Role Of Sodium Channels Research Articles

The role of sodium channels in direct current stimulation-axonal perspective.

Transcranial neurostimulation methods are utilized as therapies for various neuropsychiatric disorders. Primarily, they entail the delivery of weak subthreshold currents across the brain, which modulate neuronal excitability. However, it is still a puzzle how such weak electrical fields actuate their effects. Previous studies showed that axons are the most sensitive subcellular compartment for direct current stimulation, and maximal polarization is achieved at their terminals. Nonetheless, polarization of axon terminals according to models was predicted to be weak, and the mechanism for substantial axon terminals polarization was obscure. Here, we show that a weak subthreshold electrical field modifies the conductance of voltage-dependent sodium channels in axon terminals, subsequently amplifying their membrane polarization. Moreover, we show that this amplification has substantial effects on synaptic functioning. Finally, we employ analytical modeling to explain how sodium currents modifications enhance axon terminal polarization. These findings relate to the mechanistic aspects of any neurostimulation technique.

The Role of Sodium Channels in Direct Current Stimulation-Axonal Perspective

Transcranial neurostimulation methods are utilized as therapies for various neuropsychiatric disorders. Mostly, they entail the delivery of weak subthreshold currents across the brain, which modulate neuronal excitability. However, it is still a puzzle how such weak electrical fields actuate their effects. Previous studies showed that axons are the most sensitive subcellular compartment for direct current stimulation, and that maximal polarization is achieved at their terminals. Nonetheless, the polarization of axon terminals according to models was predicted to be weak, and the mechanism for substantial axon terminals polarization was obscure. Here, we show that weak subthreshold electrical field modifies the conductance of voltage-dependent sodium channels in axon terminals, subsequently amplifying their membrane polarization. Moreover, we show that this amplification has substantial effects on synaptic functioning. Finally, we employed analytical modeling to explain how sodium currents modifications enhance axon terminal polarization. These findings relate to the mechanistic aspects of any neurostimulation technique.

The role of sodium channels in sudden unexpected death in pediatrics.

BackgroundSudden Unexpected Death in Pediatrics (SUDP) is a tragic event, likely caused by the complex interaction of multiple factors. The presence of hippocampal abnormalities in many children with SUDP suggests that epilepsy‐related mechanisms may contribute to death, similar to Sudden Unexplained Death in Epilepsy. Because of known associations between the genes SCN1A and SCN5A and sudden death, and shared mechanisms and patterns of expression in genes encoding many voltage‐gated sodium channels (VGSCs), we hypothesized that individuals dying from SUDP have pathogenic variants across the entire family of cardiac arrhythmia‐ and epilepsy‐associated VGSC genes.MethodsTo address this hypothesis, we evaluated whole‐exome sequencing data from infants and children with SUDP for variants in VGSC genes, reviewed the literature for all SUDP‐associated variants in VGSCs, applied a novel paralog analysis to all variants, and evaluated all variants according to American College of Medical Genetics and Genomics (ACMG) guidelines.ResultsIn our cohort of 73 cases of SUDP, we assessed 11 variants as pathogenic in SCN1A, SCN1B, and SCN10A, genes with long‐standing disease associations, and in SCN3A, SCN4A, and SCN9A, VGSC gene paralogs with more recent disease associations. From the literature, we identified 82 VGSC variants in SUDP cases. Pathogenic variants clustered at conserved amino acid sites intolerant to variation across the VGSC genes, which is unlikely to occur in the general population (p < .0001). For 54% of variants previously reported in literature, we identified conflicting evidence regarding pathogenicity when applying ACMG criteria and modern population data.ConclusionWe report variants in several VGSC genes in cases with SUDP, involving both arrhythmia‐ and epilepsy‐associated genes. Accurate variant assessment as well as future studies are essential for an improved understanding of the contribution of sodium channel‐related variants to SUDP.

