Voltage-gated Channels Research Articles

A novel method for expressing and purifying large quantities of functional and stable human voltage-gated proton channel (hHv1).

Purifying membrane proteins has been the limiting step for studying their structure and function. The challenges of the process include the low expression levels in heterologous systems and the requirement for their biochemical stabilization in solution. The human voltage-gated proton channel (hHv1) is a good example of that: the published protocols to express and purify hHv1 produce low protein quantities at high costs, which is an issue for systematically characterizing its structure and function. Based on a pipeline approach, we developed a novel method to produce large quantities of properly folded and fully functional hHv1. We found that using the correct Escherichia coli strain in an autoinduction medium at low temperatures maximized protein expression. Furthermore, solubilization screenings showed that the detergent Anzergent 3-12 was a better alternative than Fos-choline-12 to purify hHv1, considerably reducing the costs. Buffers with high ionic strength increased the protein extracted during detergent solubilization and the stability of hHv1 during downstream processing. Finally, a further improvement was achieved when an enterokinase cutting site was inserted at the N-terminus of the protein. Our novel method produces properly folded and fully functional hHv1, increasing the protein yield by 100 times and reducing the cost by 96% while improving the protein stability compared to the previously published protocols. Our work will accelerate studies on hHv1 and its possible future therapeutic use, while serving as an example for developing purification methodologies for other challenging membrane proteins.

Efficient stochastic simulation of piecewise-deterministic Markov processes and its application to the Morris-Lecar model of neural dynamics.

Piecewise-deterministic Markov processes combine continuous in time dynamics with jump events, the rates of which generally depend on the continuous variables and thus are not constants. This leads to a problem in a Monte-Carlo simulation of such a system, where, at each step, one must find the time instant of the next event. The latter is determined by an integral equation and usually is rather slow in numerical implementation. We suggest a reformulation of the next event problem as an ordinary differential equation where the independent variable is not the time but the cumulative rate. This reformulation is similar to the Hénon approach to efficiently constructing the Poincaré map in deterministic dynamics. The problem is then reduced to a standard numerical task of solving a system of ordinary differential equations with given initial conditions on a prescribed interval. We illustrate the method with a stochastic Morris-Lecar model of neuron spiking with stochasticity in the opening and closing of voltage-gated ion channels.

Activation of the voltage-Gated Potassium channels by Amphiphilic Glycopeptides.

Voltage-gated ion channels (VGICs) are allosterically modulated by glycosaminoglycan proteoglycans and sialic acid glycans. However, the structural diversity and heterogeneity of these biomolecules pose significant challenges to precisely delineate their underlying structure-activity relationships. Herein, we demonstrate how heparan sulfate (HS) and sialic acid synthetic glycans appended on amphiphilic glycopeptide backbone influence cell membrane persistence and modulate the gating of the Kv2.1 channel. Utilizing a panel of amphiphilic glycopeptides comprising HS disaccharides and sialic acid trisaccharide glycans, we observed that sulfation of HS and flexible α(2-6) sialylation result in prolonged persistence of glycopeptides on the cell membrane compared to non-sulfated HS and α(2-3) sialylation respective. This variation in glycocalyx composition was associated with a noticeable difference in the effects of these compounds on the activation and inactivation properties of the voltage-gated Kv2.1 channel with our strongest membrane associating compound demonstrating the most potent channel-activation propensity. Our findings demonstrate that sulfation charges on glycopeptide play a critical role in their membrane association propensities and endow them with VGIC activation properties. and provide a valuable insight into the role of cell surface glycans in VGIC activities.

Integrating Forensic Autopsies with Proteomic Profiling for Suicide Risk Assessment: A Comprehensive Review of Literature.

