Physiology and Pathophysiology of Sodium Channel Inactivation

Mr, Ghovanloo; Aimar, K; Ghadiry-Tavi, R; A, Yu; Pc, Ruben

doi:10.1016/bs.ctm.2016.04.001

Cited by 39 publications

(44 citation statements)

References 144 publications

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“…Notably, the concept that slow inactivation is tied to a VSDIV transition subsequent to activation supports previous models proposing that Na v channel voltage sensor immobilization and slow inactivation are coupled (1,(15)(16)(17)(18)36). Taken together, our results provide support for a VSDIV-centric model of Na v 1.1 inactivation in which both fast and slow inactivation processes are coupled to sequential movements of this voltage sensor (Fig.…”

Section: Resultssupporting

confidence: 76%

“…The first step initiates fast inactivation and corresponds to the transition of VSDIV from the resting state to the activated state, a step that accounts for the majority of gating charge movement (15,(32)(33)(34)(35). The second, more weakly voltage-dependent, transition moves the activated VSDIV to an immobilized state that is coupled to selectivity filter collapse and slow inactivation, as has been proposed for other voltage-gated channels (14,17,36). The effect of Hm1a (10) on Na v 1.1 (Figs.…”

Section: Resultsmentioning

confidence: 99%

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Pharmacology of the Na _v 1.1 domain IV voltage sensor reveals coupling between inactivation gating processes

Osteen

Sampson

Iyer

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Significance Na v 1.1 is a potential therapeutic target for brain disorders, such as epilepsy, Alzheimer's disease, and autism. Moreover, this voltage-gated sodium (Na v ) channel subtype contributes to mechanical pain by regulating excitability in a specific subset of sensory neurons within the peripheral nervous system. The results of our study shed light on the molecular mechanisms underlying Na v 1.1 inactivation and suggest pharmacologic approaches to address relevant disease-related phenotypes.

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Section: Resultssupporting

confidence: 76%

Section: Resultsmentioning

confidence: 99%

Pharmacology of the Na _v 1.1 domain IV voltage sensor reveals coupling between inactivation gating processes

Osteen

Sampson

Iyer

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…The sodium current passing through these channels initiates action potentials in neurons, and skeletal and cardiac muscles. Nav channels are hetero-multimeric proteins composed of large, ion conducting α-subunits and smaller auxiliary β-subunits [1][2][3][4][5][6][7]. The α-subunit is made up of a single gene transcript that encodes four 6-transmembrane segment domains [1].…”

Section: Introductionmentioning

confidence: 99%

“…The α-subunit is made up of a single gene transcript that encodes four 6-transmembrane segment domains [1]. Each one of these four structural domains can be divided by function into the voltagesensing domain (VSD) and the pore domain (PD) [1,2]. These two functional domains are connected through the intracellular S4-S5 linker [1,8].…”

Section: Introductionmentioning

confidence: 99%

“…These two functional domains are connected through the intracellular S4-S5 linker [1,8]. The VSD is formed by the first four transmembrane segments of each domain and the PD is formed by the 5 th and 6 th segments along with the extracellular pore loop that connects them [1,2]. In a simplified model, the sodium channel can exist in three fundamental states: resting, open, and inactivated [1].…”

Section: Introductionmentioning

confidence: 99%

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Effects of acidosis on neuronal voltage-gated sodium channels: Nav1.1 and Nav1.3

2018

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Voltage-gated sodium channels are key contributors to membrane excitability. These channels are expressed in a tissue-specific manner. Mutations and modulation of these channels underlie various physiological and pathophysiological manifestations. The effects of changes in extracellular pH on channel gating have been studied on several sodium channel subtypes. Among these, Nav1.5 is the most pH-sensitive channel, with Nav1.2 and Nav1.4 being mostly pH-resistant channels. However, pH effects have not been characterized on other sodium channel subtypes. In this study, we sought to determine whether Nav1.1 and Nav1.3 display resistance or sensitivity to changes in extracellular pH. These two sodium channel subtypes are predominantly found in inhibitory neurons. The expression of these channels highly depends on age and the developmental stage of neurons, with Nav1.3 being found mostly in neonatal neurons, and Nav1.1 being found in adult neurons. Our present results indicate that, during extracellular acidosis, both channels show a depolarization in the voltage-dependence of activation and moderate reduction in current density. Voltage-dependence of steady-state fast inactivation and recovery from fast inactivation were unchanged. We conclude that Nav1.1 and Nav1.3 have similar pH-sensitivities.

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Recent advances in computational studies on voltage‐gated sodium channels: Drug design and mechanism studies

Wang

Chen

et al. 2022

WIREs Comput Mol Sci

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Voltage-gated sodium channels (VGSCs/Na v s), which control the flow of Na + and affect the generation of action potentials (APs), have been regarded as essential targets for many diseases. The biological and pharmacological functions of VGSCs have been extensively studied and many efforts have been made to discover and design ligands of VGSCs as potential therapies. Here, we summarize the recent and representative studies of VGSCs from the perspective of computer-aided drug design (CADD) and molecular modeling, including the structural biology of VGSCs, virtual screening and drug design toward VGSCs based on CADD, and functional studies using molecular modeling technologies. Furthermore, we conclude the achievements that have been made in the field of VGSCs and discuss the shortcomings found in previous studies. We hope that this review can provide some inspiration and reference for future investigations of VGSCs and drug design. This article is categorized under:Structure and Mechanism > Computational Biochemistry and Biophysicscomputer-aided drug design, molecular dynamic simulation, structural biology, voltage-gated sodium channels | INTRODUCTIONVoltage-gated sodium channels (VGSCs/Na v s) are widely expressed in eukaryotes and prokaryotes, and play especially important roles in the generation and propagation of action potentials (APs). 1,2 Since Hodgkin and Huxley successfully recorded the first Na + -based APs from the giant axons of the squid Loligo, 3,4 researchers came to realize the important role of VGSCs in nerve impulse conduction, which opened a new door for VGSCs studies. To date, 10 subtypes of VGSCs (Na v 1.1-Na v 1.9 and Nax) have been found in mammals, and each subtype has its own unique functions (Table S1). Na v 1.1, Na v 1.2, Na v 1.3, and Na v 1.6 are primarily expressed in the central nervous system (CNS), and associated with many diseases such as epilepsy, migraine, autism, and ataxia. 5 Na v 1.4 is predominantly expressed in skeletal

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Physiology and Pathophysiology of Sodium Channel Inactivation

Cited by 39 publications

References 144 publications

Pharmacology of the Na _v 1.1 domain IV voltage sensor reveals coupling between inactivation gating processes

Pharmacology of the Na _v 1.1 domain IV voltage sensor reveals coupling between inactivation gating processes

Effects of acidosis on neuronal voltage-gated sodium channels: Nav1.1 and Nav1.3

Recent advances in computational studies on voltage‐gated sodium channels: Drug design and mechanism studies

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Physiology and Pathophysiology of Sodium Channel Inactivation

Cited by 39 publications

References 144 publications

Pharmacology of the Na v 1.1 domain IV voltage sensor reveals coupling between inactivation gating processes

Pharmacology of the Na v 1.1 domain IV voltage sensor reveals coupling between inactivation gating processes

Effects of acidosis on neuronal voltage-gated sodium channels: Nav1.1 and Nav1.3

Recent advances in computational studies on voltage‐gated sodium channels: Drug design and mechanism studies

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Pharmacology of the Na _v 1.1 domain IV voltage sensor reveals coupling between inactivation gating processes

Pharmacology of the Na _v 1.1 domain IV voltage sensor reveals coupling between inactivation gating processes