Voltage-gated sodium channel and painful diabetic neuropathy

Sodium channel provides a new idea for the study of painful diabetic neuropathy. Based on the research status of sodium channel and painful diabetic neuropathy at home and abroad, five sodium channels with high correlation with diabetic painful neuropathy were selected, and the characteristics of these sodium channels were summarized.The expression status of sodium channel in diabetic painful neuropathy model was summarized, and the role of sodium channel in the pathogenesis of diabetic painful neuropathy was summarized. The relationship between sodium channel and diabetic painful neuropathy was analyzed, as well as the difficulties facing the current research, in order to provide references for the research and application of sodium channel in the treatment of diabetic painful neuropathy. Key words: Sodium channels; Diabetic neuropathies; Review

Anti-Angiogenic Activity of Flunarizine by In Ovo, In Vitro, and In Vivo Assays.

The involvement of T-type calcium channels in cell proliferation and the role of sodium channels in cell migration have been extensively studied in angiogenesis. In the present study, flunarizine, a dual sodium/calcium channel blocker; was selected to evaluate its anti-angiogenic potential. This can be therapeutically beneficial in diseases caused by pathologically excessive angiogenesis. The anti-angiogenic activity of ion channel blocker was screened by chick chorioallantoic membrane assay (in ovo), rat aortic ring assay, endothelial cell proliferation assay, transwell migration assay, Matrigel cord-like morphogenesis assay (in vitro), and sponge implantation method (in vivo). The anti-angiogenic activity of the test drug was compared with the standard anti-angiogenic drug bevacizumab and, in addition, the test responses were compared with the angiogenic factor vascular endothelial growth factor at a maximal concentration of 500 pM. All the groups were compared with the control group using one-way ANOVA, followed by a post hoc test, Dunnett's test, to compare the mean of all the groups with the control mean. In the chick chorioallantoic membrane assay, the number of branching points and angiogenic score were evaluated and significant results were observed at 10-5 M and 10-4 M. In the aortic ring assay a reduction in the area of sprouts was observed with 5-10 μM and significant reductions in the weight of sponges, number of blood vessels formed, and hemoglobin content were observed at all three tested concentrations of flunarizine in the sponge implantation method. In the studies on human umbilical vein endothelial cells the test drug (1-100 nM) showed significant inhibition of proliferation and migration and a decrease in the network length of cord-like tubes in a dose-dependent manner. Flunarizine has significant anti-angiogenic action by inhibiting cell proliferation, migration, and cord-like tube formation, which resulted from blocking of the T-type calcium and sodium channels. Further studies on the structural modifications of flunarizine for repurposing this ion channel modulator will lead to treatment of the diseases due to excessive angiogenesis from the root cause.

Pathophysiology of R222Q mutant SCN5a channels

Consistent with the role of sodium channels in initiating action potentials throughout myocardial tissue, mutations in SCN5a are associated with arrhythmias and cardiomyopathy. The present studies aim to advance understanding of the mechanism underlying the arrhythmias and dilated cardiomyopathy (DCM) observed in patents with an SCN5a mutation (c.665G>A/R222Q) located in one of the voltage sensor regions. Induced pluripotent stem cells (iPSCs) were generated from a patient heterozygous for the R222Q mutation. Isogenic controls were generated by corrected the mutation. Directed differentiation techniques were used to produce ventricular CMs characterized by the expression of cTnT (Control: 85.10±2.90%, Mutant: 83.14±4.46%) and ventricular-specific MLC2v (Control: 45.62±7.02%, Mutant: 43.92±3.86%). The SCN5a gene undergoes extensive alternative splicing, which is developmentally regulated, resulting in the R222Q loci being expressed exclusively in adult SCN5a mRNA. Consistent with an immature phenotype in our iPSC-derived CMs, about half of the SCN5a mRNA is the adult isoform (Control: 54.40±9.29%, Mutant: 48.45±6.21%, n=4), indicating that ~25% of the SCN5a channels expressed in mutant CMs contain the R222Q mutation. Optical mapping of our 2-dimentional tissue model (monolayers) reveal slower conduction velocities in mutant compared to control monolayers (13.14±0.74cm/s, n=10, vs. 25.09±1.99cm/s, n=7, p<0.05). Treatment with flecainide (10 μM), a sodium channel blocker associated with arrhythmia reduction and DCM reversal in R222Q patients results in conduction slowing (Control: 25.09±1.99cm/s to 18.47±3.20cm/s, n=7, p<0.05, Mutant: 13.14±0.74cm/s to 8.92±0.64cm/s, n=10, p<0.05) and a reduction in maximum capture rates (Control: 3.22±0.14Hz to 1.42±0.13Hz, n=5, p<0.05, Mutant: 3.43±0.18 to 2.38±0.22Hz, n=10, p<0.05). We are currently performing electrophysiological studies to further assess the mechanisms underlying R222Q-associated cardiomyopathy and arrhythmias and advancement of therapeutic options for R222Q patients.

