What do voltage gated sodium channels do

The Hodgkin-Huxley model describes how action potentials in neurons are initiated and propagated [ 4 ]. Originally developed to fit action potential dynamics of squid giant axon, this model has been successfully applied to a wide range of neurons. It describes the electrical properties of excitable membranes as typical electrical circuit components. From Hodgkin-Huxley model, the total cell membrane current, I, can be calculated by Eq. In , an extracellular recording technique, electrocardiography, was invented by Willem Einthoven Nobel Laureate ; in , intracellular recording technique was developed by Alan Hodgkin and Andrew Huxley Nobel Laureates ; and in , Erwin Neher and Bert Sackmann Noble Laureates succeeded in measuring the ionic current of single channels in the cell membrane by developing patch clamp technique.

These works were fundamental in revealing the physiological function of ion channels. Since then, the field of electrophysiology had undergone rapid evolution, especially after the introduction of automated patch clamp in the early s. Manual patch clamp technique employs glass microelectrode s with desired filling solution and tip diameter to perform either voltage or current clamp. By applying different following-up manipulations, the patch-clamp can be achieved in four configurations: cell-attached patch, whole-cell patch, inside-out patch, and outside-out patch, as shown in Figure 3.

Manual patch clamp configurations and procedures. After a cell is approached by a pipette A , a high-resistance seal is achieved through application of negative pressure, resulting in the cell-attached configuration B.

Further application of negative pressure ruptures the membrane, resulting in the whole-cell configuration, i. Inside-out and outside-out configurations are achieved by pulling the pipette away from the cell D and E. F An equivalent electrical circuit of a cell in whole-cell configuration during acquisition of data.

Modified from [ 5 ]. Many other electrophysiological techniques have been developed for various applications, including extracellular recordings such as electroencephalography EEG , electrocardiography ECG or EKG , and electromyography EMG for clinical diagnosis; artificial lipid bilayer recording for studying activities of reconstituted ion channel proteins; automated patch clamp recording to enable high-throughput recordings; and optogenetics to employ light to switch on and off ion channel activities.

The technology evolution has brought the ion channel research and drug discovery to a new era, which will be discussed in later part of this chapter.

Nav channels were the first ion channel family discovered back in [ 1 , 4 ] and cloned in [ 6 ]. Its pedigree spans across prokaryotic and eukaryotic kingdoms [ 7 ]. The BacNavs regulate the survival response to extreme pH, electrophiles, and hypoosmotic shock. Despite their markedly difference in physiology function, voltage dependence and kinetics, BacNavs share common features of mammalian Nav channels, thus serving as surrogates in the study of molecular evolution and channel architecture.

Nav family belongs to the voltage-gated ion channel VGIC superfamily, with less intrafamily variation comparing to the other two VGIC families, voltage-gated potassium channels Kvs and voltage-gated calcium channels Cavs. The first four transmembrane segments form a voltage-sensing domain VSD and the last two form the pore domain PD.

The central PD is responsible for ion-transduction through the structural top funnel, selectivity filter and gate, and all other domains are served as regulatory modlues for activation, fast and slow inactivation, albeit with different natures and structures. A typical Nav channel has at least three distinct states, resting closed , activated open , inactivated closed , which itself includes fast-inactivated within milliseconds and slow-inactivated seconds , and recovering from inactivation repriming , which is a period in which the channel is not available to open in response to a depolarization.

Each Nav channel can be characterized by these different voltage-dependent biophysiological preporties, and pharmacological perporties according to its expression pattern and modulation. Structures of voltage-gated sodium channels. Modified from [ 12 , 15 ]. A Schematic representation of BacNav. B Schematic representation of eukaryotic Navs. E The pore domain sodium permeation path including selectivity filter, central cavity, and intracellular activation gate are colored in brown and annotated with pore radius.

In human, there are 9 Nav channels Nav1. Thus, Nax was classified as a different Nav subfamily type 2 [ 16 , 17 ]. Due to their fundamental role in regulating central and peripheral nervous systems function, skeletal muscle contraction and heart rhythm, much of the early works on Navs involved characterizing their expression patterns, biophysiological properties, structure-function, and molecular pharmacology.

Compared to Cav and Kv channel family, the rise of Nav family is relatively recent [ 18 ]. This is supported by the finding that the four domains of Navs have higher similarity to their corresponding domains in the Cav channels than to each other. The ancestral Navs and Cavs genes might have evolved by two rounds of gene duplication, i.

