Ranolazine block of human NaV1.4 sodium channels and paramyotonia congenita mutants

Nesrine El-Bizri, Kristopher M. Kahlig, John C. Shryock, Alfred L. George, Luiz Belardinelli, Sridharan Rajamani*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

The antianginal drug ranolazine exerts voltage- and use-dependent block (UDB) of several Na+ channel isoforms, including NaV1.4. We hypothesized that ranolazine will similarly inhibit the paramyotonia congenita NaV1.4 gain-of-function mutations, R1448C, R1448H and R1448P that are associated with repetitive action potential firing. Whole-cell Na+ current (INa) was recorded from HEK293 cells expressing the hNaV1.4 WT or R1448 mutations. At a holding potential (HP) of -140 mV, ranolazine exerted UDB (10 hz) of WT and R1448 mutations (IC50 = 59-71 μM). The potency for ranolazine UDB increased when the frequency of stimulation was raised to 30 hz (IC50 = 20-27 μM). When the HP was changed to -70 mV to mimic the resting potential of an injured skeletal muscle fiber, the potency of ranolazine to block INa further increased; values of ranolazine IC50 for block of WT, R1448C, R1448H and R1448P were 3.8, 0.9, 6.3 and 0.9 μM, respectively. Ranolazine (30 μM) also caused a hyperpolarizing shift in the voltage-dependence of inactivation of WT and R1448 mutations. The effects of ranolazine (30 μM) to reduce INa were similar (∼35% I Na inhibition) when different conditioning pulse durations (2-20 msec) were used. Ranolazine (10 μM) suppressed the abnormal INa induced by slow voltage ramps for R1448C channels. In computer simulations, 3 μM ranolazine inhibited the sustained and excessive firing of skeletal muscle action potentials that are characteristic of myotonia. Taken together, the data indicate that ranolazine interacts with the open state and stabilizes the inactivated state(s) of NaV1.4 channels, causes voltage- and use-dependent block of INa and suppresses persistent INa. These data further suggest that ranolazine might be useful to reduce the sustained action potential firing seen in paramyotonia congenita.

Original languageEnglish (US)
JournalChannels
Volume5
Issue number2
DOIs
StatePublished - 2011

Keywords

  • Action potential
  • Angina
  • Excitability
  • Markov model
  • Na channels
  • Paramyotonia congenita
  • SCN4A
  • Skeletal muscle

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry

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