[Suppression of trace depolarization of myelinated nerve fibers by intra-axonal blocking of potassium channels with cesium ions].
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Early infantile developmental and epileptic encephalopathy: clinical spectrum, diagnosis, outcomes, and evolving treatment strategies.
Early infantile developmental and epileptic encephalopathy (EIDEE) is among the most severe epilepsy syndromes, with onset before three months of age and an estimated incidence of approximately 10 per 100,000 live births. The 2022 International League Against Epilepsy classification unified the historically distinct Ohtahara syndrome and early myoclonic encephalopathy under a single diagnostic framework defined by frequent drug-resistant tonic and/or myoclonic seizures, an abnormal neurological examination, and an abnormal interictal electroencephalogram-most characteristically a burst-suppression pattern. This narrative review synthesizes the clinical, electrophysiological, neuroimaging, genetic, and therapeutic literature within the EIDEE framework. The clinical phenotype is characterized by central hypotonia, postnatal microcephaly, cortical visual impairment, and age-dependent syndromic evolution toward infantile epileptic spasms syndrome or Lennox-Gastaut syndrome in the majority of patients. Electroencephalography remains essential for syndromic classification, while systematic metabolic screening and early trio whole-exome or whole-genome sequencing are central to the etiologic workup, achieving diagnostic yields of 60-65%. The most commonly identified genetic causes include STXBP1, KCNQ2, and SCN2A variants. Outcomes are poor overall and strongly etiology-dependent: vitamin-responsive disorders carry a substantially more favorable prognosis, whereas mortality reaches 25% in genetic cohorts. Genotype-guided pharmacotherapy is now applicable to a clinically meaningful subset of patients, with sodium channel blockers, potassium channel openers, and emerging antisense oligonucleotide therapies representing important therapeutic advances. Gene therapy trials are underway but have encountered early safety signals, underscoring the vulnerability of this population. Critical unmet needs include earlier molecular diagnosis, precision therapies targeting developmental outcomes beyond seizure control, and prospective international registries to characterize the long-term natural history of EIDEE.
Humans↗
Effects of strychnine on the sodium conductance of the frog node of Ranvier.
Strychnine blocks sodium conductance in the frog node of Ranvier. This block was studied by reducing and slowing sodium inactivation with scorpion venom. The block is voltage and time dependent. The more positive the axoplasm the greater the block and the faster the approach to equilibrium. Some evidence is presented suggesting that only open channels can be blocked. The block is reduced by raising external sodium or lithium but not impermeant cations. A quaternary derivative of strychnine was synthesized and found to have the same action only when applied intracellularly. We conclude that strychnine blocks sodium channels by a mechanism analogous to that by which it blocks potassium channels. The potassium channel block had previously been found to be identical to that by tetraethylammonium ion derivatives. In addition, strychnine resembles procaine and its derivatives in both its structure and the mechanism of sodium channel block.
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Modified K-channel gating by exhaustion and the block by internally applied TEA+ and 4-aminopyridine in muscle.
Voltage clamp experiments on frog sartorius muscle fibres suggest that the large increase in resting potassium conductance during metabolic exhaustion is due to a change in the gating of activated potassium channels to a permanently open state. gK in exhausted fibres is less sensitive to externally applied blockers as Zn2+ and 4-aminopyridine (4-AP) while TEA+, Rb+ and Ba2+ act similarly, both in normal and exhausted fibres. In addition, injection experiments provide evidence that TEA+ and 4-AP applied internally to normal fibres effectively block potassium outward current, whereas in exhausted fibres the block seems to be smaller. These results suggest modifications in the structure of the potassium channels during metabolic exhaustion.
Animals↗
Genome-wide identification of potassium transporters and channels in Malus domestica genome.
