Advances in the discovery of selective NaV1.8 inhibitors for pain management.

All-optical diamond heater-thermometer enables versatile and reliable thermal modulation of ion channels at the single-cell level.

Voltage-gated sodium channels undergo reversible voltage/time-dependent transitions from closed to open and inactivated states. The voltage setpoints and efficiency of cardiac sodium channel Nav1.5 state transitions are crucial for tuning the initiation and conduction of myocardial action potentials. The channel's cytoplasmic carboxyl-terminal domain (CTD) regulates gating by intramolecular interactions and by serving as a hub for the binding of accessory proteins. We have investigated the roles of the CTD in intrinsic and FGF homologous factor (FHF)-modulated Nav1.5 gating through structure-guided CTD subdomain mutagenesis. The EF-hand module within the CTD was found to exert the most profound effects on channel gating, strongly influencing voltage dependence of inactivation and activation, accelerating inactivation from the closed state, decelerating inactivation from the open state, minimizing persistent sodium current, and serving as the binding domain for FHF proteins. Nav1.5D1788K bearing a missense mutation in the EF-hand motif displayed a depolarizing shift in voltage dependence of activation and generated enhanced persistent sodium current without altering the voltage dependence of channel inactivation. Another EF-hand mutant, Nav1.5L1861A, underwent closed-state inactivation at more negative membrane potential and at an accelerated rate but did not display other phenotypes associated with CTD deletion. Missense mutation Nav1.5V1776A in the juxtamembrane region between the EF-hand and the channel pore helices did not alter intrinsic gating properties but impaired FHF modulation of inactivation gating. Our channel physiology studies, together with the prior structural data from others, suggest that the voltage and rate of channel inactivation from the closed state are governed by an intramolecular hydrophobic interaction of the CTD EF-hand with the cytoplasmic inactivation loop helix and the extension of this binding interface upon FHF-induced restructuring of the juxtamembrane region. The CTD also tunes voltage-dependent activation and helps minimize persistent sodium current through distinct, presumed electrostatic mechanisms.

Heterologous expression of Nilaparvata lugens (Stål) voltage-gated sodium channels in Sf9 cells for electrophysiological and pyrethroid modulation studies.

The voltage-gated sodium channel mutation and detoxification enzymes associated with the resistance of Grapholita molesta (Busck) (Lepidoptera: Tortricidae) to lambda-cyhalothrin.

The pesticide fungicide difenoconazole modulates the biophysical properties of sodium channel Nav1.5.

Basal release of 6-cyanodopamine in human vas deferens, a new endogenous catecholamine that enhances smooth muscle contractility.

GCaMP6f-expressing chromaffin cells in murine adrenal slices exhibit dynamic spontaneous calcium responses that do not require nerve input.

Innervation Changes in Apical Periodontitis and its Correlation with Preoperative Symptoms.

Exploration of the mechanism of action of cenobamate.

Self-building sodium modified g-C3N4/CN for fast kinetics in sodium‑sulfur batteries by first-principles calculations.

Substrate stiffness attenuates cardiomyocyte depolarization slope via sodium channel kinetics modulation.

Clinical and genetic analysis of epilepsy in children with SCN8A gene variants.

Sodium regulation is a potentially major driver of cancer metastasis. Voltage-gated sodium channels (VGSCs) and Na,K-ATPase are sodium transporters that are upregulated in many advanced carcinomas and are implicated as metastatic drivers. However, little is known about what drives this overexpression, how these proteins influence metastatic behavior, or whether these complementary sodium transporters are co-regulated in cancer. Using sodium transporter regulation in healthy neurons as a model, the present study demonstrated that the inflammatory mediator tumor necrosis factor alpha (TNFα) affects the expression of VGSCs and Na,K-ATPase in an in vitro model of metastatic breast cancer. Acute TNFα challenge increased RNA for sodium transporter subtypes by 20–100%, TNFα reduced the overall expression of VGSCs by 20–30% at all time-points examined, and long-term administration increased nuclear localization of the α1 subtype of Na,K-ATPase while increasing the overall expression of the α3 subtype. This study established that VGSCs and Na,K-ATPase are co-regulated by TNFα at the RNA level, and it was demonstrated that both TNFα and sodium transport-blocking drugs can significantly impact cellular metastasis-like behavior. Together these data are evidence that inflammation in metastatic breast cancer co-regulates the expression of VGSCs and Na,K-ATPase, and this regulatory system may contribute to carcinogenesis.

