scholarly journals Trafficking and Function of the Voltage-Gated Sodium Channel β2 Subunit

Biomolecules ◽  
2019 ◽  
Vol 9 (10) ◽  
pp. 604 ◽  
Author(s):  
Eric Cortada ◽  
Ramon Brugada ◽  
Marcel Verges
Keyword(s):  
Sodium Channel ◽  
Electrical Coupling ◽  
Surface Expression ◽  
Current Data ◽  
Cell Surface Expression ◽  
Gene Encoding ◽  
Voltage Gated Sodium Channel ◽  
Α Subunit ◽  
Voltage Gated

The voltage-gated sodium channel is vital for cardiomyocyte function, and consists of a protein complex containing a pore-forming α subunit and two associated β subunits. A fundamental, yet unsolved, question is to define the precise function of β subunits. While their location in vivo remains unclear, large evidence shows that they regulate localization of α and the biophysical properties of the channel. The current data support that one of these subunits, β2, promotes cell surface expression of α. The main α isoform in an adult heart is NaV1.5, and mutations in SCN5A, the gene encoding NaV1.5, often lead to hereditary arrhythmias and sudden death. The association of β2 with cardiac arrhythmias has also been described, which could be due to alterations in trafficking, anchoring, and localization of NaV1.5 at the cardiomyocyte surface. Here, we will discuss research dealing with mechanisms that regulate β2 trafficking, and how β2 could be pivotal for the correct localization of NaV1.5, which influences cellular excitability and electrical coupling of the heart. Moreover, β2 may have yet to be discovered roles on cell adhesion and signaling, implying that diverse defects leading to human disease may arise due to β2 mutations.

scholarly journals Novel mutation of SCN9A gene causing generalized epilepsy with febrile seizures plus in a Chinese family

2020 ◽  
Vol 41 (7) ◽  
pp. 1913-1917 ◽  
Author(s):  
Tian Zhang ◽  
Mingwu Chen ◽  
Angang Zhu ◽  
Xiaoguang Zhang ◽  
Tao Fang
Keyword(s):  
Sodium Channel ◽  
Febrile Seizures ◽  
Chinese Family ◽  
Heterozygous Mutation ◽  
Gene Encoding ◽  
Voltage Gated Sodium Channel ◽  
Α Subunit ◽  
Voltage Gated ◽  
Generalized Epilepsy ◽  
Febrile Seizures Plus

Abstract Generalized epilepsy with febrile seizures plus (GEFS+) is a complex familial epilepsy syndrome. It is mainly caused by mutations in SCN1A gene, encoding type 1 voltage-gated sodium channel α-subunit (NaV1.1), and GABRA1 gene, encoding the α1 subunit of the γ-aminobutyric acid type A (GABAA) receptor, while seldom related with SCN9A gene, encoding the voltage-gated sodium channel NaV1.7. In this study, we investigated a Chinese family with an autosomal dominant form of GEFS+. DNA sequencing of the whole coding region revealed a novel heterozygous nucleotide substitution (c.5873A>G) causing a missense mutation (p.Y1958C). This mutation was predicted to be deleterious by three different bioinformatics programs (The polyphen2, SIFT, and MutationTaster). Our finding reports a novel likely pathogenic SCN9A Y1958C heterozygous mutation in a Chinese family with GEFS+ and provides additional supports that SCN9A variants may be associated with human epilepsies.

Abstract 17384: Cardiac-Specific Overexpression of Human Mutant Desmoplakin in Mice Disrupts Cardiac Voltage-Gated Sodium Channel Expression

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Subat Turdi ◽  
Jeffrey A Towbin
Keyword(s):  
Sodium Channel ◽  
Fatty Infiltration ◽  
Electrical Coupling ◽  
Cx43 Expression ◽  
Voltage Gated Sodium Channel ◽  
Voltage Gated ◽  
Intercalated Discs ◽  
Channel Expression ◽  
Life Threatening ◽  
And Function

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.

scholarly journals In vivo optogenetic activation of Nav1.8+ cutaneous nociceptors and their responses to natural stimuli

2017 ◽  
Vol 117 (6) ◽  
pp. 2218-2223 ◽  
Author(s):  
Megan L. Uhelski ◽  
Daniel J. Bruce ◽  
Philippe Séguéla ◽  
George L. Wilcox ◽  
Donald A. Simone
Keyword(s):  
Sodium Channel ◽  
Blue Light ◽  
Functional Properties ◽  
Nerve Fibers ◽  
Voltage Gated Sodium Channel ◽  
Voltage Gated ◽  
Multiple Stimulus ◽  
C Fiber ◽  
Stimulus Modalities