In choanoflagellate the sister group of animals , the rapid long-distance communication among excitable cells is achieved at the emergence of Metazoa represented by bilaterian animals and cnidarians through the use of Nav channel [ 20 , 21 ]. The gene organization, biophysical, and pharmacological properties of invertebrate sodium channels are largely similar to their mammalian counterparts, suggesting that the primordial Nav channels were established before the evolutionary separation of the invertebrates from the vertebrates, and evolution of Navs played a critical role in the emergence of nervous systems in animals [ 19 , 22 ].

Of note, sodium selectivity might be acquired independently in BacNav and mammalian Nav channels as indicated by phylogenetic analysis [ 23 ]. Therefore, BacNav channels can serve as models for studying Navs structure function, but evolutionary variation should be taken into consideration.

Historically, the tissue distribution of mammalian Nav isoforms was obtained by methods such as quantitative PCR, expressed sequence tag EST profiling, and pharmacology study using isoform selective toxins. Now, we know that Nav1. Interestingly, all of these CNS-enriched isoforms are sensitive to tetrodotoxin TTX at nanomolar concentrations, and their genes are clustered on chromosome 2 in both mice and humans.

Sodium channel body atlas in human. More sensitive approaches have detected Nav1. These two Nav isoforms can be distinguished from each other and from the CNS isoforms on the basis of toxin sensitivity. Adult skeletal muscle-enriched Nav1. In addition, Nav1. This PNS-specific localization of Nav1.

The structure complexity and high-sequence homology make it difficult to design subtype-selective drugs. In , the first X-ray crystal structure of bacterial Arcobacter butzleri Nav channels NavAb was determined [ 32 ].

Subsequently, structures for several BacNavs and a BacNav-human Nav chimeric channel have been resolved, representing closed [ 33 , 34 ], open [ 34 , 35 ], and potentially inactive states of the channels [ 36 , 37 ]. In , the first two eukaryotic Nav structures for American cockroach and electric eel Ee Nav1. Findings from crystal and cryo-EM structures are mostly consistent, and collectively provided important insights into Nav channel structure-function and structure-based drug design.

Voltage-sensing domains VSDs. The S1 to S4 segments form voltage-sensing domain. There are four VSDs in a sodium channel. These charge clusters move toward the extracellular surface upon membrane depolarization and return to their resting positions upon membrane repolarization.

Thus, the outward and inward movements of S4 result in channel opening and closing, respectively. For examples, the four VSDs have nonconserved intra- and extracellular loops, and the different charge clusters in S4, i.

Also, the S2 in each VSD also makes asymmetric functional contributions to Nav channel activation and inactivation [ 38 ]. The functional entities along the ion permeation pathway in PD include the selectivity filter SF , the central cavity, and the intracellular activation gate, as shown in Figure 4E. The outer vestibule and selectivity filter are formed in P-loop reentering membrane segments, designated as P1-SF-P2 funnel.

The outer vestibule and SF structures were further discerned by using bacteria KcsA channel X-ray structure as template and guanidinium toxins TTX and saxitoxin, STX , which successfully defined the first pharmacological relevant site on Nav channels, site 1 [ 42 ].

In most cases, sodium channel Nav1. However, the TTX-R resurgent currents exhibit much slower kinetics, occur at more depolarized voltages, and are sensitive to the Nav1.

Moreover, coimmunopptn. We propose that these slow TTX-R resurgent currents contribute to the membrane excitability of nociceptive DRG neurons under normal conditions and that enhancement of both types of resurgent currents by inflammatory mediators could contribute to sensory neuronal hyperexcitability assocd.

Pathophysiological role of omega pore current in channelopathies Front. Biophysics, pathophysiology, and pharmacology of ion channel gating pores Front. Noncanonical roles of voltage-gated sodium channels Neuron , 80 2 — Google Scholar There is no corresponding record for this reference. De novo mutations revealed by whole-exome sequencing are strongly associated with autism Nature , — Google Scholar There is no corresponding record for this reference.

Regulation of cough and action potentials by voltage-gated Na channels Pulm. Elsevier Ltd. The classical role ascribed to voltage-gated Na channels is the conduction of action potentials. Some excitable tissues such as cardiac muscle and skeletal muscle predominantly express a single voltage-gated Na channels isoform.

Of the nine voltage-gated Na channels, seven are expressed in neurons, of these Nav 1. Nav 1. Voltage-gated Na channel isoforms expressed in airway sensory neurons produce multiple distinct Na currents that underlie distinct aspects of sensory neuron function.

The interaction between voltage-gated Na currents underlies the characteristic ability of airway sensory nerves to encode encounters with irritant stimuli into action potential discharge and evoke the cough reflex.

