voltage-gated Na channel

An asymmetric dual-grating gate bilayer graphene-based field effect transistor (ADGG-GFET) with an integrated bowtie antenna was fabricated and its response as a Terahertz (THz) detector was experimentally investigated. The device was cooled down to 4.5 K, and excited at different frequencies (0.15, 0.3 and 0.6 THz) using a THz solid-state source. The integration of the bowtie antenna allowed to obtain a substantial increase in the photocurrent response (up to 8 nA) of the device at the three studied frequencies as compared to similar transistors lacking the integrated antenna (1 nA)...

Voltage-gated sodium channels (Nav ) undergo conformational shifts in response to membrane potential changes, a mechanism known as the electromechanical coupling. To delineate the structure-function relationship of human Nav channels, we have performed systematic structural analysis using human Nav 1.7 as a prototype. Guided by the structural differences between wild-type (WT) Nav 1.7 and an eleven mutation-containing variant, designated Nav 1.7-M11, we generated three additional intermediate mutants and solved their structures at overall resolutions of 2...

Since their discovery 21 years ago, channelrhodopsins have come of age and have become indispensable tools for optogenetic control of excitable cells such as neurons and myocytes. Potential therapeutic utility of channelrhodopsins has been proven by partial vision restoration in a human patient. Previously known channelrhodopsins are either proton channels, non-selective cation channels almost equally permeable to Na+ and K+ besides protons, or anion channels. Two years ago, we discovered a group of channelrhodopsins that exhibit over an order of magnitude higher selectivity for K+ than for Na+ ...

Voltage-gated sodium channel (NaV ) inhibitors are used to treat neurological disorders of hyperexcitability such as epilepsy. These drugs act by attenuating neuronal action potential firing to reduce excitability in the brain. However, all currently available NaV -targeting antiseizure medications nonselectively inhibit the brain channels NaV 1.1, NaV 1.2, and NaV 1.6, which potentially limits the efficacy and therapeutic safety margins of these drugs. Here, we report on XPC-7724 and XPC-5462, which represent a new class of small molecule NaV -targeting compounds...

Iron is a common and essential element for maintaining life in bacteria, plants and animals and is found in soil, fresh waters and marine waters; however, over exposure is toxic to organisms. Iron is used in electron transport complexes within mitochondria as well as a co-factor in many essential proteins. It is also established that iron accumulation in the central nervous system in mammals is associated with various neurological disorders. Ample studies have investigated the long-term effects of iron overload in the nervous system...

Postoperative atrial fibrillation (POAF) is the most common complication after cardiac surgery and a significant cause of increased morbidity and mortality. The development of novel POAF therapeutics has been limited by an insufficient understanding of molecular mechanisms promoting atrial fibrillation. In this observational cohort study, we enrolled 28 patients without a history of atrial fibrillation that underwent mitral valve surgery for degenerative mitral regurgitation and obtained left atrial tissue samples along the standard atriotomy incision in proximity to the right pulmonary veins...

Voltage-gated Na+ channels are crucial to action potential propagation in excitable tissues. Because of the high amplitude and rapid activation of the Na+ current, voltage-clamp measurements are very challenging and are usually performed at room temperature. In this study, we measured Na+ current voltage-dependence in stem cell-derived cardiomyocytes at physiological temperature. While the apparent activation and inactivation curves, measured as the dependence of current amplitude on voltage, fall within the range reported in previous studies, we identified a systematic error in our measurements...

Mutations of the SCN1A gene, which encodes the voltage-dependent Na+ channel's α subunit, are associated with diverse epileptic syndromes ranging in severity, even intra-family, from febrile seizures to epileptic encephalopathy. The underlying cause of this variability is unknown, suggesting the involvement of additional factors. The aim of our study was to describe the properties of mutated channels and investigate genetic causes for clinical syndromes' variability in the family of five SCN1A gene p...

UNLABELLED: The sodium (Na + ) leak channel (NALCN) is a member of the four-domain voltage-gated cation channel family that includes the prototypical voltage-gated sodium and calcium channels (Na V s and Ca V s, respectively). Unlike Na V s and Ca V s, which have four lateral fenestrations that serve as routes for lipophilic compounds to enter the central cavity to modulate channel function, NALCN has bulky residues (W311, L588, M1145 and Y1436) that block these openings. Structural data suggest that oc-cluded lateral fenestrations underlie the pharmacological resistance of NALCN to lipophilic compounds, but functional evidence is lacking...

Electrolyte-gated transistors (EGTs) are promising candidates as artificial synapses owing to their precise conductance controllability, quick response times, and especially their low operating voltages resulting from ion-assisted signal transmission. However, it is still vague how ion-related physiochemical elements and working mechanisms impact synaptic performance. Here, to address the unclear correlations, we suggest a methodical approach based on electrochemical analysis using poly(ethylene oxide) EGTs with three alkali ions: Li+ , Na+ , and K+ ...