Potassium (K+) is an essential nutrient for plants. It contributes to most physiological and biochemical pathways for plant metabolism, growth, and development. It is the most available plant nutrient, comprising 10–15% of plant weight. Plants have a sophisticated system of K+ transporters and channels for distribution in plant body. Apple is one of the most consumed fruits in the world. Its fruit quality and yield are positively affected by K+. However, limited information is available about K+ transport systems in Apple. In this study, 47 candidate genes (26 K+ transporters and 21 K+ channels) have been identified in Apple (Malus domestica) genome. The phylogenetic comparisons with other plants (Glycine max, Arabidopsis thaliana, and Oryza sativa) indicated that the K+ transport system is much conserved among different plants. The analysis of Gene structure showed the presence of specific introns and exon patterns for these gene families. Transcriptomic data analysis and RT-qPCR demonstrated significant variations in the transcript abundance of these genes in response to abiotic stresses. The current project represents the first report about the K+ transport system in Apple. Therefore, it may act as a starting point for further functional characterizations.
Malus↗
Proteomic characterization of Tityus championi venom and recombinant expression of its major neurotoxin.
BACKGROUND: Tityus championi is a species endemic to the southern Talamanca Mountain Range, along the border region between Costa Rica and Panama, and has been associated with severe clinical cases. Despite its medical relevance, the composition of its venom remains poorly studied. The present study aimed to characterize the proteomic composition of T. championi venom, identify its main toxin families, and recombinantly produce one of its most abundant and lethal toxins for potential use in antivenom development. METHODS: Venom composition was analyzed by tandem mass spectrometry (MS/MS), enabling the identification of venom proteins. Subsequently, one of its primary lethal toxins (Tcham27) was identified and recombinantly expressed. RESULTS: Proteomic analysis revealed that the most abundant family in the venom corresponded to metalloproteases, with 43 protein groups (17% of the total identifications), which are associated with processes such as hemorrhage, edema, inflammation, hypotension, and necrosis. CIIMET family toxins comprised 27 protein groups (11%). Among ion channel-acting toxins, 18 protein groups (7%) corresponded to sodium channel toxins and 14 (6%) to potassium channel toxins, homologous to components from geographically proximate species such as Tityus discrepans, Tityus cf. asthenes, and Tityus jaimei. Other relevant families included cysteine-rich secretory proteins (CRISPs; 6 proteins, 3%), serine proteases (5 proteins, 2%), and lectins (5 proteins, 2%). In addition, low-abundance components such as insulin-like growth factors, nucleotide pyrophosphatases, hyaluronidase, α-amylase, lipolysis-activated toxins, and chitinase were detected, contributing to the functional diversity of the venom. CONCLUSIONS: Proteomic characterization of T. championi venom demonstrates that metalloproteases constitute a major protein family alongside neurotoxins. Recombinant production of its most abundant toxic peptide, which is identical to toxins in the venom of geographically proximate Tityus species, provides a key tool for developing specific antivenoms.
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Biosafety and efficacy of Kv7 activating rdHSV-CA8∗ analgesic gene therapy for chronic pain via the intra-articular route in mice.
Chronic pain remains a global health challenge, often resistant to available treatments with socioeconomic and psychological burdens. All chronic pain is believed due to neuronal signaling imbalances, resulting in increased excitability. Gene therapy represents a promising molecular therapy targeting molecular pain processing pathways, by offering precise, localized, long-lasting neuromodulation while minimizing systemic exposure and side effects. In model systems, replication-defective, disease-free, herpes simplex virus (rdHSV) gene therapy expressing an analgesic carbonic anhydrase-8 (CA8∗) peptide variant corrects somatosensory hyperexcitability by activating Kv7 voltage-gated potassium channels, produces profound, long-lasting analgesia and treats chronic pain from knee osteoarthritis (OA). In these studies, we provide the first non-glucagon-like peptide (GLP) biosafety, efficacy, biodistribution, shedding, and histopathology examination of this rdHSV-CA8∗. Naive mice were examined for clinical safety, biodistribution across all major tissues, knee histopathology, and analgesic efficacy via the intra-articular knee route of administration. We observed no signs of persistent toxicity, viral genomes remained where they were injected, and there was no evidence of shedding. Profound analgesia persisted for 6 months without functional impairments. These initial biosafety and efficacy data support further development of rdHSV-CA8∗ for treating chronic knee pain due to moderate to severe OA.