Cardiac sodium channel, its mutations and their spectrum of arrhythmia phenotypes

The mechanisms of cellular excitability and propagation of electrical signals in the cardiac muscle are very important functionally and pathologically. The heart is constituted by three types of muscle: atrial, ventricular, and specialized excitatory and conducting fi bers. From a physiological and pathophysiological point of view, the conformational states of the sodium channel during heart function constitute a signifi cant aspect for the diagnosis and treatment of heart diseases. Functional states of the sodium channel (closed, open, and inactivated) and their structure help to understand the cardiac regulation processes. There are areas in the cardiac muscle with anatomical and functional differentiation that present automatism, thus subjecting the rest of the fi bers to their own rhythm. The rate of these (pacemaker) areas could be altered by modifi cations in ions, temperature and especially, the autonomic system. Excitability is a property of the myocardium to react when stimulated. Another electrical property is conductivity, which is characterized by a conduction and activation process, where the action potential, by the all-or-nothing law, travels throughout the heart. Heart relaxation also stands out as an active process, dependent on the energetic output and on specificion and enzymatic actions, with the role of sodium channel being outstanding in the functional process. In the gene mutation aspects that encode the rapid sodium channel (SCN5A gene), this channel is responsible for several phenotypes, such as Brugada syndrome, idiopathic ventricular fibrillation, dilated cardiomyopathy, early repolarization syndrome, familial atrial fibrillation, variant 3 of long QT syndrome, multifocal ectopic ventricular contractions originating in Purkinje arborizations, progressive cardiac conduction defect (Lenègre disease), sudden infant death syndrome, sick sinus syndrome, sudden unexplained nocturnal death syndrome, among other sodium channel alterations with clinical overlapping. Finally, it seems appropriate to consider the “sodium channel syndrome” (mutations in the gene of the α subunit of the sodium channel, SCN5A gene) as a single clinical entity that may manifest in a wide range of phenotypes, to thus have a better insight on these cardiac syndromes and potential outcomes for their clinical treatment.

Role of Sodium Channels in Epilepsy.

Voltage-gated sodium channels (VGSCs) are fundamentally important for the generation and coordinated transmission of action potentials throughout the nervous system. It is, therefore, unsurprising that they have been shown to play a central role in the genesis and alleviation of epilepsy. Genetic studies on patients with epilepsy have identified more than 700 mutations among the genes that encode for VGSCs attesting to their role in pathogenesis. Further, many common antiepileptic drugs act on VGSCs to suppress seizure activity. Here, we present an account of the role of VGSCs in epilepsy, both through their pathogenic dysfunction and as targets for pharmacotherapy.