Suicide is a major global public health concern that affects people of all ages, with over 700000 individuals intentionally ending their lives every year. Suicide is a multifactorial event related to multiple risk factors interlocking with each other, among which neurobiological factors are considered to be an objective measure of the incidence of this phenomenon and can be used as a measurable tool for evaluating suicidal tendencies. The aim of this study is to thoroughly examine available data and assess candidate proteins as prospective biomarkers for predicting suicides and ascertaining the manner of death in forensic cases. An electronic search was conducted on PubMed, Science Direct Scopus, and the Excerpta Medica Database. The systematic review adhered to PRISMA guidelines and encompassed case series, prospective and retrospective studies, and short communications published in English. The focus was on proteomics and suicide, specifically, those studies where researchers conducted human proteomic analyses on specimens obtained from individuals who completed or attempted suicide. A total of 14 studies met the inclusion criteria, resulting in a dataset of numerous candidate protein biomarkers. These include tenascin-C, potassium voltage-gated channel subfamily Q member 3, vimentin-immunoreactive astrocytes, glutathione S-transferase theta 1, iron transport proteins, Acrystallin chain B, manganese superoxide dismutase, glial fibrillary acidic protein, various glycolytic pathway proteins, 14-3-3 eta and 14-3-3 theta proteins, specific cytoskeleton proteins, C-reactive protein, serum amyloid A protein 1, extrinsic coagulation pathway proteins, the vacuolar-type proton pump ATPase subunit, plasma apolipoprotein A-IV, and ER stress proteins. These proteins are proposed as a panel of biomarkers to be evaluated in conjunction with other clinical predictors of suicide. This review aims to provide a comprehensive summary of all proteomic studies conducted on cases of attempted or completed suicide. By doing so, it seeks to bridge existing gaps in knowledge and pave the way for future investigations. The ultimate goal is to potentially identify a suicide biomarker.

Small molecule inhibits KCNQ channels with a non-blocking mechanism.

Voltage-gated ion channels (VGICs) are crucial targets for neuropsychiatric therapeutics owing to their role in controlling neuronal excitability and the established link between their dysfunction and neurological diseases, highlighting the importance of identifying modulators with distinct mechanisms. Here we report two small-molecule modulators with the same chemical scaffold, Ebio2 and Ebio3, targeting a potassium channel KCNQ2, with opposite effects: Ebio2 acts as a potent activator, whereas Ebio3 serves as a potent and selective inhibitor. Guided by cryogenic electron microscopy, patch-clamp recordings and molecular dynamics simulations, we reveal that Ebio3 attaches to the outside of the inner gate, employing a unique non-blocking inhibitory mechanism that directly squeezes the S6 pore helix to inactivate the KCNQ2 channel. Ebio3 also showed efficacy in inhibiting currents of KCNQ2 pathogenic gain-of-function mutations, presenting an avenue for VGIC-targeted therapies. Overall, these findings contribute to the understanding of KCNQ2 inhibition and provide insights into developing selective, non-blocking VGIC inhibitors.

Power spectral analysis of voltage-gated channels in neurons

This article develops a fundamental insight into the behavior of neuronal membranes, focusing on their responses to stimuli measured with power spectra in the frequency domain. It explores the use of linear and nonlinear (quadratic sinusoidal analysis) approaches to characterize neuronal function. It further delves into the random theory of internal noise of biological neurons and the use of stochastic Markov models to investigate these fluctuations. The text also discusses the origin of conductance noise and compares different power spectra for interpreting this noise. Importantly, it introduces a novel sequential chemical state model, named p2, which is more general than the Hodgkin–Huxley formulation, so that the probability for an ion channel to be open does not imply exponentiation. In particular, it is demonstrated that the p2 (without exponentiation) and n4 (with exponentiation) models can produce similar neuronal responses. A striking relationship is also shown between fluctuation and quadratic power spectra, suggesting that voltage-dependent random mechanisms can have a significant impact on deterministic nonlinear responses, themselves known to have a crucial role in the generation of action potentials in biological neural networks.

Molecular Dynamics Study of Protein-Mediated Electroporation of Kv Channels Induced by nsPEFs: Advantages of Bipolar Pulses.