Animals↗
The effect of fampridine on working memory: a randomized controlled trial based on a genome-guided repurposing approach.
Working memory (WM), a key component of cognitive functions, is often impaired in psychiatric disorders such as schizophrenia. Through a genome-guided drug repurposing approach, we identified fampridine, a potassium channel blocker used to improve walking in multiple sclerosis, as a candidate for modulating WM. In a subsequent double-blind, randomized, placebo-controlled, crossover trial in 43 healthy young adults (ClinicalTrials.gov, NCT04652557), we assessed fampridine's impact on WM (3-back d-prime, primary outcome) after 3.5 days of repeated administration (10 mg twice daily). Independently of baseline cognitive performance, no significant main effect was observed (Wilcoxon P = 0.87, r = 0.026). However, lower baseline performance was associated with higher working memory performance after repeated intake of fampridine compared to placebo (rs = -0.37, P = 0.014, n = 43). Additionally, repeated intake of fampridine lowered resting motor threshold (F(1,37) = 5.31, P = 0.027, R2β = 0.01), the non-behavioral secondary outcome, indicating increased cortical excitability linked to cognitive function. Fampridine's capacity to enhance WM in low-performing individuals and to increase brain excitability points to its potential value for treating WM deficits.
Adult↗
Effects of conditioning polarization on the membrane ionic currents in rat myometrium.
Membrane ionic currents were measured in pregnant rat uterine smooth muscle under voltage clamp conditions by utilizing the double sucrose gap method, and the effects of conditioning pre-pulses on these currents were investigated. With depolarizing pulses, the early inward current was followed by a late outward current. Cobalt (1 mM) abolished the inward current and did not affect the late outward current per se, but produced changes in the current pattern, suggesting that the inward current overlaps with the initial part of the late outward current. After correction for this overlap, the inward current reached is maximum at about +10 mV and its reversal potential was estimated to be +62 mV. Tetraethylammonium (TEA) suppressed the outward currents and increased the apparent inward current. The increase in the inward current by TEA thus could be due to a suppression of the outward current. The reversal potential for the outward current was estimated to be -87 mV. Conditioning depolarization and hyperpolarization both produced a decrease in the inward current. Complete depolarization block occurred at membrane potential of -20 mV. Conditioning hyperpolarization experiments in the presence of cobalt and/or TEA revealed that the decrease in the inward current caused by conditioning hyperpolarization was a result of an increase in the outward current overlaping with the inward current. It appears that a part of the potassium channel population is inactivated at the resting membrane potential and that this inactivation is removed by hyperpolarization.
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The compensation of potential changes produced by trivalent erbium ion in squid giant axon with applied potentials.
The transmembrane potential of voltage-clamped squid giant axon is increased to compensate for a reduction in the rate of potassium channel kinetics when artificial seawater with trivalent erbium ion is substituted for artificial seawater. The additional potential required to produce an equivalent rise time is a measure of the potential shift produced by the erbium ions. When the kinetics of K+ channels are matched in this manner, the maximal K+ currents are larger for the larger transmembrane potential. This observation requires a functional separation of the open K+ channel and the voltage sensor for the gating mechanism of this channel.
Animals↗
A fully coupled transient excited state model for the sodium channel. II. Implications for action potential generation, threshold, repetitive firing, and accommodation.