Clinical utility of axonal excitability testing in toxic neuropathies

The peripheral nervous system is highly susceptible to the development of toxicity. Conventional nerve conduction studies may only identify nerve damage once significant axonal disturbance has occurred, due to the high safety factor of impulse transmission. Over the past 20 years, axonal excitability techniques have been developed to identify aberrant membrane and ion channel function in vivo. These techniques have been successfully utilized in the clinical research setting to provide insights into pathophysiology in a number of peripheral nerve disorders. Studies in patients with neurotoxic marine poisoning have provided important evidence of the role of sodium channels in determining peripheral axonal excitability, critical to the validation of axonal excitability techniques. Subsequent assessment of toxic neuropathies has demonstrated the advantages of axonal excitability techniques in sensitively identifying peripheral nerve dysfunction. Such examples include early detection of nerve damage in chemotherapy-induced peripheral neuropathy and the identification of potential changes in nerve function with immunomodulatory drugs. To further strengthen the clinical utility of axonal excitability studies, translation of these techniques into widely available clinical tools will be needed.

Role of sodium channels in the spontaneous excitability of early embryonic cardiomyocytes.

Sodium channels play an important role in action potentials. Moreover, some evidences recently suggested that sodium channels were responsible for murine sinoatrial node pacemaking. The aim of this study was to investigate the role of sodium channels in pacemaking in embryonic cardiomyocytes in early development stage (EDS). Whole-cell patch-clamp technique was employed to record sodium current of murine early embryonic cardiomyocytes. Current clamp technique was used to record the effect of 0.1, 1 and 10 μM tetrodotoxin (TTX) on embryonic cardiomyocytes pacemaking. Electro- physiology properties of sodium channels in embryonic cardiomyocytes corresponded to Nav1.5, and the IC₅₀ of TTX was 5.24 μM. TTX at 0.1 μM concentration had no effects on the pacemaking. TTX at 1 μM concentration, however, dramatically slowed the spontaneous beating rate from 73.975 ± 10.478 to 50.268 ± 10.476 cycle/min (P < 0.05), and the maximum upstroke velocity (dV/dtmax) of phase 4 from 0.074 ± 0.006 to 0.046 ± 0.007 V/s (P < 0.01). Furthermore, 1 μM TTX reduced the dV/dtmax of phase 0 from 16.405 ± 0.056 to 12.801 ± 0.084 V/s (P < 0.01), and increased the period of phase 4 from 710.342 ± 110.983 to 1320.618 ± 250.483 ms (P < 0.05). TTX at 1 μM also had some effects on the peak of phase 0 decreasing it from 40.621 ± 3.012 to 37.407 ± 2.749 mV (P < 0.05). But TTX at 1 μM had no effects on the period of phase 0. In some cells (9/13), TTX at 10 μM caused complete cessation of spontaneous action potentials. Our results suggested that the main expression subtype of sodium channels was Nav1.5 of early embryonic cardiomyocytes. And TTX-resistant sodium channels contributed to the initiation of action potentials of early embryonic cardiomyocytes, while TTX-sensitive sodium channels were not involved in initiation of action potentials.

The role of sodium channels in painful diabetic and idiopathic neuropathy.

Painful neuropathies are frequently encountered in clinical practice as an early or late complication of several systemic disorders. Among them, diabetes is one of the most important due to its epidemiology and the relevance for regulatory agencies in the assessment of efficacy of new analgesics. However, the presentation and course of painful neuropathies, as well as the response to available drugs, are highly variable and unpredictable, posing significant challenges in the management of patients. Experimental and clinical studies have suggested that polymorphisms and mutations in pain-related genes are involved in the facilitation or inhibition of nociception, and might modulate neuropathic pain and the response to analgesics in patients. Voltage-gated sodium channel genes are among the most relevant, due to the key role of these membrane proteins in the physiology of nociception and their involvement in the pathogenesis of idiopathic painful small fiber neuropathies. These compelling features make sodium channel candidate targets for a novel approach to painful diabetic and idiopathic neuropathies, which will hopefully allow a new classification of patients and more effective targeted treatments.

