Search Results (379)

Kv11.1 (hERG1) channels, encoded by KCNH2, mediate the rapid delayed rectifier potassium current (I_Kr) crucial for cardiac repolarization. Disruptions, via mutations or antiarrhythmic drugs like dofetilide cause severe arrhythmogenic disorders, including Long QT Syndrome Type 2 (LQT2), Brugada Syndrome (BrS), and Torsades de Pointes (TdP). While Kv11.1’s role in channelopathies and drug-induced arrhythmias is established, understanding its complex regulation and therapeutic targeting remains a challenge. This review synthesizes the structural, functional, and regulatory aspects of Kv11.1 channels and their clinical implications. Recent studies using iPSC-derived cardiomyocytes highlight regulation by PI3K/Akt, PKC, and PKA signaling via phosphorylation (Ser283, Ser890) and interactions with proteins like 14-3-3. Beyond electrophysiology, Kv11.1 influences pathological hypertrophy and non-cardiac functions including insulin secretion. Pharmacological efforts focus on activators to shorten action potential duration and suppress TdP, and blockers with overdose risks. Mutation heterogeneity, exemplified by trafficking impairment (G785D) in LQT2 and gain-of-function (R397C) in BrS, complicates precision therapy. Clinically, systematic risk stratification using electrocardiographic parameters and genotype-specific approaches enables personalized management. Beta-blockers remain first-line therapy for LQTS2, while rigorous avoidance of QT-prolonging medications and electrolyte monitoring form the cornerstones of preventive care. Advancing Kv11.1-targeted therapies with approaches like CRISPR-Cas9 and pharmacological chaperones (e.g., lumacaftor) holds promise for personalized treatments, ultimately reducing arrhythmic events and sudden cardiac death. Full article

Kv4.2 channels are the principal mediators of the fast transient outward K⁺ current (I_tof) in the heart and the A-type current (I_A) in the nervous system, both of which play a relevant role in shaping cardiac action potentials and neuronal excitability. This review focuses on how interactions with ancillary subunits, such as potassium channel interacting proteins (KChIPs) and dipeptidyl peptidase-like proteins (DPPs), beyond regulating trafficking, membrane expression, and gating properties of Kv4.2 channels, significantly influence channel drug response, demonstrating that Kv4.2 does not represent a fixed pharmacological entity but rather a dynamic macromolecular complex whose drug responsiveness depends on its subunit composition. Understanding this accessory subunit-dependent modulation is important, as the pharmacological profile of Kv4.2-containing channels may differ depending on the predominant accessory subunit composition in each tissue. Full article

Background/Objectives: Type 2 diabetes mellitus (T2DM) is characterized by chronic hyperglycemia and insulin resistance, leading to progressive metabolic dysfunction. Flavonoids, such as astragalin, have reported antidiabetic potential; however, their direct effects on pancreatic β-cell ionic mechanisms and insulin secretion remain unclear. This study aimed to investigate the effects of astragalin on glucose uptake, insulin secretion, and membrane ionic currents in pancreatic β-cell lines. Methods: Murine MIN6 and rat INS-1 pancreatic β-cells were used as experimental models. Following astragalin treatment, glucose uptake was quantified by bioluminescence, and insulin secretion was measured by ELISA. Ionic currents were analyzed using the whole-cell patch-clamp technique. Selective pharmacological blockers targeting ATP-sensitive K⁺ channels (KATP), voltage-dependent K⁺ channels (K_v), and L-type voltage-dependent Ca²⁺ channels were applied to elucidate the underlying mechanisms. Results: Astragalin increased glucose uptake in a time-dependent manner, reaching a plateau between 3 and 5 h. Insulin secretion was significantly enhanced after 1 h of exposure to 100 µM astragalin. Patch-clamp recordings demonstrated that astragalin reduced potassium channel currents in pancreatic β-cells. Pharmacological modulation confirmed the involvement of KATP, K_v, and L-type Ca²⁺ channels. Verapamil attenuated the insulinotropic effect, supporting the role of calcium influx in astragalin-induced insulin exocytosis. Conclusions: Astragalin enhances glucose uptake and stimulates insulin secretion in pancreatic β-cells through modulation of potassium and calcium channels, promoting calcium-dependent exocytosis. These findings support its potential as a candidate for antidiabetic therapeutic strategies. Full article