The axon membrane is simulated by standard Hodgkin-Huxley leakage and potassium channels plus a coupled transient excited state kinetic scheme for the sodium channel. This scheme for the sodium channel is as proposed previously by the author. Simulations are presented showing the form of the action potential, threshold behavior, accommodation, and repetitive firing. It is seen that the form of the individual action potential, its all-or-none nature, and its refractory period are well simulated by this model, as they are by the standard Hodgkin-Huxley model. However, the model differs markedly from the Hodgkin-Huxley model with respect to repetitive firing and accommodation to stimulating currents of slowly rising intensity, in ways that are shown to be related to those features of the sodium inactivation which are anomalous to the H-H model. The tendency for repetitive firing is highly dependent on that parameter which primarily determines the existence of the inactivation shift in voltage clamp experiments, in such a way that the more pronounced the inactivation shift, the less the tendency for repetitive firing. The tendency for accommodation is highly dependent on that parameter which primarily determines the 'tauc-tauh' separation, in such a way that the greater the separation the greater the tendency for the membrane to accommodate without firing action potentials to a slowly rising current.
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Mechanosensitive channels dominate the minimal ion channel repertoire in prokaryotes.
The eukaryotic genomes encode hundreds of proteins that function as ion channels and transporters. Essential for sustaining life, these proteins mediate the movement of inorganic ions (e.g., K+, Na+, Cl-, and Ca2+) across the plasma membrane according to their electrochemical gradients. In multicellular organisms, a diverse array of ion channels contributes to the maintenance of the resting membrane potential, the regulation of pH, osmolarity, and cell volume, and the control of secretion, electrical excitability, and synaptic activity, among many other fundamental physiological processes. Although independent evolutionary origins have been proposed for several ion channel families, their relative hierarchical importance for cellular viability remains poorly understood. To advance our knowledge of ion channel evolutionary history, we focused on determining the minimal combination of permeabilities that allows cellular viability. To this end, we conducted a survey of representative prokaryotes with small genomes across bacterial and archaeal phyla. By focusing on the smallest genomes, our approach enabled the identification of five ion channel architectures shared among prokaryotes. Among these, non-selective mechanosensitive channels (MscS and MscL) are the most abundant, followed by potassium channels, CLC-type channels and proton channels of the MotA/TolQ/ExbB family. The conservation of the mechanosensitive protein architecture across archaeal and bacterial membranes suggests that the capacity to monitor physical membrane integrity predates the requirements for electrical communication.
Journal Article↗
TEA and 4-AP affect separate potassium and calcium channels differently in aplysia S and F cells.
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Selectivity Filter KCND3 Variant Causes Spinocerebellar Ataxia 19/22 and KV4.3 Functional Loss.
BACKGROUND: Spinocerebellar ataxia type 19/22 (SCA19/22) is a rare autosomal dominant neurodegenerative disorder caused by KCND3 variants encoding the KV4.3 potassium channel. While most pathogenic variants result in loss-of-function (LOF), no pathogenic variants were previously identified in the channel's selectivity filter, a critical domain for ion selectivity. OBJECTIVES: To elucidate the genetic cause and functional LOF mechanisms underlying severe early-onset cerebellar ataxia and neurodevelopmental impairment in monozygotic twins. METHODS: We evaluated twins presenting with early-onset cerebellar ataxia, developmental delay, and cognitive impairment. Whole-exome sequencing (WES) identified a KCND3 c.1103T>C (p.L368P) variant. Functional impacts were assessed through HEK293T cell protein expression, Xenopus oocyte electrophysiology, and structural homology modeling. RESULTS: WES identified a heterozygous de novo p.L368P variant in the "TLGYG" selectivity filter sequence. Modeling predicted a pore radius reduction, blocking potassium permeation. Biochemical analyses revealed markedly reduced protein expression and impaired trafficking. Electrophysiological recordings confirmed complete potassium current loss and a strong dominant-negative effect on wild-type KV4.3 currents. Clinically, the twins exhibited severe intellectual disability, developmental delay, and cerebellar atrophy with pontine flattening, without epilepsy. CONCLUSIONS: Identifying the first pathogenic variant in the KV4.3 selectivity filter highlights its critical role in channel proteostasis and ion conductance. The p.L368P variant produces a pronounced LOF phenotype and broadens the SCA19/22 clinical spectrum, indicating the filter's structural integrity is a key determinant of disease severity. © 2026 International Parkinson and Movement Disorder Society.