Nanosecond pulsed electric fields (nsPEFs) can induce protein-mediated electroporation (PMEP) in voltage-gated ion channels. However, their effects on the tetrameric structure of voltage-gated potassium (Kv) channels remain unexplored. Our study pioneered the molecular dynamics (MD) investigation of the open-state (O) Kv channel to understand the effects of PMEP under unipolar and bipolar pulses (UP and BP). Our findings revealed that BP induces pore formation more effectively than UP. Additionally, the frequency of pore formation shows a more consistent decline with increased pulse interval under BP. We further examined three other distinct functional states─intermediate (C*), inactivated (I), and resting closed (C)─of Kv channels under BP. SF pores formed exclusively in the O state, while complex pores formed only in the O and C states. In conclusion, our study highlights BP's role in enhancing pore formation and specificity, offering insights into Kv channel PMEP and its therapeutic potential.

In silico toxicology investigation of μ-conotoxin KIIIA on human Na+ channel Nav1.2.

Conotoxins(CTXs) can specifically act on multiple ion channels, which are crucial for the development of neurobiology and novel targeted drug development. At present, >10,000 kinds of CTXs have been sequenced, it would be extremely laborious to conduct experiments for each. μ-CTX KIIIA is a type of substance that can selectively recognize voltage-gated sodium ion channels. This article constructs four derivatives of KIIIA and predicts their 3D structures; afterwards, their molecular orbital arrangements and physicochemical properties were calculated using DFT; then, predicted their toxicokinetic parameters such as absorption, distribution, metabolism, excretion (ADME) and toxicity (T) through Machine Learning (ML); finally, molecular docking and molecular dynamics are used to investigate the interaction modes and binding affinity. The results indicate that the toxicity of KIIIA and its derivatives (KIIIA-1 -KIIIA-4) to the human body is mainly concentrated in the liver and respiratory tract. Among four derivatives, KIIIA-2 (5 Ser→Arg) has better toxicokinetics properties and its binding energy to Nav1.2 is -65.32kcal/mol, which is higher than that of wild type(-32.13kcal/mol). This study indicate that computational toxicology can facilitate the druggability research of CTXs, and KIIIA-2 can be developed as a potential antiepileptic drug.

Design, synthesis, and evaluation of the pharmacological activity of novel NMDA receptor antagonists based on the germacrone scaffold.

The NMDA receptor has long attracted researchers' attention due to its potential as a drug target and its central role in the central nervous system. The NMDA receptor is a ligand-gated and voltage-dependent ion channel widely distributed in the central nervous system. In this study, we employed a drug design strategy combining "molecular assembly" and "combinatorial chemistry." By reducing the carbonyl group of germacrone to a hydroxyl group and esterifying it with alanine and linarinic acid, we successfully obtained nine novel germacrone derivatives through two rounds of structural optimization. We evaluated the neuroprotective activity of these nine derivatives using the MTT assay. The results revealed that compound C1 exhibited particularly outstanding activity, achieving a cell protection rate of 29.63±1.56% at a concentration of 0.05μM, outperforming the positive control drug, ifenprodil. Further experiments on NMDA-induced Ca2+ influx verified that the action site of compound C1 was the NMDA receptor, and demonstrated its superior antagonistic effect on the NMDA receptor compared to germacrone and ifenprodil. Additionally, molecular docking studies and ADMET property predictions were conducted for compound C1. The results showed that compound C1 tightly bound to the active site of the NMDA receptor and possessed favorable pharmacokinetic properties. In conclusion, compound C1, characterized by a germacrone-linarinic acid structure, not only exhibits strong antagonistic effects on the NMDA receptor but also demonstrates excellent pharmacokinetic properties, indicating its potential for further development as a therapeutic drug for central nervous system diseases.

Amiodarone Advances the Apoptosis of Cardiomyocytes by Repressing Sigmar1 Expression and Blocking KCNH2-related Potassium Channels.