Huwentoxin-XI (HWTX-XI) is a 55-amino acid peptide belonging to the family of spider Kuntiz-type toxins (KTTs), isolated from the venom of the Chinese tarantula Cyriopagopus schmidti. Under whole-cell voltage-clamp conditions, HWTX-XI was found to block Kv1.1 potassium channels but had no effect on other potassium channel subunits (Kv1.4, Kv2.1, Kv3.1 and Kv4.2), sodium channels or calcium channels. In the present study, it was found that the substitution of Tyr379 by the valine in the filter region significantly decreased the affinity of toxin HWTX-XI by about 90-fold, indicating that the Kv1.1 filter region is a critical determinant of HWTX-XI potassium channel activity. After intrathecal or intraplantar injections, HWTX-XI decreased the mechanical nociceptive threshold (hyperalgesia) for a long-lasting period. HWTX-XI also significantly increased the firing frequency in mouse DRG neurons. The novel function of HWTX-XI makes it a new tool for studying the relationship between spider toxins and Kv1.1 channels and suggests that Kv1.1 channels might be a novel potential target for preventing and/or treating neuropathic pain. Full article

Voltage-gated potassium channel Kv1.3 plays an important role in the regulation of survival and apoptosis in many cell types, including both normal and cancer cells. Inhibitors of these channels may potentially find clinical applications in the treatment of various diseases, including certain cancers characterized by the over-expression of Kv1.3. In this study, the effects of isobavachalcone (IBC) and two non-prenylated chalcones—2′-hydroxy-4,3′-dimethoxychalcone (HDC) and 2′-hydroxy-2-methoxychalcone (HMC)—on Kv1.3 channel activity were investigated in the Jurkat T cancer cell line using the whole-cell patch-clamp technique. The electrophysiological measurements were preceded by experiments assessing cell viability, and the patch-clamp data were consistent with results obtained from MTT-based assays. We observed an almost complete and irreversible inhibition of Kv1.3 in the presence of IBC. The non-prenylated chalcones also inhibited the channels, but with lower potency and in a reversible and incomplete manner. The inhibitory effect of IBC was significantly enhanced upon co-application with simvastatin (SIM) and mevastatin (MEV). In contrast, inhibition by the non-prenylated chalcones was significantly increased only in the presence of mevastatin, but not simvastatin. The channel inhibition may be related to the anti-proliferative and pro-apoptotic activities of these compounds in Kv1.3-expressing cancer cells. Altogether, our results indicate that both prenylated and non-prenylated chalcones, particularly in combination with statins, may represent biologically active scaffolds, warranting further optimization and preclinical evaluation. Full article

Calophyllum spp. infusions are used to treat varicose veins, hemorrhoids, and hypertension. However, the chemical composition and mechanisms of action are poorly understood. Accordingly, the aim of this study was to investigate the phytochemical composition and vascular effects of hydroalcoholic extracts of Calophyllum longifolium. Phytochemical profiling was performed using ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-ESI-Q-TOF-MS). Extract effects on rat aortic rings and aortic vascular smooth muscle cells (VSMCs) were evaluated using wire myography and photometric measurement of intracellular Ca²⁺, respectively. UHPLC-ESI-Q-TOF-MS revealed the presence of coumarins, xanthones, flavonoids, triterpenes, and phenolic acids. Coumarin–resveratrol hybrids, such as gut-70 derivatives, were also abundant. In aortic rings from normotensive rats, C. longifolium induced a biphasic vascular response whereby low concentrations (1 μg/mL) produced significant vascular relaxation, whereas high concentrations (100 μg/mL) produced contraction. Blockade of ATP-sensitive (K_ATP) or voltage-gated (K_V) potassium channels attenuated these effects. Furthermore, effects were not observed in preparations preincubated with L-NG-Nitro-L-arginine methyl ester (L-NAME) or in endothelium-denuded rings. In aortic VSMCs, extracts (1 µg/mL) rapidly reduced sarcoplasmic reticulum (SR) Ca²⁺ content. This study provides the first UHPLC-ESI-Q-TOF-MS chemical profile of C. longifolium, revealing diverse bioactive metabolites. It is also the first to demonstrate that C. longifolium exerts an endothelium-dependent, nitric oxide- and Ca²⁺-mediated biphasic effect on vascular function. Taken together, these findings highlight C. longifolium as a potential novel source of vasculotropic phytopharmaceuticals. Full article