KCND3↗
[Separation of potassium and calcium channels in the nerve cell soma membrane].
Calcium inward and potassium outward currents were studied on internally dialysed isolated neurons of the snail Helix pomatia. Different sensitivity of the corresponding channels to changes in external pH was found. This difference was used for separation of their activation regions on the potential axis so that the characteristics of the inward and outward currents could be studied with minimal overlap. It is shown that the outward current channels possess a definite permeability to Tris ions (PTris :PK=0.05). This explains the impossibility to switch off this current by substituting Tris for internal potassium. The channels for the inward calcium current inactivate slowly with a first order kinetic; their instantaneous current-voltage characteristic reveals considerable Goldman-type rectification. The selectivity of the calcium channels to other bivallent cations is Ba:Sr:Ca:Mg=2.8:2.6:1.0:0.2.
Animals↗
Voltage-dependent changes in the permeability of nerve membranes to calcium and other divalent cations.
Transmitter release from depolarized nerve terminals seems to be preceded by a rise in the intracellular concentration of ionized calcium. In squid giant axons, depolarization promotes calcium entry by two routes: one that is blocked by tetrodotoxin and one that is insensitive to tetrodotoxin. The TTX-sensitive route seems to be the sodium channel of the action potential; but the TTX-insensitive route seems to be quite distinct from the sodium and potassium channels of the action potential. It is blocked by Mg-2+, Mn-2+ and Co-2+ ions and by the organic calcium antagonist D-600 and has many features in common with the mechanism that couples excitation to secretion.
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Some electrical properties of the membrane of the barnacle muscle fibers under internal perfusion.
Intracellular perfusion technique has been applied to the muscle fibers of the barnacle species, Balanus nubilus. In these fibers, generation and the form of the calcium spike was governed by the frequency of stimulation and intra- and extracellular calcium concentrations. Voltage-clamp experiments showed that the magnitude of the potassium outward current was controlled by the intracellular calcium concentration whose increase, nearly 10(3)-fold, raised the resting membrane conductance and the outward potassium current. On the other hand, application of 10 mM zinc ions inside the muscle fiber had no effect on either the resting potential or the outward potassium current but suppressed the early inward calcium current. Similarly, the inward calcium current was decreased by low concentration of sodium ions in the extracellular fluid only when its ionic strength was made low by substituting sucrose for the sodium salt. Measurement of outward current with the muscle fiber in calcium-free ASW solution and intracellularly perfused with several cationic solutions established the selectivity sequence TEA less than Cs less than Li less than Tris less than Rb less than Na less than K for the potassium channel.
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Mechanism of blockage of amphotericin B channels in a lipid bilayer.
A number of organic compounds (non-electrolytes, tetraalkylammonia, etc.) with a molecular size of 6--8 angstrom decrease the conductance of ionic channels formed in the lipid bilayer by a polyene antibiotic amphotericin B. It is suggested that these compounds, upon entering the channel, block the passage of inorganic ions. The extent of conductance blockage by organic ions depends on the membrane potential and electrolyte concentration. In the presence of ionic blockers, for instance tetraethylammonium, amphotericin B-containing membranes assume some properties characteristic of excitable membranes, i.e. the current-voltage characteristic acquires the negative resistance region, and in response to a potential step activation followed by inactivation of conductance is observed. It is shown that the potential dependence of the blockage is due to interaction inside the channel of the blocker ion with penetrating ions, by a mechanism similar to that described by Armstrong ((1979) Q. Rev. Biophys. 7, 179--210) for blockage of squid axon potassium channels by ammonium derivatives.
Amphotericin B↗