title: Mechanisms of a human skeletal myotonia produced by mutation in the C-terminus of NaV1.4: is Ca2+ regulation defective?
abstract: 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 (hNaV1.4F1705I) has been linked to cold aggravated myotonia. The functional effects of altered regulation of hNaV1.4F1705I are incompletely understood. The location of the hNaV1.4F1705I 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 NaV1.4 channel regulation by Ca(2+) and CaM. hNaV1.4F1705I inactivation gating is Ca(2+)-sensitive compared to wild type hNaV1.4 which is Ca(2+) insensitive and the mutant channel exhibits a depolarizing shift of the V1/2 of inactivation with CaM over expression. In contrast the same mutation in the rNaV1.4 channel background (rNaV1.4F1698I) 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 NaV1.4 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 INa decay in a Ca(2+)-sensitive fashion. The combination of the altered voltage dependence and kinetics of INa decay contribute to the myotonic phenotype and may involve the Ca(2+)-sensing apparatus in the CT of NaV1.4.
authors: Department of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors: Subrata
authors: S
authors: Biswas
authors: Deborah A
authors: DA
authors: DiSilvestre
authors: Peihong
authors: P
authors: Dong
authors: Gordon F
authors: GF
authors: Tomaselli
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism*; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating; D007700:Kinetics; D008564:Membrane Potentials / Q000235:genetics*; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009222:Myotonia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D062553:NAV1.4 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D017434:Protein Structure, Tertiary; D051381:Rats
chemical_list: D002147:Calmodulin; D062553:NAV1.4 Voltage-Gated Sodium Channel; C106251:SCN4A protein, human; D002118:Calcium