Heart failure (HF) is the ultimate transformation result of various cardiovascular diseases. Mitochondria-mediated cardiomyocyte apoptosis has been uncovered to be associated with this disorder. This study mainly delves into the mechanism of the anti-arrhythmic drug amiodarone on mitochondrial toxicity of cardiomyocytes. The viability of H9c2 cells treated with amiodarone at 0.5, 1, 2, 3, and 4 μM was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and Sigmar1 expression was examined by quantitative real-time PCR (qRTPCR). After transfection, the viability, apoptosis, reactive oxygen species (ROS) level, mitochondrial membrane potential (MMP), and potassium voltage-gated channel subfamily H member 2 (KCNH2) expression in H9c2 cells were assessed by MTT, flow cytometry, ROS assay kit, mitochondria staining kit, and Western blot. Amiodarone at 1-4 μM notably weakened H9c2 cell viability with IC50 value of 2.62 ± 0.43 μM. Amiodarone at 0.5-4 μM also evidently suppressed the Sigmar1 level in H9c2 cells. Amiodarone repressed H9c2 cell viability and KCNH2 level and triggered apoptosis, ROS production and mitochondrial depolarization, while Sigmar1 upregulation reversed its effects. Moreover, KCNH2 silencing neutralized the combined modulation of amiodarone and Sigmar1 up-regulation on H9c2 cell viability, apoptosis, and ROS production. Amiodarone facilitates the apoptosis of H9c2 cells by restraining Sigmar1 expression and blocking KCNH2-related potassium channels.

Longitudinally persisting KCNA2-autoantibodies in mild amnestic dementia with Alzheimer´s pathology - Report and literature review.

Neural autoantibodies are being increasingly detected in conjunction with neurodegenerative dementias such as Alzheimer's disease dementia (AD), yet their significance is not well clarified. In this case report, we report the previously unreported long-lasting persistence of potassium voltage-gated channel subfamily A member 2 (KCNA2) antibodies in biomarker-supported AD. We report on a 77-year-old, male patient evaluated in our outpatient memory clinic of the Department of Psychiatry and Psychotherapy, University Medical Center Göttingen. Neuropsychological test results and autoantibody testing in serum over a period of 4-5 years is provided. Our patient exhibited mild dementia syndrome and was diagnosed with AD on the basis of a prototypical biomarker profile (reduced Aβ42/40 ratio and elevated p-tau181 protein in cerebrospinal fluid). Within a 5-year follow-up with regular visits to our memory clinic, we observed a nearly stable neuropsychological profile of mild, amnestic variant dementia that did not noticeably progress. KCNA2 autoantibodies were also detectable in serum over 4 years with increasing titers over time. Combined anti-dementia therapy with donepezil, multimodal therapy including non-pharmacological cognitive therapy, and immunotherapy with intravenous methylprednisolone was carried out as an individual treatment approach. KCNA2 autoantibody persistence in biomarker-supported AD does not necessarily trigger a poor outcome in the long-term, as cognitive impairment did not progress subsequently. At the same time, mild immunotherapy did not result in less immunoreactivity in conjunction with the detection of KCNA2 autoantibodies. This detection of KCNA2 autoantibodies in AD could provide indices of a potentially benign long-term AD course that should be further evaluated in studies.

Adaptive remodeling of rat adrenomedullary stimulus-secretion coupling in a chronic hypertensive environment

Chronic elevated blood pressure impinges on the functioning of multiple organs and therefore harms body homeostasis. Elucidating the protective mechanisms whereby the organism copes with sustained or repetitive blood pressure rises is therefore a topical challenge. Here we address this issue in the adrenal medulla, the master neuroendocrine tissue involved in the secretion of catecholamines, influential hormones in blood pressure regulation. Combining electrophysiological techniques with catecholamine secretion assays on acute adrenal slices from spontaneously hypertensive rats, we show that chromaffin cell stimulus-secretion coupling is remodeled, resulting in a less efficient secretory function primarily upon sustained cholinergic challenges. The remodeling is supported by revamped both cellular and tissular mechanisms. This first includes a decrease in chromaffin cell excitability in response to sustained electrical stimulation. This hallmark was observed both experimentally and in a computational chromaffin cell model, and occurs with concomitant changes in voltage-gated ion channel expression. The cholinergic transmission at the splanchnic nerve-chromaffin cell synapses and the gap junctional communication between chromaffin cells are also weakened. As such, by disabling its competence to release catecholamines in response sustained stimulations, the hypertensive medulla has elaborated an adaptive shielding mechanism against damaging effects of redundant elevated catecholamine secretion and associated blood pressure.

