Cardiovascular pharmacologyElectrophysiological and trafficking defects of the SCN5A T353I mutation in Brugada syndrome are rescued by alpha-allocryptopine
Graphical abstract
Introduction
BrS is an inherited disorder that is characterised by an ECG pattern that consists of an ST elevation in the right precordial leads, and it increases the susceptibility for ventricular arrhythmias (Brugada and Brugada, 1992, Brugada et al., 1998). BrS appears to be inherited in an autosomal dominant manner, and there is often a family history of unexplained sudden cardiac death. This disease has been linked to the presence of mutations in the α-subunit of the human cardiac sodium channel (Nav1.5). These identified BrS-associated mutations result in a lower sodium peak current (Ipeak) (Vatta et al., 2002b, Vatta et al., 2002a, Vatta et al., 2002b, Takehara et al., 2004; Vatta et al.; Deschenes et al., 2000).
At position 353, the threonine-to-isoleucine missense mutation (T353I or TI) reported by Pfahnl et al. (2007) is adjacent to the pore-lining region of domain I of the cardiac sodium channel family. This mutant has typical Brugada-type ECG changes, which are associated with mutations in Nav1.5; these changes demonstrate a decrease in sodium currents with loss-of-function channel properties (Amin et al., 2005, Baroudi et al., 2004). However, the T353I channel SCN5A produces an observably sustained current (Isus) or late current and simultaneously induces LQT3 (Horne et al., 2011). Overnight exposure to mexiletine, a Na+ channel blocking agent, increases the Ipeak of T353I, which increases channel protein trafficking to the membrane up to almost normal levels, with Isus being unaffected.
All, a derivative of tetrahydropalmatine, is extracted from Corydalis decumbens (Thunb.) Pers. Papaveraceae (Ye et al., 2009, Chen et al., 2009). Several studies have indicated that All exhibits potential anti-arrhythmic effects in various animal models, which indicates that All exerts an inhibitory effect in an aconitine-induced arrhythmic animal model that has abnormal sodium currents (Liu et al., 2006, Li et al., 2005). In the present study, we investigated the responses of the T353I mutant to All. This study focused on the effect of All on the rescue of T353I-induced trafficking deficiency.
Section snippets
Reagents
All was supplied by the Pharmaceutical Department of Lanzhou University (molecular weight: 365), with melting point: 168 °C; it was a white crystal powder at 99.0% purity. Its structure is shown in Fig. 1. It was dissolved in dimethyl sulfoxide (DMSO) to obtain a stock solution of 1.0 M. We investigated the effect of the maximum concentration of 0.5 mM of All. Based on the largest drug concentrations, DMSO was added to the medium, to produce a final concentration of 0.1%. The drug stock solution
Characteristics of the SCN5A current before and after All treatment
INa was elicited using depolarising steps from −70 mV to +40 mV for 500 ms from a holding potential of −120 mV. The current amplitudes were normalised to the cellular membrane capacitance in the form of current densities. INa representative current traces of WT and T353I channels with or without co-incubation with All for 24 h are shown in Fig. 2A and B. Compared with the control, the peak current densities of T353I were markedly increased from −143.6±12.7 pA/pF to −205.7±21.1 pA/pF with 30 μΜ All
Discussion
Loss-of-function mutations of the Nav1.5 channel cause BrS, cardiac conduction disease, and sick sinus syndrome. BrS is a rare disease but causes high susceptibility to potentially lethal ventricular tachyarrhythmias. However, no effective treatments are available for this disorder except for invasive implantation of defibrillators or pacemakers in some cases (Coronel et al., 2005, Papadatos et al., 2002). The T353I mutation is predicted to be in the pore-lining segment of the first channel
Acknowledgements
We would like to thank Prof. Silvia G. Priori from Molecular Cardiology, and Fondazione Salvatore Maugeri, I.R.C.C.S., at the University of Pavia in Italy, for generously providing the SCN5A plasmid. This work was supported by grants obtained from the National Natural Science Foundation of China (Nos: 81170177, 81100215, 81373835, 81430098, 81030002 and 30770901). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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These authors contributed equally to this work.