Persistent current blockers of voltage-gated sodium channels: a clinical opportunity for controlling metastatic disease Recent Pat. Channelopathy pathogenesis in autism spectrum disorders Front. Frontiers in genetics , 4 , ISSN: Autism spectrum disorder ASD is a syndrome that affects normal brain development and is characterized by impaired social interaction as well as verbal and non-verbal communication and by repetitive, stereotypic behavior.

ASD is a complex disorder arising from a combination of multiple genetic and environmental factors that are independent from racial, ethnic and socioeconomical status. The high heritability of ASD suggests a strong genetic basis for the disorder. Furthermore, a mounting body of evidence implies a role of various ion channel gene defects channelopathies in the pathogenesis of autism.

Indeed, recent genome-wide association, and whole exome- and whole-genome resequencing studies linked polymorphisms and rare variants in calcium, sodium and potassium channels and their subunits with susceptibility to ASD, much as they do with bipolar disorder, schizophrenia and other neuropsychiatric disorders.

Moreover, animal models with these genetic variations recapitulate endophenotypes considered to be correlates of autistic behavior seen in patients. An ion flux across the membrane regulates a variety of cell functions, from generation of action potentials to gene expression and cell morphology, thus it is not surprising that channelopathies have profound effects on brain functions. In the present work, we summarize existing evidence for the role of ion channel gene defects in the pathogenesis of autism with a focus on calcium signaling and its downstream effects.

BioMed Central Ltd. Background: SCN2A is a gene that codes for the alpha subunit of voltage-gated, type II sodium channels, and is highly expressed in the brain. Sodium channel disruptions, such as mutations in SCN2A, may play an important role in psychiatric disorders. Case Presentation: We describe results from clin.

Psychiatric interview and gold std. Genetic testing by whole exome sequencing revealed four de novo events, including a splice site mutation c. VI change in the TLE1 gene, and two synonymous mutations c. The participant met new DSM-5 criteria for ASD, presenting with social and communication impairment, repetitive behaviors, and sensory reactivity issues. The participant's adaptive and cognitive skills fell in the low range of functioning.

Describing the specific phenotype assocd. Nonfunctional Na v 1. Sodium channels, inherited epilepsy, and antiepileptic drugs Annu. Annual Reviews. Voltage-gated sodium channels initiate action potentials in brain neurons, mutations in sodium channels cause inherited forms of epilepsy, and sodium channel blockers-along with other classes of drugs-are used in therapy of epilepsy.

A mammalian voltage-gated sodium channel is a complex contg. Extensive structure-function studies have revealed many aspects of the mol. These seizure syndromes are treated with antiepileptic drugs that offer differing degrees of success. The recent advances in understanding of disease mechanisms and sodium channel structure promise to yield improved therapeutic approaches. Channelopathies, painful neuropathy, and diabetes: which way does the causal arrow point? Trends Mol. Hoeijmakers, Janneke G.

Diabetes mellitus, a major global health problem, is commonly assocd. Despite its clin. It has traditionally been thought that diabetes may cause neuropathy in patients with appropriate genetic makeup. We suggest that mutations of sodium channel NaV1. Diabetes , 63 , — Google Scholar There is no corresponding record for this reference.

The Na v 1. The voltage-gated sodium channel NaV1. Genetic and functional studies have added to the evidence that NaV1. Painful and painless channelopathies Lancet Neurol. The discovery of genetic variants that substantially alter an individual's perception of pain has led to a step-change in our understanding of mol.

For example, the voltage-gated sodium ion channel Nav1. Heterozygous mutations in TRPA1, which encodes the transient receptor potential cation channel, can cause familial episodic pain syndromes, and variants of genes coding for the voltage-gated sodium channels Nav1.

Furthermore, other genetic polymorphisms have been identified that contribute to risk or severity of more complex pain phenotypes. Novel models of sensory disorders are in development-eg, using human sensory neurons differentiated from human induced pluripotent stem cells.

Understanding rare heritable pain disorders not only improves diagnosis and treatment of patients but may also reveal new targets for analgesic drug development. Neuropathy-associated Na v 1. Wiley-Liss, Inc. Small-fiber neuropathy SFN is characterized by injury to small-diam. Although mechanisms underlying loss of IENF in SFN are poorly understood, available data suggest that it results from axonal degeneration and reduced regenerative capacity.

Gain-of-function variants in sodium channel NaV1. In the present study, to det. IM-induced redn. These in vitro observations provide evidence supporting a contribution of the IM variant NaV1. Ann Neurol Paroxysmal itch caused by gain-of-function Na v 1.