Pimozide Inhibits Type II but Not Type I Hair Cells in Chicken Embryo and Adult Mouse Vestibular Organs.

Pimozide is a conventional antipsychotic drug of the diphenylbutylpiperidine class, widely used for treating schizophrenia and delusional disorders and for managing motor and phonic tics in Tourette's syndrome. Pimozide is known to block dopaminergic D2 receptors and various types of voltage-gated ion channels. Among its side effects, dizziness and imbalance are the most frequently observed, which may imply an effect of the drug on the vestibular sensory receptors, the hair cells. Amniotes possess two classes of vestibular hair cells, named type I and type II hair cells, which differ in terms of signal processing and transmission. We previously reported that Pimozide [3 μM] significantly increased a delayed outward rectifying K+ current (IK,V). In the present study, using the whole-cell patch-clamp technique we additionally show that Pimozide decreases the inward rectifying K+ current (IK,1) and the mixed Na+/K+ current (Ih) of chicken embryo type II hair cells, whereas it does not affect type I hair cells' ionic currents. Since ion channels' expression can vary depending on age and animal species, in the present study, we also tested Pimozide in adult mouse vestibular hair cells. We found that, like in the chicken embryo, Pimozide significantly increases IK,V and decreases IK,1 and Ih in type II hair cells. However, in the adult mouse, Pimozide also slightly increased the outward rectifying K+ current in type I hair cells. While providing a possible explanation for the vestibular side effects of Pimozide in humans, its inhibitory action on mammalian hair cells might be of interest for the local treatment of vestibular disorders characterized by altered vestibular input, like Ménière's disease.

C2230, a preferential use- and state-dependent CaV2.2 channel blocker, mitigates pain behaviors across multiple pain models.

Antagonists (e.g., Ziconotide, Gabapentin) of the CaV2.2 (N-type) calcium channels are used clinically as analgesics for chronic pain. However, their use is limited by narrow therapeutic windows, difficult dosing routes (Ziconotide), misuse and overdoses (Gabapentin), as well as a litany of adverse effects. Expansion of novel pain therapeutics may emerge from mechanism-based interrogation of CaV2.2. Here we report the identification of C2230, an aryloxy-hydroxypropylamine, as a CaV2.2 blocker. C2230 trapped and stabilized inactivated CaV2.2 in a slow-recovering state and accelerated the open-state inactivation of the channel, conferring an advantageous use-dependent inhibition profile. C2230 inhibited CaV2.2 during high-frequency stimulation, while sparing other voltage-gated ion channels. C2230 inhibited CaV2.2 in dorsal root and trigeminal ganglia neurons from rats, marmosets, and humans in a G-protein-coupled receptor-independent manner. Further, C2230 reduced evoked excitatory postsynaptic currents and excitatory neurotransmitter release in the spinal cord, leading to relief of neuropathic, orofacial, and osteoarthritic pain-like behaviors via three different routes of administration. C2230 also decreased fiber photometry-based calcium responses in the parabrachial nucleus, mitigated aversive behavioral responses to mechanical stimuli after neuropathic injury, and preserved protective pain responses, all without affecting motor or cardiovascular function. Finally, site-directed mutation analysis demonstrated that C2230 binds differently than other known CaV2.2 blockers, making it a promising lead compound for analgesic development.