Role of sodium channels in recovery of sciatic nerve‐stretch injury in rats

To elucidate the mechanism of functional recovery after gradual nerve-stretch injury, we used rats in which the femur length was increased by 15 mm at 1.5 mm/day. We performed electrophysiology, mRNA analysis of tetrodotoxin-resistant voltage-gated sodium channels (TTX-R VGSCs) in dorsal root ganglia, and histology of unmyelinated sciatic nerve fibers and examined pain thresholds at 1, 10, 20, and 30 days after cessation of lengthening. Electrophysiology revealed conduction block after cessation that recovered after 30 days. TTX-R VGSC levels decreased immediately after cessation but were restored after 10 (Nav1.9) or 20 (Nav1.8) days. Histology revealed that injured unmyelinated nerve fibers regenerate 30 days after cessation. Pain threshold decreased gradually during lengthening but had not recovered to the control group level after 30 days. Early restoration of TTX-R VGSC mRNA in dorsal root ganglia preceded functional recovery of stretched nerves before regeneration of injured unmyelinated nerve fibers.

Role of sodium channels in IBS

Role of sodium channels in IBS

A role for sodium channels in regulation of macrophage-mediated pathology in multiple sclerosis lesions

Disease mechanisms in MS: A role for sodium channels in regulation of macrophage-mediated pathology in multiple sclerosis lesions

The role of sodium channels in chronic pain

Here we review recent research into the mechanisms of chronic pain that has focused on neuronal sodium channels, a target of classic analgesic agents. We first discuss evidence that specific sodium channel isoforms are essential for the detection and conduction of normal acutely painful stimuli from nociceptors. We then review findings that show changes in sodium channel expression and localization in chronic inflammation and nerve injury in animal and human tissues. We conclude by discussing the role that myelination plays in organizing and maintaining sodium channel clusters at nodes of Ranvier in normal development and how inflammatory processes or nerve injury alter the characteristics of such clusters. Based on these findings, we suggest that chronic pain may in part result from partial demyelination of axons during chronic injury, which creates aberrant sodium channel clusters that serve as sites of ectopic sensitivity or spontaneous activity.

Role of Sodium Channel on Cardiac Action Potential

Sudden cardiac death is a major cause of death worldwide. In most cases, it's caused by abnormal action potential propagation that leads to cardiac arrhythmia. The aim of this article is to study the abnormal action potential propagation through sodium ion concentration variations. We use a new electrophysiological model that is both detailed and computationally efficient. This efficient model is based on the partial differential equation method. The central finite difference method is used for numerical solving of the two-dimensional (2D) wave propagation equation. Simulations are implemented in two stages, as a single cardiac cell and as a two-dimensional grid of cells. In both stages, the normal action potential formation in case of a single cell and it's normal propagation in case of a two-dimensional grid of cells were simulated with nominal sodium ion conductance. Then, the effect of sodium ion concentration on the action potential signal was studied by reducing the sodium ion conductance. It is concluded that reducing the sodium ion conductance, decreases both passing ability and conduction velocity of the action potential wave front.

Sodium channels, the electrogenisome and the electrogenistat: lessons and questions from the clinic

In the six decades that have followed the work of Hodgkin and Huxley, multiple generations of neuroscientists and biophysicists have built upon their pivotal contributions. It is now clear that, in mammals, nine genes encode nine distinct voltage-gated sodium channels with different amino acid sequences and different physiological and pharmacological properties. The different sodium channel isoforms produce a multiplicity of distinct sodium currents with different time-dependent characteristics and voltage dependencies, which interact with each other and with the currents produced by other channels (including calcium and potassium channels) to shape neuronal firing patterns. Expression of these sodium channel isoforms is highly dynamic, both in the normal nervous system, and in the injured nervous system. Recent research has shed light on the roles of sodium channels in human disease, a development that may open up new therapeutic strategies. This article examines the pain-signalling system as an example of a neuronal network where multiple sodium channel isoforms play complementary roles in electrogenesis and a strong link with human disease has been established. Recent research suggests that it may be possible to target specific sodium channel isoforms that drive hyperexcitability in pain-signalling neurons, thereby providing new therapeutic strategies for chronic pain, and providing an illustration of the impact of the Hodgkin-Huxley legacy in the clinical domain.

