Multiple Nav1.5 isoforms are functionally expressed in the brain and present distinct expression patterns compared with cardiac Nav1.5

Wang, Jun; Ou, Shaowu; Bai, Ya Na; Wang, Yun‐Jie; Xu, Zhi‐Qing David; Luan, Guoming

doi:10.3892/mmr.2017.6654

Cited by 10 publications

(8 citation statements)

References 47 publications

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“…Electrophysiological analysis of Nav1.5 in rat brain slices revealed that the TTX-resistant Na current is activated at ¡40 mV and reaches a maximum amplitude at 0 Mv. 57 This study with electrophysiological analysis further confirmed the functional expression of Nav1.5 in brain neurons. Thus, the significance of specific Nav1.5 channel variants in the CNS and their relationship with the normal and abnormal electrophysiological activities of neurons warrants further investigation.…”

Section: Vgsc a Subunits In The Cnssupporting

confidence: 66%

“…25,[53][54][55][56] Recently, we systematically investigated the expression of various Nav1.5 splice variants and their associated electrophysiological properties in rat brain tissue via biochemical analyses and wholecell patch-clamp recording methods. 57 The results demonstrated that several Nav1.5 splice variants are expressed in the rat brain at different expression ratios. Electrophysiological analysis of Nav1.5 in rat brain slices revealed that the TTX-resistant Na current is activated at ¡40 mV and reaches a maximum amplitude at 0 Mv.…”

Section: Vgsc a Subunits In The Cnsmentioning

confidence: 88%

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Distribution and function of voltage-gated sodium channels in the nervous system

2017

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Voltage-gated sodium channels (VGSCs) are the basic ion channels for neuronal excitability, which are crucial for the resting potential and the generation and propagation of action potentials in neurons. To date, at least nine distinct sodium channel isoforms have been detected in the nervous system. Recent studies have identified that voltage-gated sodium channels not only play an essential role in the normal electrophysiological activities of neurons but also have a close relationship with neurological diseases. In this study, the latest research findings regarding the structure, type, distribution, and function of VGSCs in the nervous system and their relationship to neurological diseases, such as epilepsy, neuropathic pain, brain tumors, neural trauma, and multiple sclerosis, are reviewed in detail.

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Section: Vgsc a Subunits In The Cnssupporting

confidence: 66%

Section: Vgsc a Subunits In The Cnsmentioning

confidence: 88%

Distribution and function of voltage-gated sodium channels in the nervous system

2017

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“…Interestingly, co-expression of the Tyr-181 or Cys-162 b1 mutants resulted in increased peak I Na density and maximal conductance. Finally, although Na v 1.5 is the major cardiac VGSC, a sizable body of work in recent years has also identified Na v 1.5 in the brain (51)(52)(53), suggesting that our results may be applicable to other VGSCs.…”

Section: Discussionmentioning

confidence: 73%

Sodium channel β1 subunits are post-translationally modified by tyrosine phosphorylation, S-palmitoylation, and regulated intramembrane proteolysis

Bouza

Philippe

Edokobi

et al. 2020

Journal of Biological Chemistry

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Voltage-gated sodium channel (VGSC) β1 subunits are multifunctional proteins that modulate the biophysical properties and cell-surface localization of VGSC α subunits and participate in cell–cell and cell–matrix adhesion, all with important implications for intracellular signal transduction, cell migration, and differentiation. Human loss-of-function variants in SCN1B, the gene encoding the VGSC β1 subunits, are linked to severe diseases with high risk for sudden death, including epileptic encephalopathy and cardiac arrhythmia. We showed previously that β1 subunits are post-translationally modified by tyrosine phosphorylation. We also showed that β1 subunits undergo regulated intramembrane proteolysis (RIP) via the activity of β-secretase 1 (BACE1) and γ-secretase, resulting in the generation of a soluble intracellular domain, β1-ICD, which modulates transcription. Here, we report that β1 subunits are phosphorylated by FYN kinase. Moreover, we show that β1 subunits are S-palmitoylated. Substitution of a single residue in β1, Cys-162, to alanine prevented palmitoylation, reduced the level of β1 polypeptides at the plasma membrane, and reduced the extent of β1 RIP, suggesting that the plasma membrane is the site of β1 proteolytic processing. Treatment with the clathrin-mediated endocytosis inhibitor Dyngo-4a restored plasma membrane association of β1-p.C162A to WT levels. Despite these observations, palmitoylation-null β1-p.C162A modulated sodium current and sorted to detergent-resistant membrane fractions normally. This is the first demonstration of S-palmitoylation of a VGSC β subunit, establishing precedence for this post-translational modification as a regulatory mechanism in this protein family.

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“…Here, we attempted to reconcile this apparent disconnect between structural and electrophysiological studies. Because β-subunits have been shown to alter voltage sensor movements to produce their functional changes in Nav1.5 channels (Zhu et al, 2017), we began by investigating the contributions of each voltage sensor to the gating of Nav1.5e, a neonatal form of Nav1.5 that is expressed in the brain (Wang et al, 2017). Using voltage-sensor neutralization experiments, voltage-clamp fluorometry (VCF), and kinetic modelling, we find that the functional contributions of each voltage sensor are not fixed.…”

Section: Introductionmentioning

confidence: 99%

Intrinsic Gating Behavior of Voltage-Gated Sodium Channels Predetermines Regulation by Auxiliary β-subunits

Brake

Yan

et al. 2021

Preprint

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Voltage-gated sodium (Nav) channels mediate rapid millisecond electrical signaling in excitable cells. Auxiliary subunits, β1-β4, are thought to regulate Nav channel function through covalent and/or polar interactions with the channel's voltage-sensing domains. How these interactions translate into the diverse and variable regulatory effects of β-subunits remains unclear. Here, we find that the intrinsic movement order of the voltage-sensing domains during channel gating is unexpectedly variable across Nav channel isoforms. This movement order dictates the channel's propensity for closed-state inactivation, which in turn modulates the actions of β1 and β3. We show that the differential regulation of skeletal muscle, cardiac, and neuronal Nav channels is explained by their variable levels of closed-state inactivation. Together, this study provides a unified mechanism for the regulation of all Nav channel isoforms by β1 and β3, which explains how the fixed structural interactions of auxiliary subunits can paradoxically exert variable effects on channel function.

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Multiple Nav1.5 isoforms are functionally expressed in the brain and present distinct expression patterns compared with cardiac Nav1.5

Cited by 10 publications

References 47 publications

Distribution and function of voltage-gated sodium channels in the nervous system

Distribution and function of voltage-gated sodium channels in the nervous system

Sodium channel β1 subunits are post-translationally modified by tyrosine phosphorylation, S-palmitoylation, and regulated intramembrane proteolysis

Intrinsic Gating Behavior of Voltage-Gated Sodium Channels Predetermines Regulation by Auxiliary β-subunits

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