An SCN9A channelopathy causes congenital inability to experience pain Nature , — Google Scholar There is no corresponding record for this reference. Nociceptor-specific gene deletion reveals a major role for Na v 1. Pain , 10 , 7 — 32 Google Scholar There is no corresponding record for this reference. Loss-of-function mutations in sodium channel Na v 1.

Geoffrey; Wood, John N. Here we show that Nav1. We examd. To establish the essential role of Nav1. In the absence of Nav1. The mutant mice no longer display vital, odor-guided behaviors such as innate odor recognition and avoidance, short-term odor learning, and maternal pup retrieval.

Our study creates a mouse model of congenital general anosmia and provides new strategies to explore the genetic basis of the human sense of smell. Global Na v 1. Public Library of Science. The global deletion is reported lethal in mice, however, and studies of mice with promoter-specific deletions of Nav1.

We developed genetic and animal husbandry strategies that overcame the neonatal-lethal phenotype and enabled construction of a global Nav1. Knockouts were anatomically normal, reached adulthood, and had phenotype wholly analogous to human congenital indifference to pain CIP : compared to littermates, knockouts showed no defects in mech.

Knockouts also showed no painful behaviors resulting from peripheral injection of nonselective sodium channel activators, did not develop complete Freund's adjuvant-induced thermal hyperalgesia, and were insensitive to intra-dermal histamine injection.

Tetrodotoxin-sensitive sodium current recorded from cell bodies of isolated sensory neurons and the mech. Results support a role for Nav1. Results further suggest that Nav1. Distinct Na v 1. Human acute and inflammatory pain requires the expression of voltage-gated sodium channel Nav1. Ablating Nav1. Surprisingly, responses to the hotplate test, as well as neuropathic pain, are unaffected when SCN9A is deleted in all sensory neurons.

However, deleting SCN9A in both sensory and sympathetic neurons abolishes these pain sensations and recapitulates the pain-free phenotype seen in humans with SCN9A loss-of-function mutations. These observations demonstrate an important role for Nav1. The molecular basis of acid insensitivity in the African naked mole-rat Science , — Google Scholar There is no corresponding record for this reference.

Gain-of-function Na v 1. The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways Nature Neurosci. Akopian, Armen N. Nature America. Many damage-sensing neurons express tetrodotoxin TTX -resistant voltage-gated sodium channels. Here the authors examd. These mice expressed only TTX-sensitive sodium currents on step depolarizations from normal resting potentials, showing that all slow TTX-resistant currents are encoded by the sns gene.

Null mutants were viable, fertile and apparently normal, although lowered thresholds of elec. Behavioral studies demonstrated a pronounced analgesia to noxious mech.

These data show that SNS is involved in pain pathways and suggest that blockade of SNS expression or function may produce analgesia without side effects. Small interfering RNA-mediated selective knockdown of Na v 1. Methylglyoxal modification of Na v 1. Voltage-gated sodium channel in grasshopper mice defends against bark scorpion toxin Science , — Google Scholar There is no corresponding record for this reference.

Oliver; Stoedberg, Tommy; Hennings, J. The sensation of pain protects the body from serious injury. Using exome sequencing, we identified a specific de novo missense mutation in SCN11A in individuals with the congenital inability to experience pain who suffer from recurrent tissue damage and severe mutilations.

Heterozygous knock-in mice carrying the orthologous mutation showed reduced sensitivity to pain and self-inflicted tissue lesions, recapitulating aspects of the human phenotype. SCN11A encodes Nav1. Mutant Nav1. The gain-of-function mechanism that underlies this channelopathy suggests an alternative way to modulate pain perception. Many ion channel genes have been assocd.

Here we report two large Chinese families with autosomal-dominant episodic pain. We performed a genome-wide linkage scan with microsatellite markers after excluding mutations in three known genes SCN9A, SCN10A, and TRPA1 that cause similar pain syndrome to our findings, and we mapped the genetic locus to a 7.

By using whole-exome sequencing followed by conventional Sanger sequencing, we identified two missense mutations in the gene encoding voltage-gated sodium channel Nav1. ArgCys and c. AlaGly one in each family. Each mutation showed a perfect cosegregation with the pain phenotype in the corresponding family, and neither of them was detected in 1, normal individuals. Both missense mutations were predicted to change a highly conserved amino acid residue of the human Nav1.

We expressed the two SCN11A mutants in mouse dorsal root ganglion DRG neurons and showed that both mutations enhanced the channel's elec. Taken together, our results suggest that gain-of-function mutations in SCN11A can be causative of an autosomal-dominant episodic pain disorder. Upregulation of sodium channel Na v 1. Hains, Bryan C. Spinal cord injury SCI can result in hyperexcitability of dorsal horn neurons and central neuropathic pain.