A novel image segmentation method based on spatial autocorrelation identifies A-type potassium channel clusters in the thalamus

Unsupervised segmentation in biological and non-biological images is only partially resolved. Segmentation either requires arbitrary thresholds or large teaching datasets. Here, we propose a spatial autocorrelation method based on Local Moran’s I coefficient to differentiate signal, background, and noise in any type of image. The method, originally described for geoinformatics, does not require a predefined intensity threshold or teaching algorithm for image segmentation and allows quantitative comparison of samples obtained in different conditions. It utilizes relative intensity as well as spatial information of neighboring elements to select spatially contiguous groups of pixels. We demonstrate that Moran’s method outperforms threshold-based method in both artificially generated as well as in natural images especially when background noise is substantial. This superior performance can be attributed to the exclusion of false positive pixels resulting from isolated, high intensity pixels in high noise conditions. To test the method’s power in real situation, we used high power confocal images of the somatosensory thalamus immunostained for Kv4.2 and Kv4.3 (A-type) voltage-gated potassium channels in mice. Moran’s method identified high-intensity Kv4.2 and Kv4.3 ion channel clusters in the thalamic neuropil. Spatial distribution of these clusters displayed strong correlation with large sensory axon terminals of subcortical origin. The unique association of the special presynaptic terminals and a postsynaptic voltage-gated ion channel cluster was confirmed with electron microscopy. These data demonstrate that Moran’s method is a rapid, simple image segmentation method optimal for variable and high noise conditions.

A novel image segmentation method based on spatial autocorrelation identifies A-type potassium channel clusters in the thalamus.

Unsupervised segmentation in biological and non-biological images is only partially resolved. Segmentation either requires arbitrary thresholds or large teaching datasets. Here, we propose a spatial autocorrelation method based on Local Moran's I coefficient to differentiate signal, background, and noise in any type of image. The method, originally described for geoinformatics, does not require a predefined intensity threshold or teaching algorithm for image segmentation and allows quantitative comparison of samples obtained in different conditions. It utilizes relative intensity as well as spatial information of neighboring elements to select spatially contiguous groups of pixels. We demonstrate that Moran's method outperforms threshold-based method in both artificially generated as well as in natural images especially when background noise is substantial. This superior performance can be attributed to the exclusion of false positive pixels resulting from isolated, high intensity pixels in high noise conditions. To test the method's power in real situation, we used high power confocal images of the somatosensory thalamus immunostained for Kv4.2 and Kv4.3 (A-type) voltage-gated potassium channels in mice. Moran's method identified high-intensity Kv4.2 and Kv4.3 ion channel clusters in the thalamic neuropil. Spatial distribution of these clusters displayed strong correlation with large sensory axon terminals of subcortical origin. The unique association of the special presynaptic terminals and a postsynaptic voltage-gated ion channel cluster was confirmed with electron microscopy. These data demonstrate that Moran's method is a rapid, simple image segmentation method optimal for variable and high noise conditions.

Calcium Ions in the Physiology and Pathology of the Central Nervous System.

Calcium ions play a key role in the physiological processes of the central nervous system. The intracellular calcium signal, in nerve cells, is part of the neurotransmission mechanism. They are responsible for stabilizing membrane potential and controlling the excitability of neurons. Calcium ions are a universal second messenger that participates in depolarizing signal transduction and contributes to synaptic activity. These ions take an active part in the mechanisms related to memory and learning. As a result of depolarization of the plasma membrane or stimulation of receptors, there is an extracellular influx of calcium ions into the cytosol or mobilization of these cations inside the cell, which increases the concentration of these ions in neurons. The influx of calcium ions into neurons occurs via plasma membrane receptors and voltage-dependent ion channels. Calcium channels play a key role in the functioning of the nervous system, regulating, among others, neuronal depolarization and neurotransmitter release. Channelopathies are groups of diseases resulting from mutations in genes encoding ion channel subunits, observed including the pathophysiology of neurological diseases such as migraine. A disturbed ability of neurons to maintain an appropriate level of calcium ions is also observed in such neurodegenerative processes as Alzheimer's disease, Parkinson's disease, Huntington's disease, and epilepsy. This review focuses on the involvement of calcium ions in physiological and pathological processes of the central nervous system. We also consider the use of calcium ions as a target for pharmacotherapy in the future.

Kv4 channels improve the temporal processing of auditory neurons in the cochlear nucleus.

