Differential calcium sensitivity in NaV1.5 mixed syndrome mutants

Abstract

Introduction

Inherited arrhythmias may arise from mutations in the SCN5a gene, which encodes the cardiac voltage-gated sodium channel, Na_V1.5. Mutants in Na_V1.5 result in Brugada Syndrome (BrS1), Long-QT Syndrome (LQT3), or mixed syndromes (an overlap of BrS1/LQT3). Exercise is a potential arrhythmogenic trigger in mixed syndromes. We sought to determine the effects of elevated cytosolic calcium, common during exercise, in mixed syndrome Na_V1.5 mutants.

Methods

We used whole-cell patch-clamp to assess the biophysical properties of Na_V1.5 wild-type (WT), ∆KPQ, E1784K, 1795insD, and Q1909R mutants in Human Embryonic Kidney (HEK293) cells transiently transfected with the Na_V1.5 α subunit (WT or mutants), β1 subunit, and eGFP. Voltage-dependence and kinetics were measured at approximately 0 nm, 500 nm, and 2500 nm cytosolic calciumlevels. In silico, action potential (AP) model simulations were performed using a modified O'Hara Rudy model.

Results

Elevated cytosolic calciumattenuates the late sodium current in ∆KPQ, 1795insD, and Q1909R but not in E1784K. Elevated cytosolic calcium restores steady-state slow inactivation (SSSI) to the WT-form in Q1909R, but depolarized SSSI in E1784K. Our AP simulations showed a frequency-dependent reduction of action potential duration (APD) in ∆KPQ, 1795insD, and Q1909R carriers. In E1784K, APD is relatively prolonged at both low and high heart rates, resulting in a sodium overload.

Conclusions

Cellular perturbations during exercise may affect BrS1/LQT3 patients differently depending on their individual genetic signature. Thus, exercise may be therapeutic or may be an arrhythmogenic trigger in some SCN5a patients.

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