We hypothesized that these phenomena are consequences, in part, of dysregulated expression of voltage-gated sodium channels. Because the rapidly repriming TTX-sensitive sodium channel Nav1. In this study, adult male Sprague Dawley rats underwent T9 spinal contusion injury.

Four weeks after injury when extracellular recordings demonstrated hyperexcitability of L3-L5 dorsal horn multireceptive nociceptive neurons, and when pain-related behaviors were evident, quant. RT-PCR, in situ hybridization, and immunocytochem. Intrathecal administration of antisense oligodeoxynucleotides ODNs targeting Nav1. Expression of Nav1.

Responses to normally noxious stimuli and motor function were unchanged in SCI animals administered Nav1. These results demonstrate for the first time that Nav1. Treatment of Na v 1. Pain , 4 , ISSN:. Voltage sensor interaction site for selective small molecule inhibitors of voltage-gated sodium channels Proc.

Kay; Swain, Nigel A. National Academy of Sciences. Voltage-gated sodium Nav channels play a fundamental role in the generation and propagation of elec.

Here the authors describe two unique structurally related nanomolar potent small mol. Nav channel inhibitors that exhibit up to fold selectivity for human Nav1. Using both chimeras and single point mutations, the authors demonstrate that this unique class of sodium channel inhibitor interacts with the S1-S4 voltage sensor segment of homologous Domain 4. Amino acid residues in the "extracellular" facing regions of the S2 and S3 transmembrane segments of Nav1.

The unique interaction region on the Domain 4 voltage sensor segment is distinct from the structural domains forming the channel pore, as well as previously characterized interaction sites for other small mol. However, this interaction region does include at least one amino acid residue [E Nav1.

The present study provides a potential framework for identifying subtype selective small mol. Ion channel voltage sensors: structure, function, and pathophysiology Neuron , 67 6 — Google Scholar There is no corresponding record for this reference.

Two tarantula peptides inhibit activation of multiple sodium channels Biochemistry , 41 50 — [ ACS Full Text ], Google Scholar There is no corresponding record for this reference. Discovery of a selective Na v 1. A monoclonal antibody that targets a Na v 1. The phenotype of congenital insensitivity to pain due to the Na v 1.

LP Eur. Tetrodotoxin-resistant voltage-gated sodium channels Na v 1. O'Brien, Brendan J. Bumsted; Luo, Songjiang; Levinson, S. Voltage-gated sodium channels VGSCs are one of the fundamental building blocks of elec. These channels are responsible for the generation of action potentials that are required for the communication of neuronal signals over long distances within a cell.

VGSCs are encoded by a family of nine genes whose products have widely varying biophys. Our mol. The fact that these channels exist in the central nervous system CNS and exhibit robust TTX resistance requires a re-evaluation of prior physiol.

The investigational anticonvulsant lacosamide selectively enhances slow inactivation of voltage-gated sodium channels Mol. Block of human cardiac sodium channels by lacosamide: evidence for slow drug binding along the activation pathway Mol. Gating pore current in an inherited ion channelopathy Nature , 76 — 78 [ Crossref ], [ PubMed ], [ CAS ], Google Scholar 65 Gating pore current in an inherited ion channelopathy.

Ion channelopathies are inherited diseases in which alterations in control of ion conductance through the central pore of ion channels impair cell function, leading to periodic paralysis, cardiac arrhythmia, renal failure, epilepsy, migraine and ataxia.

Here we show that, in contrast with this well-established paradigm, three mutations in gating-charge-carrying arginine residues in an S4 segment that cause hypokalemic periodic paralysis induce a hyperpolarization-activated cationic leak through the voltage sensor of the skeletal muscle NaV1. This gating pore current' is active at the resting membrane potential and closed by depolarizations that activate the voltage sensor.

The inorg. Our results reveal gating pore current in naturally occurring disease mutations of an ion channel and show a clear correlation between mutations that cause gating pore current and hypokalemic periodic paralysis.

This gain-of-function gating pore current would contribute in an important way to the dominantly inherited membrane depolarization, action potential failure, flaccid paralysis and cytopathol. A survey of other ion channelopathies reveals numerous examples of mutations that would be expected to cause gating pore current, raising the possibility of a broader impact of gating pore current in ion channelopathies. The role of late I Na in development of cardiac arrhythmias Handb.

Late I Na is an integral part of the sodium current, which persists long after the fast-inactivating component. The magnitude of the late I Na is relatively small in all species and in all types of cardiomyocytes as compared with the amplitude of the fast sodium current, but it contributes significantly to the shape and duration of the action potential.