Treatment of neuropathic pain (NP) remains a challenge in clinical practice because the current treatment approaches produce satisfactory pain alleviation in only 30% of patients. This necessitates developing novel drugs or repurposing existing medications intended to manage other diseases. When the repurposing intendance is chosen, similarity in the pharmacological properties should be hosted by the candidate drugs. Herein, this review sheds light on the mechanisms of certain centrally acting skeletal muscle relaxants (CMRs), specifically tolperisone. So far, data indicate that tolperisone displays voltage-gated sodium channel (VGSC) blocking properties with modulatory effect on voltage-gated calcium channels (VGCCs). These properties have led to recent preclinical research initiatives testing tolperisone in NP, resulting in positive outcomes. Furthermore, the review highlights the currently available VGSC blockers and proposes a strategy based on combining them with VGCC blockers that have been proven for the treatment of NP. This proposal is supported by the fact that tolperisone, in combination with pregabalin, has recently been shown to acutely halt NP.

R-limonene has been integrated into various pest control practices as a repellent or an insecticide. However, how limonene induces aversion or mortality remains largely unknown. To elucidate the underlying mechanisms, we conducted behavioral, toxicological, and electrophysiological assays in Aedes aegypti, a primary vector of human diseases. To investigate whether limonene acts on voltage-gated sodium channels and/or the Rdl (Resistance to dieldrin) receptor, two major targets of neuroactive insecticides, we characterized the effect of limonene on Ae. aegypti sodium and Rdl channels expressed in Xenopus oocytes. Limonene significantly potentiated GABA-induced chloride currents through Rdl in a concentration-dependent manner but had no effect on sodium channels. For repellency, limonene evoked spatial repellency in wild-type mosquitoes; however, the spatial repellency by limonene was significantly reduced in knockout mutants of Orco-/- (odorant receptor co-receptor) and TRPA1-/- (Transient Receptor Protein, subfamily A and member 1). These results indicate that limonene likely targets the Rdl receptor for insecticidal activity and limonene spatial repellency requires both Orco and TRPA1 channels. Our results reveal the involvement of multiple ion channels and receptors in the mosquito nervous system for limonene's insecticidal and/or spatial repellency actions, highlighting limonene's potential as a multi-target neuroactive agent for pest control.

Chinese wolfberry (Lycium barbarum L.), a specialty crop with ecological, medical, and economic value in Ningxia province of China, is subject to severe damage from Aphis gossypii Glover. Currently, A. gossypii populations show extremely high-level resistance to beta-cypermethrin in the major wolfberry planting areas in Ningxia. The specific resistance mechanisms, however, are still not known. In this work, we collected a field A. gossypii strain (HSP) from a wolfberry orchard in Ningxia in 2021 using a single-time sampling method, and its resistance to beta-cypermethrin was determined to be extremely high (994.74-fold) as compared with that of a susceptible strain (SS). Then we explored the potential resistance mechanisms from two aspects, namely, metabolic detoxification and target-site alterations. Bioassays of beta-cypermethrin with or without a synergist showed that piperonyl butoxide (PBO) significantly increased the toxicity of beta-cypermethrin (4.72-fold) to the HSP strain, while triphenyl phosphate (TPP) and diethyl maleate (DEM) exhibited no significant synergistic effects. Correspondingly, the O-demethylase activity of cytochrome P450s in the HSP strain was 1.68-fold higher than that in the susceptive strain (SS), whereas changes in carboxylesterases and glutathione S-transferases activities were unremarkable. Also, fifteen upregulated P450 genes were identified by both RNA-Seq and qRT-PCR technologies, containing eleven CYP6 genes, three CYP4 genes, and one CYP380 gene. Especially, five CYP6 genes with high relative expression levels (>3.00-fold) were intensively expressed by beta-cypermethrin induction in the HSP aphids. These metabolism-related results indicate the key role of P450-mediated metabolic detoxification in HSP resistance to beta-cypermethrin. Sequencing of voltage-gated sodium channel (VGSC) genes identified a prevalent M918L mutation and a new G1012D mutation in HSP A. gossypii. Moreover, heterozygous 918 M/L and 918 M/L + G1012D mutations were the dominant genotypes with frequencies of 60.00% and 36.67% in the HSP population, respectively. Overall, VGSC mutations along with P450-mediated metabolic resistance contributed to the extremely high resistance of the HSP wolfberry aphids to beta-cypermethrin, providing support for A. gossypii control and resistance management in the wolfberry planting areas of Ningxia using insecticides with different modes of action.

