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Mutations in the cytoplasmic tail (CT) of voltage gated sodium channels cause a spectrum of inherited diseases of cellular excitability, yet to date only one mutation in the CT of the human skeletal muscle voltage gated sodium channel (hNa V 1.4 F1705I ) has been linked to cold aggravated myotonia. The functional effects of altered regulation of hNa V 1.4 F1705I  are incompletely understood. The location of the hNa V 1.4 F1705I  in the CT prompted us to examine the role of Ca 2+  and calmodulin (CaM) regulation in the manifestations of myotonia. To study Na channel related mechanisms of myotonia we exploited the differences in rat and human Na V 1.4 channel regulation by Ca 2+  and CaM. hNa V 1.4 F1705I  inactivation gating is Ca 2+ -sensitive compared to wild type hNa V 1.4 which is Ca 2+  insensitive and the mutant channel exhibits a depolarizing shift of the V 1/2  of inactivation with CaM over expression. In contrast the same mutation in the rNa V 1.4 channel background (rNa V 1.4 F1698I ) eliminates Ca 2+  sensitivity of gating without affecting the CaM over expression induced hyperpolarizing shift in steady-state inactivation. The differences in the Ca 2+  sensitivity of gating between wild type and mutant human and rat Na V 1.4 channels are in part mediated by a divergence in the amino acid sequence in the EF hand like (EFL) region of the CT. Thus the composition of the EFL region contributes to the species differences in Ca 2+ /CaM regulation of the mutant channels that produce myotonia. The myotonia mutation F1705I slows I Na  decay in a Ca 2+ -sensitive fashion. The combination of the altered voltage dependence and kinetics of I Na  decay contribute to the myotonic phenotype and may involve the Ca 2+ -sensing apparatus in the CT of Na V 1.4.

Mechanisms of a Human Skeletal Myotonia Produced by Mutation in the C-Terminus of NaV1.4: Is Ca2+ Regulation Defective?