Patients with enhanced late I Na exhibit the type-3 long QT syndrome LQT3 characterized by high propensity for the life-threatening ventricular arrhythmias, such as Torsade de Pointes TdP , as well as for atrial fibrillation. There are several distinct mechanisms of arrhythmogenesis due to abnormal late I Na , including abnormal automaticity, early and delayed after depolarization-induced triggered activity, and dramatic increase of ventricular dispersion of repolarization.

Many local anesthetic and antiarrhythmic agents have a higher potency to block late I Na as compared with fast I Na. Several novel compds. Selective inhibition of late I Na is expected to be an effective strategy for correcting these acquired and congenital channelopathies.

Elsevier Inc. BrS is an inherited sudden cardiac death syndrome. Expression and coimmunopptn. We identified 17 SCN10A mutations in 25 probands 20 male and 5 female ; 23 of the 25 probands SCN10A mutations were found in BrS probands. The majority of mutations localized to the transmembrane-spanning regions.

The coimmunopptn. Our study identified SCN10A as a major susceptibility gene for BrS, thus greatly enhancing our ability to genotype and risk stratify probands and family members. Selective inhibition of vagal afferent nerve pathways regulating cough using Na v 1. Targeting voltage gated sodium channels Na v 1.

The failure of respiration in death by tetrodotoxin poisoning Exp. Quarterly journal of experimental physiology and cognate medical sciences , 53 2 , ISSN: Channels Austin, Tex. VGSCs are expressed in metastatic cells from a number of cancers. Expression of the Nav 1. Furthermore, repurposing existing VGSC-blocking therapeutic drugs may provide a new strategy to improve outcomes in patients suffering from metastatic disease, which is the major cause of cancer-related deaths, and for which there is currently no cure.

Ovarian cancer: ion channel and aquaporin expression as novel targets of clinical potential Eur. Cancer , 49 10 — Google Scholar There is no corresponding record for this reference. Voltage-gated sodium channels were differentially expressed in human normal prostate, benign prostatic hyperplasia and prostate cancer cells Oncol. Spandidos Publications Ltd.

Voltage-gated sodium channels VGSCs are expressed not only in excitable cells but also in numerous metastatic cells, particularly in certain types of cancer cells. In some types of cancer, including prostate cancer, the expression of VGSCs is assocd.

In the present study, quant. By comparing the relative expression levels of Nav1. To confirm whether Nav1. Regulation of voltage-gated sodium channel expression in cancer: hormones, growth factors and auto-regulation Philos.

Fraser, Scott P. Charles; Djamgoz, Mustafa B. Royal Society. Although ion channels are increasingly being discovered in cancer cells in vitro and in vivo, and shown to contribute to different aspects and stages of the cancer process, much less is known about the mechanisms controlling their expression.

Regulation of VGSCs occurs at a hierarchy of levels from transcription to post-translation. Importantly, mainstream cancer mechanisms, esp. On the whole, in major hormone-sensitive cancers, such as breast and prostate cancer, there is a neg. Activity-dependent regulation by pos. Such auto-regulation is unlike normal cells in which activity-dependent regulation occurs mostly via neg.

Throughout, we highlight the possible clin. Therapeutic potential for phenytoin: targeting Na v 1. Yang, Ming; Kozminski, David J. VGSCs are classically expressed in excitable cells, including neurons and muscle cells, where they mediate action potential firing, neurite outgrowth, pathfinding, and migration. VGSCs are also expressed in metastatic cells from a no.

The Nav1. SCN5A was up-regulated in BCa samples in several datasets, and was more highly expressed in samples from patients who had a recurrence, metastasis, or died within 5 years. SCN5A was also overexpressed as an outlier in a subset of samples, and assocd. It may thus be an effective VGSC-blocking drug in cancer cells, which typically have depolarized membrane potentials.

At a concn. We therefore propose that repurposing existing VGSC-blocking therapeutic drugs should be further investigated as a potential new strategy to improve patient outcomes in metastatic BCa. Expression of voltage-gated sodium channel Na v 1. Therapeutic potential of Na v 1. A, a potent and selective Na v 1. Mechanisms of disease: sodium channels and neuroprotection in multiple sclerosis-current status Nature Clin.

Axon degeneration is a major contributor to disability in multiple sclerosis, and sodium channels have been shown to have a crucial role in this process. In this article, Waxman reviews the development of the concept of sodium channel blockers as neuroprotectants in multiple sclerosis, and discusses recent attempts to translate this approach from the lab. Sodium channels can provide a route for a persistent influx of sodium ions into neurons.