Optogenetic methods that utilize expression of the light-sensitive protein channelrhodopsin-2 (ChR2) in neurons have enabled selective activation of specific subtypes or groups of neurons to determine their functions. Using a transgenic mouse model in which neurons natively expressing Nav1.8 (a tetrodotoxin-resistant voltage-gated sodium channel) also express the light-gated channel ChR2, we have been able to determine the functional properties of Nav1.8-expressing cutaneous nociceptors of the glabrous skin in vivo. Most (44 of 53) of the C-fiber nociceptors isolated from Nav1.8-ChR2+ mice were found to be responsive to blue (470 nm) light. Response characteristics, including conduction velocity and responses to mechanical stimuli, were comparable between nociceptors isolated from Nav1.8-ChR2+ and control mice. Interestingly, while none of the non–light-responsive C-fibers were sensitive to heat or cold, nearly all (77%) light-sensitive fibers were excited by mechanical and thermal stimuli, suggesting that Nav1.8 is predominantly expressed by C-fiber nociceptors that are responsive to multiple stimulus modalities. The ability to activate peripheral nociceptors with light provides a method of stimulation that is noninvasive, does not require mechanical interruption of the skin, and accesses receptive fields that might be difficult or impossible to stimulate with standard stimuli while allowing repeated stimulation without injuring the skin. NEW & NOTEWORTHY Transgenic mice that express the blue light-sensitive protein channelrhodopsin2 (ChR2) in nociceptive nerve fibers that contain voltage-gated sodium channel Nav1.8 were used to determine functional properties of these afferent fibers. Electrophysiological recordings in vivo revealed that most nociceptive fibers that possess Nav1.8 are C-fiber nociceptors that respond to multiple stimulus modalities. Furthermore, responses evoked by blue light stimulation were comparable to those elicited by noxious mechanical, heat, and cold stimuli.

scholarly journals Interactions of disulfide-deficient selenocysteine analogs of μ-conotoxin BuIIIB with the α-subunit of the voltage-gated sodium channel subtype 1.3

FEBS Journal ◽  
2014 ◽  
Vol 281 (13) ◽  
pp. 2885-2898 ◽  
Author(s):  
Brad R. Green ◽  
Min-Min Zhang ◽  
Sandeep Chhabra ◽  
Samuel D. Robinson ◽  
Michael J. Wilson ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Voltage Gated Sodium Channel ◽  
Α Subunit ◽  
Voltage Gated

scholarly journals The voltage-gated sodium channel β2 subunit associates with lipid rafts by S-palmitoylation

2021 ◽  
Vol 134 (6) ◽  
Author(s):  
Eric Cortada ◽  
Robert Serradesanferm ◽  
Ramon Brugada ◽  
Marcel Verges
Keyword(s):  
Sodium Channel ◽  
Lipid Rafts ◽  
Lipid Raft ◽  
Cholesterol Depletion ◽  
Slight Reduction ◽  
Apical Surface ◽  
Voltage Gated Sodium Channel ◽  
Α Subunit ◽  
Voltage Gated ◽  
Partial Overlap

ABSTRACT The voltage-gated sodium channel is critical for cardiomyocyte function. It consists of a protein complex comprising a pore-forming α subunit and associated β subunits. In polarized Madin–Darby canine kidney cells, we show evidence by acyl-biotin exchange that β2 is S-acylated at Cys-182. Interestingly, we found that palmitoylation increases β2 association with detergent-resistant membranes. β2 localizes exclusively to the apical surface. However, depletion of plasma membrane cholesterol, or blocking intracellular cholesterol transport, caused mislocalization of β2, as well as of the non-palmitoylable C182S mutant, to the basolateral domain. Apical β2 did not undergo endocytosis and displayed limited diffusion within the plane of the membrane; such behavior suggests that, at least in part, it is cytoskeleton anchored. Upon acute cholesterol depletion, its mobility was greatly reduced, and a slight reduction was also measured as a result of lack of palmitoylation, supporting β2 association with cholesterol-rich lipid rafts. Indeed, lipid raft labeling confirmed a partial overlap with apical β2. Although β2 palmitoylation was not required to promote surface localization of the α subunit, our data suggest that it is likely implicated in lipid raft association and the polarized localization of β2.

Sign in / Sign up

Export Citation Format

Share Document