Kv4 channels generate A-type current known to regulate neuronal excitability. Its role in processing timing information is understudied, especially in the auditory system where temporal information is crucial for hearing. In the cochlear nucleus, principal bushy neurons are specialized for temporal processing with distinct biophysical properties owing to their expression of various voltage-gated ion channels. Previous studies reported conflicting information regarding the expression and potential role of Kv4 channels in these neurons. We explored these questions using electrophysiology in CBA/CaJ mice of either sex. A-type current was isolated from 88% of bushy neurons using Kv4 channel-selective blocker Jingzhaotoxin-X (JZ-X), which increased the intrinsic excitability of bushy neurons without altering their synaptic input. During high-rate activity, JZ-X treatment significantly increased the spike jitter and reduced the firing threshold of bushy neurons. In old mice, A-type current in bushy neurons reduced in magnitude but maintained current density, accompanied by decreased membrane surface area. In contrast, TEA-sensitive Kv3 current reduced in both magnitude and current density, indicative of a greater contribution to the altered biophysical properties of bushy neurons during ageing. Our findings suggest that Kv4 channels play significant roles in regulating neuronal excitability and improving the temporal processing of bushy neurons. Such function is likely retained with age and is not the primary mechanism driving compromised temporal processing under age-related hearing loss. KEY POINTS: Most bushy neurons of the cochlear nucleus exhibit Kv4-mediated A-type current. A-type current regulates neuronal excitability of bushy neurons without contributing to the synaptic transmission at the endbulb of Held. A-type current increases the firing threshold and improves the temporal precision of spikes in bushy neurons during high-rate activity. A-type current reduces peak amplitude in bushy neurons during ageing but maintains current density. Decreased Kv3 current, rather than Kv4 current, likely play more significant roles in altering the biophysical properties of bushy neurons during ageing, contributing to compromised temporal processing during age-related hearing loss.

Biophysical mechanism of animal magnetoreception, orientation and navigation

We describe a biophysical mechanism for animal magnetoreception, orientation and navigation in the geomagnetic field (GMF), based on the ion forced oscillation (IFO) mechanism in animal cell membrane voltage-gated ion channels (VGICs) (IFO-VGIC mechanism). We review previously suggested hypotheses. We describe the structure and function of VGICs and argue that they are the most sensitive electromagnetic sensors in all animals. We consider the magnetic force exerted by the GMF on a mobile ion within a VGIC of an animal with periodic velocity variation. We apply this force in the IFO equation resulting in solution connecting the GMF intensity with the velocity variation rate. We show that animals with periodic velocity variations, receive oscillating forces on their mobile ions within VGICs, which are forced to oscillate exerting forces on the voltage sensors of the channels, similar or greater to the forces from membrane voltage changes that normally induce gating. Thus, the GMF in combination with the varying animal velocity can gate VGICs and alter cell homeostasis in a degree depending, for a given velocity and velocity variation rate, on GMF intensity (unique in each latitude) and the angle between velocity and GMF axis, which determine animal position and orientation.

Insight into a multifunctional potassium channel Kv1.3 and its novel implication in chronic kidney disease.

Chronic kidney disease (CKD), a global public health problem, causes substantial morbidity and mortality worldwide. Innovative therapeutic strategies to mitigate the progression of CKD are needed due to the limitations of existing treatments. Kv1.3, a voltage-gated potassium ion channel, plays a crucial role in multiple biological processes, including cell proliferation, apoptosis, energy homeostasis, and migration. Inhibition of the Kv1.3 channels has shown beneficial effects in the therapy of a wide range of human diseases such as cancer, autoimmune and neuroinflammatory diseases. Increasing evidence reveals a close link between Kv1.3 and CKD. This review summarises the most recent insights into the physiological functions of the Kv1.3 channel and its pharmacological modulators. Furthermore, the therapeutic potential of targeting Kv1.3 for CKD is also discussed. Collectively, these studies suggested that Kv1.3 channels may serve as a novel target for CKD therapy.