Over the past decade, it has emerged that sustained sodium influx can, in turn, trigger calcium ion influx, which produces axonal injury in neuroinflammatory disorders such as multiple sclerosis MS. The development of sodium channel blockers as potential neuroprotectants in MS has proceeded rapidly, and two clin. The route from the lab. This article reviews the development of the concept of sodium channel blockers as neuroprotectants in MS, the path from lab.

A channelopathy contributes to cerebellar dysfunction in a model of multiple sclerosis Ann. Annals of neurology , 71 2 , ISSN:. OBJECTIVE: Cerebellar dysfunction in multiple sclerosis MS contributes significantly to disability, is relatively refractory to symptomatic therapy, and often progresses despite treatment with disease-modifying agents. We previously observed that sodium channel Nav1.

Here, we tested the hypothesis that upregulation of Nav1. We also measured EAE symptom progression in mice lacking Nav1. Finally, we administered the Nav1. Additionally, we show that Nav1. Finally, we demonstrate that abnormal patterns of Purkinje neuron firing and MS-like deficits in EAE can be partially reversed by pharmacotherapy using a Nav1.

Our data suggest that Nav1. Mechanism of tetrodotoxin block and resistance in sodium channels Biochem. The structure of Zetekitoxin AB, a saxitoxin analog from the Panamanian golden frog Azelopus zeteki : a potent sodium channel blocker Proc.

Isolation of 6-deoxytetrodotoxin from the pufferfish, Takfugu padalis , and a comparison of the effects of the C-6 and C hydroxy groups of tetrodotoxin on its activity J. Synthesis of 5- and 8-deoxytetrodotoxin Chem.

Tetrodotoxin, a toxic principle of puffer fish intoxication, is one of the most famous marine natural products owing to its complex structure and potent biol. Continuous synthetic studies on tetrodotoxin and its analogs to elucidate biol. With the aim of investigating the structure-activity relationship of tetrodotoxin with voltage-gated sodium channels, this study describes the first total syntheses of 5-deoxytetrodotoxin, a natural analog of tetrodotoxin, and 8-deoxytetrodotoxin, an unnatural analog, from a newly designed, versatile intermediate in an efficient manner.

An estn. Toxicon , 37 1 — Google Scholar There is no corresponding record for this reference. Conformational analysis of the sodium channel modulator, brevetoxin A, comparison with brevetoxin B. Synthetic ciguatoxins selectively activate Na v 1. Species selective resistance of cardiac muscle voltage gated sodium channels: characterization of brevetoxin and ciguatoxin binding sites in rat and fish Toxicon , 48 , — Google Scholar There is no corresponding record for this reference.

Neurotoxicity and reactive astrogliosis in the anterior cingulate cortex in acute ciguatera poisoning Neuromol. Ciguatera fish poisoning and climate change: analysis of national poison center data in the united states — Environ. Health Perspect.

Ciguatera fish poisoning in Hong Kong—a 10 year perspective on the class of ciguatoxins Toxicon , 86 , 96 — Google Scholar There is no corresponding record for this reference. Preparation of anti-ciguatoxin monoclonal antibodies using synthetic haptens: sandwich ELISA detection of ciguatoxins J. AOAC Int. Neuroprotective effects of rosmarinic acid on ciguatoxin in primary human neurons Neurotox. Braidy, N. Ciguatoxin CTX , is a toxic compd. To det. We also showed that pre- and post-treatment with rosmarinic acid RA , the active constituent of the Heliotropium foertherianum Boraginaceae can attenuate CTX-mediated neurotoxicity.

The active principle of the Colombian arrow poison frog, Phyllobates bicolor J. Japan Institute of Heterocyclic Chemistry.

The detn. The BTXs function by locking open sodium-ion channels of nerve and muscle, thereby depolarizing them. The structures and pharmacol. The source of the BTXs, not synthesized but sequestered from diet by the frogs, was briefly discussed, in the context of the occurrence of BTXs in birds of Papua New Guinea and in a small melyrid beetle found there.

Emphasized is the crit. Poor alkaloid sequestration by arrow poison frogs of the genus Phyllobates from Costa Rica Toxicon , 80 , 73 — 77 Google Scholar There is no corresponding record for this reference. Batrachotoxin analogues, compositions, uses, and preparations thereof. US, June 19 , Effects of veratridine on sodium currents and fluxes Rev. Solution NMR analysis of the binding mechanism of DIVS6 model peptides of voltage-gated sodium channels and the lipid soluble alkaloid veratridine Bioorg.