Possible role of sodium channels and NMDA receptors in painful patellar tendinopathy: an open-label pilot study using a heated lidocaine/tetracaine topical patch

Possible role of sodium channels and NMDA receptors in painful patellar tendinopathy: an open-label pilot study using a heated lidocaine/tetracaine topical patch

Contributions of Conserved Negative Surface Potentials in S2 and S3 to Voltage-Gating of Sodium Channels

The question of how S4 charges are stabilized in the hydrophobic membrane environment is of critical importance to understand the function of voltage-gated ion channels (VGICs). Besides lipids, proteinaceous interactions are thought to play an important role and, indeed, the electronegative surface potentials of aromatic side chains and the net negative charge of acidic side chains are well suited to fulfill this role. Interestingly, a single aromatic side chain in S2 and a number of acidic side chains in S2 and S3 are highly conserved among VGICs. These residues have been extensively studied in potassium channels but little is known about their role in sodium channels. Here we incorporate unnatural amino acids to probe their contributions to channel gating in the skeletal sodium channel isoform (Nav1.4). Replacing the S2 aromatic in domains I-IV with fluorinated Phe derivatives does not affect channel gating, ruling out a cation-pi interaction with S4 charges. Trp substitutions in this position lead to a significant right-shift in the GV in domain I only, highlighting not only the functional differences between Nav domains, but also sodium and potassium channels, as the latter show a dramatic left-shift in the GV when Trp is introduced at the equivalent position in S2. Furthermore, we replaced Glu side chains with the neutral isosteric Glu analog nitrohomolalanine (Nha). Our data show that neutralizing a negative charge in S2 near the extracellular end of S4 leads to a significant right-shift in the GV in domain I, while neutralizing negative charges in S2 and S3 near the intracellular end of S4 result in small or no shifts in the GV. Together, these results shed new light on our understanding of voltage-gating in sodium channels.

L-pGlu-(2-propyl)-l-His-l-ProNH2 attenuates 4-aminopyridine-induced epileptiform activity and sodium current: a possible action of new thyrotropin-releasing hormone analog for its anticonvulsant potential

l-PGlu-(2-propyl)-l-His-l-ProNH2 (NP-647) is a CNS active thyrotropin-releasing hormone (TRH) analog with potential application in various CNS disorders including seizures. In the present study, mechanism of action for protective effect of NP-647 was explored by studying role of NP-647 on epileptiform activity and sodium channels by using patch-clamp methods. Epileptiform activity was induced in subicular pyramidal neurons of hippocampal slice of rat by perfusing 4-aminopyridine (4-AP) containing Mg+2-free normal artificial cerebrospinal fluid (nACSF). Increase in mean firing frequency was observed after perfusion of 4-AP and zero Mg+2 (2.10±0.47 Hz) as compared with nACSF (0.12±0.08 Hz). A significant decrease in mean firing frequency (0.61±0.22 Hz), mean frequency of epileptiform events (0.03±0.02 Hz vs. 0.22±0.05 Hz of 4-AP+0 Mg), and average number of action potentials in paroxysmal depolarization shift-burst (2.54±1.21 Hz vs. 8.16±0.88 Hz of 4-AP+0 Mg) was observed. A significant reduction in peak dV/dt (246±19 mV ms−1 vs. 297±18 mV ms−1 of 4-AP+0 Mg) and increase (1.332±0.018 ms vs. 1.292±0.019 ms of 4-AP+0 Mg) in time required to reach maximum depolarization were observed indicating role of sodium channels. Concentration-dependent depression of sodium current was observed after exposure to dorsal root ganglion neurons to NP-647. NP-647 at different concentrations (1, 3, and 10 μM) depressed sodium current (15±0.5%, 50±2.6%, and 75±0.7%, respectively). However, NP-647 did not show change in the peak sodium current in CNa18 cells. Results of present study demonstrated potential of NP-647 in the inhibition of epileptiform activity by inhibiting sodium channels indirectly.