Structure and function of a novel voltage-gated, tetrodotoxin-resistant sodium channel specific to sensory neurons.

Introduction: Arrhythmogenic cardiomyopathy (AC) is characterized by bi-ventricular dilation, fibro-fatty infiltration and life-threatening arrhythmias. Disruptions in cardiac voltage-gated sodium channel (Nav1.5) expression and function are known to cause arrhythmias. We have demonstrated that cardiac-specific overexpression of human mutant desmoplakin (DSP, Tg-R2834H) in mice leads to AC. However, whether mutant DSP expression in the heart affects the Nav1.5 distribution and function are unknown Hypothesis: Here, we tested whether Nav1.5 localization and expression are altered in the R2834H-Tg mouse hearts. Methods: Primary cardiomyocytes and frozen myocardial sections from non-transgenic (NTg), wild-type DSP (Tg-DSP) and Tg-R2834H mice were used for immunofluorescence studies to assess subcellular localization of DSP, desmin, Nav1.5, Cx43, plakoglobin and β-catenin. Western blot and qPCR were used for quantitative analysis. Results: Double staining of cardiomyocytes from NTg mice with DSP and Nav1.5 revealed that Nav1.5 was colocalized with DSP at the intercalated discs (IDs). In contrast, Tg-R2834H cardiomyocytes exhibited marked increase of mutant DSP expression at the IDs concomitant with a reduction in Nav1.5 immunoreactive signals. Tg-R2834H cardiomyocytes also revealed an aberration of DSP and desmin colocalizations at the IDs. There were not obvious differences in Cx43 expression between the genotypes, although the redistribution of Cx43 from the IDs to the sarcolemma was evident in Tg-R2834H cardiomyocytes. qPCR results correlated with reduced Nav1.5 mRNA expression in the Tg-R2834H mouse hearts. Conclusions: Defective DSP protein expression in the heart disrupts Nav1.5 localization and expression, implying an interaction between DSP and Nav1.5 to orchestrate normal mechanical and electrical coupling. Further electrophysiology studies to assess whole-cell Na + currents in these cardiomyocytes will provide insight into DSP and Nav1.5 interaction.

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Insights into the structure and function of HV1 from a meta-analysis of mutation studies

The Journal of General Physiology ◽

10.1085/jgp.201611619 ◽

2016 ◽

Vol 148 (2) ◽

pp. 97-118 ◽

Cited By ~ 16

Author(s):

Thomas E. DeCoursey ◽

Deri Morgan ◽

Boris Musset ◽

Vladimir V. Cherny

Keyword(s):

Amino Acid ◽

Ion Channel ◽

Meta Analysis ◽

Structure And Function ◽

Proton Channel ◽

Vast Array ◽

Voltage Gated ◽

Interspecies Differences ◽

And Function ◽

Sheer Number

The voltage-gated proton channel (HV1) is a widely distributed, proton-specific ion channel with unique properties. Since 2006, when genes for HV1 were identified, a vast array of mutations have been generated and characterized. Accessing this potentially useful resource is hindered, however, by the sheer number of mutations and interspecies differences in amino acid numbering. This review organizes all existing information in a logical manner to allow swift identification of studies that have characterized any particular mutation. Although much can be gained from this meta-analysis, important questions about the inner workings of HV1 await future revelation.

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