Protease-activated receptor 2 (PAR2) is a G protein-coupled receptor (GPCR) expressed in both the peripheral and central nervous systems. It plays a pivotal role in mediating neuroimmune interactions, particularly in the context of inflammation and pain. Upon activation by proteases, PAR2 modulates nociception through signaling cascades that influence key ion channels, including transient receptor potential (TRP) ion channels vanilloid 1 and 4 (TRPV1 and TRPV4), ankyrin 1 (TRPA1), acid-sensing ion channel 3 (ASIC3), P2X purinoceptor 3 (P2X3), Cav3.2 (T-type Ca²⁺ channel), and potassium Kv7 (M-current) channels, altering their expression and function. Through this crosstalk, PAR2 contributes to heightened neuronal excitability and pain hypersensitivity in various inflammatory conditions. In this narrative review, we highlight and discuss the mechanistic and functional interplay between PAR2 and nociceptive ion channels, which might be contributing to the pathogenesis of inflammatory pain. Targeting these specific molecular interactions between PAR2 and nociceptive ion channels may offer a promising therapeutic strategy for treating inflammatory pain. Full article

Filamentary mode, as a common phenomenon that appears in dielectric barrier discharge (DBD), is realized by rod-to-rod electrodes in N₂-O₂ mixtures at 80 mbar. The effects of the dielectric thickness on the characteristics of filamentary DBD are investigated through experiments and simulations. The discharges are driven by a positive unipolar nanosecond pulse voltage with 15.8 kV amplitude, 9 ns rise time (T_r^10–90%), and 14 ns pulse width. The characteristics of filamentary DBD are recorded with an intensified charge-coupled device and a Pearson current probe in the experiment, and a 2D axisymmetric fluid mode is established to analyze the discharge. Surface discharges occur on the anode and cathode dielectric after the breakdown, and the discharge is gradually extinguished as the applied voltage decreases. A thinner total dielectric thickness (D_a + D_c) leads to larger currents, stronger discharges, and wider discharge channels. These characteristics are consistent when the total dielectric thickness is the same but anode dielectric thickness and cathode dielectric thickness are different (D_a ≠ D_c ≠ 0). If the anode is a metal electrode (D_a = 0), the current will be substantially large, and two discharge modes are observed: stable mono-filament discharge mode and random multi-filament discharge mode. It is found in simulations that the dielectric thickness changes the electric field configuration. The electric field is stronger with the decrease in dielectric thickness and leads to a more intense ionization which is responsible for most of the observed effects. Full article

Venom is a key evolutionary innovation of venomous organisms in the long-term process of survival adaptation. As one of the oldest arthropods, scorpions produce venom rich in bioactive peptides that also constitute a valuable pharmacological resource. Omics-driven discovery and structural biology have expanded the peptide catalog and clarified structure–function principles across disulfide-bridged (DBPs) and non-disulfide-bridged peptides (NDBPs). Within this arsenal, ion-channel targeting neurotoxins predominantly modulate Nav, Kv, Calcium, Chloride, and TRP channels to achieve predation, defense, and competition. Owing to their unique mechanisms of action and significant therapeutic potential, scorpion venom peptides have attracted sustained interest as leads and scaffolds for drug development. This review synthesizes current knowledge of scorpion venom composition, with an emphasis on the pivotal role of neurotoxins, covering their molecular diversity, structural features, and modes of ion-channel modulation, as well as emerging applications in disease treatment. Full article

KCNV2 encodes Kv8.2, an electrically silent voltage-gated potassium channel subunit that is expressed in photoreceptors. Disease-causing variants in KCNV2 cause a monogenic disorder which is classified clinically as cone dystrophy with supernormal rod response (CDSRR). Here, we generated KCNV2-deficient human retinal organoids as a tool for gene therapy vector potency assessment. The organoids were derived from two separate sources: by generating IPSCs from patient blood and by gene editing of a control cell line. Eight KCNV2 gene therapy vectors were assessed in retinal organoids; Kv8.2 protein levels and its in situ interactions with potassium channel binding partners were quantitatively assessed. We show significant enhancements in vector potency and specificity by transgene codon optimisation and the use of the photoreceptor-specific rhodopsin kinase (RK) promoter, respectively. Single-cell RNA sequencing was performed in transduced retinal organoids to assess the performance of the AAV vectors at single-cell resolution. KCNV2-deficient photoreceptors had an upregulation in genes associated with apoptosis, oxidative stress, and hypoxia pathways which were partially restored in AAV-KCNV2 transduced photoreceptors. These data show how human retinal organoids can be used to evaluate AAV gene therapy vector potency in vitro in a physiologically relevant model for the selection of lead therapeutic candidates and to help minimise the use of animals in preclinical development. Full article

