Different flecainide sensitivity of hNa_v1.4 channels and myotonic mutants explained by state‐dependent block

Abstract

Flecainide, a class IC antiarrhythmic, was shown to improve myotonia caused by sodium channel mutations in situations where the class IB antiarrhythmic drug mexiletine was less efficient. Yet little is known about molecular interactions between flecainide and human skeletal muscle sodium (hNa v 1.4) channels. Whole-cell sodium currents (I Na ) were recorded in tsA201 cells expressing wild-type (WT) and mutant hNa v 1.4 channels (R1448C, paramyotonia congenita; G1306E, potassium-aggravated myotonia). At a holding potential (HP) of -120 mV, flecainide use-dependently blocked WT and G1306E I Na equally but was more potent on R1448C channels. For WT, the extent of block depended on a holding voltage more negative than the activation threshold, being greater at -90 mV as compared to -120 and -180 mV. This behaviour was exacerbated by the R1448C mutation since block at -120 mV was greater than that at -180 mV. Thus flecainide can bind to inactivated sodium channels in the absence of channel opening. Nevertheless, all the channels showed the same closed-state affinity constant (K R ∼480 µM) and the same inactivated-state affinity constant (K I ∼18 µM). Simulations according to the modulated receptor hypothesis mimic the voltage-dependent block of WT and mutant channels by flecainide and mexiletine. All the results suggest similar blocking mechanisms for the two drugs. Yet, since flecainide exerts use-dependent block at lower frequency than mexiletine, it may exhibit greater benefit in all myotonic syndromes. Moreover, flecainide blocks hNa v 1.4 channel mutants with a rightward shift of availability voltage dependence more specifically than mexiletine, owing to a lower K R /K I ratio. This study offers a pharmacogenetic strategy to better address treatment in individual myotonic patients.

Flecainide-Responsive Myotonia Permanens With SNEL Onset: A New Case and Literature Review

“…In fact, even though flecainide and mexiletine exhibit a similar mechanism of blocking skeletal muscle sodium channels, flecainide reportedly inhibits some mutant channels more efficiently than mexiletine. 14,15 Although flecainide has been shown to be an effective human voltage-gated sodium channel blocker in vitro, its clinical use as an antimyotonic agent has rarely been reported. 8,22 Indeed, it has been shown previously that flecainide was more efficient than mexiletine in blocking functionally expressed G1306E channels, likely because of a positive shift of channel availability voltage dependence induced by the mutation.…”

“…8,22 Indeed, it has been shown previously that flecainide was more efficient than mexiletine in blocking functionally expressed G1306E channels, likely because of a positive shift of channel availability voltage dependence induced by the mutation. 14 …”

“…Since early childhood, he had been treated with mexiletine, with limited effects. Having already demonstrated the in vitro beneficial effects of flecainide on that specific mutation, 14 the authors decided to administer, for the first time, flecainide in mother and son, and a marked improvement in symptoms was noted. 13 In 2013, Caietta et al 15 reported on 2 other SNEL patients with a p.G1306E de novo mutation.…”

Ranolazine block of human Nav1.4 sodium channels and paramyotonia congenita mutants

“…The reduction in the rate of I Na decay 26,27 and the enhanced rate of recovery from inactivation 7,8 exhibited by R1448 mutant channels are features which may increase excitability and contribute to myotonia.…”

Inherited disorders of voltage-gated sodium channels

“…A more potent Na V Ch blocker, flecainide, may also have utility in severe forms of myotonia that are resistant to mexiletine (55). The efficacy of flecainide for treating myotonia associated with certain SCN4A mutations may be greatest when there is a depolarizing shift of the steady-state fast inactivation curve for the mutant channel, whereas mutations that induce hyperpolarizing shifts in this curve are predicted to have greater sensitivity to mexiletine (56). Longterm treatment of myotonia with Na V Ch blockers is often limited by drug side effects.…”