Isolation and structure of a brain constituent that binds to the cannabinoid receptor Science , , — [ Crossref ], [ PubMed ], [ CAS ], Google Scholar 95a Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Devane, William A. Arachidonylethanolamide, an arachidonic acid deriv. The structure of this compd. Anandamide inhibited the specific binding of a radiolabeled cannabinoid probe to synaptosomal membranes in a manner typical of competitive ligands and produced a concn.

Anandamide may function as a natural ligand for the cannabinoid receptor. In vitro and in vivo effects of water extract of white cocoa tea Camellia ptilophylla against human prostate cancer Pharm. The endocannabinoid anandamide inhibits voltage-gated sodium channels Na v 1.

Background: Anandamide is an endocannabinoid that regulates multiple physiol. Recently, much attention has been paid to the analgesic effect of endocannabinoids in terms of identifying new pharmacotherapies for refractory pain management, but the mechanisms of the analgesic effects of anandamide are still obscure.

Voltage-gated sodium channels are believed to play important roles in inflammatory and neuropathic pain. Methods: We studied the effects of anandamide on Nav1. The half-maximal inhibitory concn. Moreover, anandamide showed a use-dependent block in Nav1. These results help clarify the mechanisms of the analgesic effects of anandamide. International Journal of Molecular Sciences , 14 5 , , 11 pp.

The - -gallocatechingallate GCG concn. It has been shown that catechins have analgesic properties. Voltage-gated sodium channels Nav mediate neuronal action potentials. Tetrodotoxin inhibits all Nav isoforms, but Nav1. Furthermore, the inhibition was accompanied by a depolarizing shift of the activation voltage and a hyperpolarizing shift of steady-state inactivation voltage. On the basis of these findings, we propose that GCG may be a potential analgesic agent. Antillatoxin: an exceptionally ichthyotoxic cyclic lipopeptide from the tropical cyanobacterium Lyngbya majuscula J.

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Contact us. Privacy and Cookie Policy. Sponsors list. Voltage-gated sodium channels Na V : Introduction. Introduction Voltage-gated sodium channels are responsible for action potential initiation and propagation in excitable cells, including nerve, muscle, and neuroendocrine cell types [ 30 , 32 ].

Figure 1. The primary structures of the subunits of the voltage-gated sodium channels. Bold lines represent the polypeptide chains of each subunit, with length approximately proportional to the number of amino acid residues in the brain sodium channel subtypes. Click image for full size. Sodium channel interacting proteins Many proteins have been shown to interact with sodium channels transiently in the context of channel regulation, including several protein kinases and G proteins [ 7 ].

Sodium channel structure at atomic resolution Sodium channel architecture has been revealed in three-dimensions by determination of the crystal structure of bacterial sodium channels at high resolution 2. Figure 2. Structure of the bacterial sodium channel NavAb.

The four pore modules in the center are rigid in the crystal structure and therefore are blue. The four voltage-sensing modules surround the pore and are more mobile, as illustrated by warmer colors.

Architecture of the NavAb pore. Glu side-chains, purple; pore volume, grey. The P and P2 alpha helices that form the scaffold for the selectivity filter and outer vestibule are shown in green and red, respectively. Side view of NavAb. The structural components of one subunit are highlighted , transmembrane segments S1-S6. Side view of the selectivity filter.

Glu purple interactions with Gln, Ser and the backbone of Ser are shown in the far subunit; putative cations or water molecules red spheres, Ion EX. Electron-density around Leu grey and a bound water molecule are shown in gray.

The structure of the voltage sensor. Side and of the voltage-sensing module of NavAb illustrating the extracellular negative charge-cluster red, ENC , the intracellular negative charge-cluster red, INC , hydrophobic constriction site green, HCS , residues of the S1N helix cyan and phenylalanines of the S2-S3 loop purple.

S4 segment and gating charges R1-R4 are in yellow. Examples of hydrogen bonding of gating-charges, dotted lines Sodium channel classification and nomenclature A variety of different sodium channels have been identified by electrophysiological recording, biochemical purification, and cloning [ 26 ]. Sodium channel genes To test this hypothesis more critically, the nine sodium channel amino acid sequences were aligned and compared for relatedness using a maximum parsimony procedure that measured their evolutionary distance by calculating the number of nucleotide changes required for the change in codon at each position Figure 3B.

Figure 3. Comparison of amino acid identity for rat sodium channels Na v 1. Phylogenetic relationships by maximum parsimony analysis of rat sodium channel sequences Na v 1.

To perform the analysis, the amino acid sequences for all isoforms were aligned using Clustal W.