (AP) of subepicardial, mid-myocardial and subendocardial model cells. The HEK cell's endogenous background current was completely removed by a real-time digital subtraction procedure. With WT INa, AP duration (APD) was longer than with the original Priebe–Beuckelmann model INa, due to a late INa component of ∼30 pA that could not be revealed with conventional voltage-clamp protocols. With mutant INa, this late component was larger (∼100 pA), producing a marked increase in APD (∼70–80 ms at 1 Hz for the subepicardial model cell). The late INa magnitude showed reverse frequency dependence, resulting in a significantly steeper APD–frequency relation in the mutant case. AP prolongation was more pronounced for the mid-myocardial cell type, resulting in increased APD dispersion for each of the mutants. For both mutants, a 2 s pause following rapid (2 Hz) pacing resulted in distorted AP morphology and beat-to-beat fluctuations of INa. Our dAPC data directly demonstrate the arrhythmogenic nature of LQT3-associated SCN5A mutations.
- Subjects
HEART beat; GENES; SODIUM; CELLS; MYOCARDIUM
- Publication
Journal of Physiology, 2006, Vol 570, Issue 2, p237
- ISSN
0022-3751
- Publication type
Article
- DOI
10.1113/jphysiol.2005.096578