NEDD4L is a HECT-type E3 ligase that catalyzes the addition of ubiquitin to intracellular substrates such as the cardiac voltage-gated sodium channel, NaV 1.5. The intramolecular interactions of NEDD4L regulate its enzymatic activity which is essential for proteostasis. For NaV 1.5, this process is critical as alterations in Na+ current is involved in cardiac diseases including arrhythmias and heart failure. In this study, we perform extensive biochemical and functional analyses that implicate the C2 domain and the first WW-linker (1,2-linker) in the auto-regulatory mechanism of NEDD4L...

Inherited retinal degenerations (IRDs) are a group of untreatable and commonly blinding diseases characterized by progressive photoreceptor loss. IRD pathology has been linked to an excessive activation of cyclic nucleotide-gated channels (CNGC) leading to Na+ - and Ca2+ -influx, subsequent activation of voltage-gated Ca2+ -channels (VGCC), and further Ca2+ influx. However, a connection between excessive Ca2+ influx and photoreceptor loss has yet to be proven.Here, we used whole-retina and single-cell RNA-sequencing to compare gene expression between the rd1 mouse model for IRD and wild-type (wt) mice...

Quinidine has been used as an anticonvulsant to treat patients with KCNT1-related epilepsy by targeting gain-of-function KCNT1 pathogenic mutant variants. However, the detailed mechanism underlying quinidine's blockade against KCNT1 (Slack) remains elusive. Here, we report a functional and physical coupling of the voltage-gated sodium channel NaV 1.6 and Slack. NaV 1.6 binds to and highly sensitizes Slack to quinidine blockade. Homozygous knockout of NaV 1.6 reduces the sensitivity of native sodium-activated potassium currents to quinidine blockade...

In voltage-gated Na+ and K+ channels, the hydrophobicity of non-charged residues in the S4 helix has been shown to regulate the S4 movement underlying the process of voltage-sensing domain (VSD) activation. In voltage-gated proton channel Hv 1, there is a bulky non-charged tryptophan residue located at the S4 transmembrane segment. This tryptophan remains entirely conserved across all Hv 1 members but is not seen in other voltage-gated ion channels, indicating that the tryptophan contributes different roles in VSD activation...

BACKGROUND: Silent inflammatory bowel disease (IBD) is a condition in which individuals with the active disease experience minor to no pain. Voltage-gated Na+ (NaV ) channels expressed in sensory neurons play a major role in pain perception. Previously, we reported that a NaV 1.8 genetic polymorphism (A1073V, rs6795970) was more common in a cohort of silent IBD patients. The expression of this variant (1073V) in rat sympathetic neurons activated at more depolarized potentials when compared to the more common variant (1073A)...

Tumor necrosis factor α (TNF-α) is a major pro-inflammatory cytokine, important in many diseases, that sensitizes nociceptors through its action on a variety of ion channels, including voltage-gated sodium (NaV ) channels. We show here that TNF-α acutely upregulates sensory neuron excitability and current density of threshold channel NaV 1.7. Using electrophysiological recordings and live imaging, we demonstrate that this effect on NaV 1.7 is mediated by p38 MAPK and identify serine 110 in the channel's N terminus as the phospho-acceptor site, which triggers NaV 1...

Anethole is a phenolic compound synthesized by many aromatic plants. Anethole is a substance that humans can safely consume and has been studied for years as a biologically active molecule to treat a variety of conditions, including nerve damage, gastritis, inflammation, and nociception. Anethole is thought to carry out its biological activities through direct interaction with ion channels. Anethole is beneficial for neurodegenerative Alzheimer's and Parkinson's diseases. Nevertheless, nothing has been investigated regarding the effects of anethole on voltage-gated Na+ channels (VGSCs), which are major players in neuronal function...

RATIONALE: Nav 1.1, 1.2, and 1.6 are transmembrane proteins acting as voltage-gated sodium channels implicated in various forms of epilepsy. There is a need for knowing their actual concentration in target tissues during drug development. METHODS: Unique peptides for Nav 1.1, Nav 1.2, and Nav 1.6 were selected as quantotropic peptides for each protein and used for their quantification in membranes from stably transfected HEK293 cells and rodent and human brain samples using ultra-high-performance liquid chromatography-electrospray ionization tandem mass spectrometry...

Many vectors of infectious disease include several species Aedes mosquitoes. Life cycle of Aedes aegypti, the Yellow Fever mosquito, consists of a terrestrial adult and aquatic larval life stages. Developing in coastal waters can expose larvae to fluctuating salinity causing salt and water imbalance, which is addressed by two prime osmoregulatory organs - Malpighian tubules (MTs) and anal papillae (AP). Voltage-gated ion channels (VGICs) have recently been implicated in the regulation of ion transport in the osmoregulatory epithelia of insects...

Discovery and development of new molecules directed against validated pain targets is required to advance the treatment of pain disorders. Voltage-gated sodium channels (NaV s) are responsible for action potential initiation and transmission of pain signals. NaV 1.8 is specifically expressed in peripheral nociceptors and has been genetically and pharmacologically validated as a human pain target. Selective inhibition of NaV 1.8 can ameliorate pain while minimizing effects on other NaV isoforms essential for cardiac, respiratory, and central nervous system physiology...