HighlightsThere are widespread metabolic changes in the brainstem of Scn1aA1783V/WT HET mice.Metabolomic analyses reveal age-specific metabolic alterations in the brainstem of HET mice.Several druggable protein kinases are altered in the brainstem of HET mice.The findings of this study suggest a role of metabolic alterations in the brainstem as a plausible contributor to SUDEP pathogenesisDravet Syndrome (DS) is a severe genetic epileptic encephalopathy caused by mutations in the SCN1A gene that encodes the voltage-gated sodium channel (NaV1.1) subunit alpha. DS is characterized by intractable seizures, progressive developmental delay, cognitive impairment, and high mortality due to sudden unexpected death in epilepsy (SUDEP). SUDEP is mediated by respiratory dysfunction, but the exact molecular underpinnings are unclear. Though hippocampal metabolic alterations have been reported in DS mice, such changes in brain regions controlling breathing have not been studied. We used Scn1aA1783V/WT DS mice to study temporal alterations in the brain metabolome, including analysis of brainstem and forebrain regions. Glycolytic and pentose phosphate pathway intermediates were significantly elevated in the brainstem of DS mice during the period of enhanced susceptibility to mortality (post-natal days P20–30). In older P40–P50 mice, mitochondrial aconitate and the antioxidant glutathione were significantly elevated in the brainstem. Single-nuclei RNA sequencing (snRNA seq) and proteomic analyses revealed alterations in genes associated with neurotransmission, cellular respiration, and protein translation, as well as reorganization of protein kinase-mediated pathways that are specific to the brainstem. These findings suggest that there are widespread metabolic changes in the brainstem of DS mice.

Background: The aim of this study is to assess the safety of sodium channel blocker (SCB) therapy in patients with atrial fibrillation (AF). Methods: The REGUEIFA registry is a prospective, observational, multicenter registry from a Community Health Area in Spain that recruited patients with AF, whom it followed for 2 years. Results: From the 997 patients, 632 were assigned to a rhythm control strategy and analyzed. Patients exposed to SCBs demonstrated a risk ratio (RR) of 0.38 (95% CI: 0.18–0.79; p = 0.007) for worsening heart failure (HF), and 0.40 (95% CI: 0.21–0.78; p = 0.005) for the composite endpoint (death, ischemic stroke, or worsening HF), with no significant differences in all-cause mortality, cardiovascular (CV) mortality, ischemic stroke, or bleeding compared with patients not exposed to SCBs. In the subgroup of patients with structural heart disease, no differences were observed between those exposed and those not exposed to SCBs across all the clinical outcomes analyzed (all-cause mortality, CV mortality, ischemic stroke, bleeding and composite event). However, a lower event trend was observed across all these variables. The rate of sinus rhythm at 2 years follow-up was significantly higher in the SCB group (81.8% vs. 63.9%; p < 0.001). During Cox regression analysis for all-cause mortality, SCB exposure was not identified as an independent factor (HR: 0.82; 95% CI 0.17–3.87; p = 0.802). Age (HR: 1.10; 95% CI: 1.04–1.17; p < 0.001) and HF (HR: 4.23; 95% CI: 1.63–11.00; p = 0.003) were the only predictors of mortality. Conclusions: SCB therapy appears to be safe and effective, both in the overall cohort and in the patient subgroup with AF and structural heart disease. These agents may play a role in AF management in patients with revascularized coronary heart disease, left ventricular hypertrophy, and HF with preserved left ventricular ejection fraction.

Amiodarone is classified as a class III antiarrhythmic agent that primarily inhibits adrenergic stimulation by blocking alpha and beta-adrenergic receptors. This drug also affects sodium, potassium, and calcium channels and prolongs the action potential and refractory period in myocardial tissue. Amiodarone, a drug well known for its wide range of side effects, can also affect the kidneys. The incidence of amiodarone-induced acute kidney failure is rare. There are limited studies regarding kidney injury caused by amiodarone. It has been reported a 45-year-old woman was admitted with leiomyoma and was scheduled for surgery. During hospitalization, the patient complained of palpitations that had been continuously present for one day. Electrocardiographic examination showed supraventricular tachycardia. The patient received intravenous amiodarone therapy followed by oral amiodarone. Renal function test results showed a decline after the patient received amiodarone therapy for 24 hours. The supraventricular tachycardia converted to normal sinus rhythm. After amiodarone was discontinued for several days, renal function returned to normal significantly. Keywords: acute kidney injury, amiodarone, renal toxicity