Voltage-gated sodium channel expression and action potential generation in differentiated NG108-15 cells

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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Molecular pharmacology of voltage-gated sodium channel expression in metastatic disease: Clinical potential of neonatal Nav1.5 in breast cancer

European Journal of Pharmacology ◽

10.1016/j.ejphar.2009.08.040 ◽

2009 ◽

Vol 625 (1-3) ◽

pp. 206-219 ◽

Cited By ~ 71

Author(s):

Rustem Onkal ◽

Mustafa B.A. Djamgoz

Keyword(s):

Breast Cancer ◽

Sodium Channel ◽

Metastatic Disease ◽

Molecular Pharmacology ◽

Voltage Gated Sodium Channel ◽

Voltage Gated ◽

Channel Expression ◽

Clinical Potential

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Neurological Effects of Marine Toxins

10.1093/med/9780199937837.003.0178 ◽

2017 ◽

Author(s):

Kazuma Nakagawa

Keyword(s):

Action Potential ◽

Domoic Acid ◽

Signs And Symptoms ◽

Na Channels ◽

Action Potential Generation ◽

Potential Generation ◽

Marine Toxins ◽

Voltage Gated ◽

Distinct Mechanism ◽

Neurological Effects

Human ingestion of marine toxins can produce various neurological effects, often involving the voltage-gated Na+ channels that are critical for action potential generation and propagation. Diagnosis for most marine neurotoxin is made clinically, and thus recognizing the signs and symptoms of each toxin, and obtaining the appropriate history, is essential. Major marine neurotoxins-tetrodotoxin, saxitoxin, ciguatoxin, brevetoxin, and domoic acid, have a distinct mechanism and clinical manifestation.

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Voltage-gated sodium channels in neocortical pyramidal neurons display Cole-Moore activation kinetics

10.1101/164210 ◽

2017 ◽

Author(s):

Mara Almog ◽

Tal Barkai ◽

Angelika Lampert ◽

Alon Korngreen

Keyword(s):

Action Potential ◽

Sodium Channels ◽

Pyramidal Neurons ◽

Brain Slices ◽

Action Potential Generation ◽

Potential Generation ◽

Voltage Gated ◽

Voltage Gated Sodium Channels ◽

Gating Mechanism ◽

Cortical Pyramidal Neurons

AbstractExploring the properties of action potentials is a crucial step towards a better understanding of the computational properties of single neurons and neural networks. The voltage-gated sodium channel is a key player in action potential generation. A comprehensive grasp of the gating mechanism of this channel can shed light on the biophysics of action potential generation. Most models of voltage-gated sodium channels assume it obeys a concerted Hodgkin and Huxley kinetic gating scheme. Here we performed high resolution voltage-clamp experiments from nucleated patches extracted from the soma of layer 5 (L5) cortical pyramidal neurons in rat brain slices. We show that the gating mechanism does not follow traditional Hodgkin and Huxley kinetics and that much of the channel voltage-dependence is probably due to rapid closed-closed transitions that lead to substantial onset latency reminiscent of the Cole-Moore effect observed in voltage-gated potassium conductances. This may have key implications for the role of sodium channels in synaptic integration and action potential generation.

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