Hydraulically Amplified Self-Healing Electrostatic (HASEL) actuators promise a future of adaptive robotics in a world where robotics is becoming increasingly integrated into our daily lives. Adaptive robotics needs to control multiple outputs with precision and speed. Unfortunately, expensive High Voltage control restricts the development of the HASEL actuator for commercial applications. This paper demonstrates a low-cost multi-channel High Voltage Power Supply (HVPS). The HVPS takes a 6 V input and controls multiple HASEL actuators from 0 to 10 kV, with a slew rate of up to 117.7 kV/s. In addition to controlling multiple channels, the low-cost HVPS can control two outputs with a single control module in an alternating pattern, similar to the way muscles control movement in alternating sequences—e.g., biceps and triceps. Previous work has shown that this low-cost HVPS is 95% cheaper than other power supplies used in the field of HASEL actuators. This work builds on the work reducing the cost of the HVPS by an additional 40%. This low-cost HVPS also reduces the amount of input required for control from four PWMs to one PWM with enable pins, drastically improving the performance of the device for multi-channel operation. Full article

Composite interphase spacers are essential components in ultra-high-voltage (UHV) transmission lines to suppress conductor galloping. This study investigates the first reported case of a core-rod fracture in a 500 kV composite spacer and elucidates its degradation mechanism through multi-scale characterization, electrical testing combined and electric field and mechanical simulation. Macroscopic inspection and industrial computed tomography (CT) show that degradation initiated at the unsheltered high-voltage sheath–core interface and propagated axially, accompanied by continuous interfacial cracks and void networks whose volume ratio gradually decreased along the spacer. Material characterizations indicate moisture-driven glass-fiber hydrolysis, epoxy oxidation, and progressive interfacial debonding. Leakage current test further indicates humidity-sensitive conductive paths in the degraded region, confirming the presence of moisture-activated interfacial channels. Electric-field simulations under two shed configurations demonstrated that local field intensification was concentrated within 20–30 cm of the HV terminal, where the sheath and core surface fields increased by approximately 9.3% and 5.5%. Mechanical modeling demonstrates a pronounced bending-induced stress concentration at the same end region. The combined effects of moisture ingress, electrical stress, mechanical loading, and chemical degradation lead to the decay-like fracture. Improving sheath hydrophobicity, enhancing interfacial bonding, and optimizing end-fitting geometry are recommended to mitigate such failures and ensure the long-term reliability of UHV composite interphase spacers. Full article

Toxins as channel probes, small guanidinium alkaloids, such as tetrodotoxin and saxitoxin, canonical pore occlusion in voltage-gated Na⁺ channels. Cystine-rich peptides from spiders, scorpions, cone snails, and sea anemones, which act as pore blockers or gating modifiers targeting voltage-sensing domains. Recent structural and electrophysiological studies have identified specific binding sites on ion channels, including the S5–S6 pore loops, outer vestibule and turret regions, and S3–S4 “paddle” motifs in NaV, Kv, and CaV channels. These discrete binding epitopes are recognized by different peptide toxins, enabling isoform- and state-specific modulation; for example, μ-conotoxins bind the NaV pore, whereas charybdotoxin and agitoxin target the Kv outer vestibule. Beyond mechanistic insights, peptide toxins inspire translational strategies, including emerging therapies for retinal degenerative diseases. Photopharmacology using chemical photoswitches allows reversible, light-controlled modulation of ion channels in retinal ganglion cells without genetic manipulation or cell transplantation. Although BENAQ was discovered by small-molecule screening rather than toxin-guided design, its ion channel control demonstrates the potential of toxin-based molecular determinants for engineering synthetic compounds. This review thus integrates structural, functional, and translational perspectives, emphasizing the versatility of animal-derived peptide toxins as molecular probes and as blueprints for precision ion channel modulation in health and disease. Full article