Channel Function Research Articles

Anesthetic- and Analgesic-Related Drugs Modulating Both Voltage-Gated Na+ and TRP Channels

Nociceptive information is transmitted by action potentials (APs) through primary afferent neurons from the periphery to the central nervous system. Voltage-gated Na+ channels are involved in this AP production, while transient receptor potential (TRP) channels, which are non-selective cation channels, are involved in receiving and transmitting nociceptive stimuli in the peripheral and central terminals of the primary afferent neurons. Peripheral terminal TRP vanilloid-1 (TRPV1), ankylin-1 (TRPA1) and melastatin-8 (TRPM8) activation produces APs, while central terminal TRP activation enhances the spontaneous release of L-glutamate from the terminal to spinal cord and brain stem lamina II neurons that play a pivotal role in modulating nociceptive transmission. There is much evidence demonstrating that chemical compounds involved in Na+ channel (or nerve AP conduction) inhibition modify TRP channel functions. Among these compounds are local anesthetics, anti-epileptics, α2-adrenoceptor agonists, antidepressants (all of which are used as analgesic adjuvants), general anesthetics, opioids, non-steroidal anti-inflammatory drugs and plant-derived compounds, many of which are involved in antinociception. This review mentions the modulation of Na+ channels and TRP channels including TRPV1, TRPA1 and TRPM8, both of which modulations are produced by pain-related compounds.

Exploring Image Decolorization: Methods, Implementations, and Performance Assessment

Decolorization is an image processing technique that converts a color input image into a grayscale image. This paper discusses the decolorization process and provides an overview of the methods based on the different principles used: basic conversion from RGB to YUV format using ITU Recommendations 601, 709, and 2020; basic conversion from RGB to LAB color space; the method using cumulative distribution function of color channels; one global decolorization method; and one based on deep learning. The grayscale images produced by these methods were evaluated using four objective metrics, allowing for a thorough analysis and comparison of the decolorization results. Additionally, the execution speed of the algorithms was assessed, providing insight into their performance efficiency. The results demonstrate that different metrics evaluate the decolorization methods differently, highlighting the importance of selecting an appropriate metric that aligns with the subsequent image processing tasks following decolorization. Furthermore, it was shown that the decolorization methods depend on the content of the images, performing better on natural images than on artificially generated ones. The decolorization methods were also examined in the context of object segmentation and edge detection. The results from segmentation and edge detection were aligned with the decolorization results, revealing that certain objective metrics for evaluating decolorization more effectively assessed the properties of the decolorized images, which are crucial for successful object segmentation and edge detection.

Exploring the nexus between medical gases and ion channel function: implications for therapeutic innovation

Exploring the nexus between medical gases and ion channel function: implications for therapeutic innovation

Theoretical Studies on the Evolution of Solar Filaments in Response to New Emerging Flux

Abstract New emerging flux (NEF) has long been considered a mechanism for solar eruptions, but the detailed process remains an open question. In this work, we explore how NEF drives a coronal magnetic configuration to erupt. This configuration is created by two magnetic sources of strengths M and S embedded in the photosphere, one electric-current-carrying flux rope (FR) floating in the corona, and an electric current induced on the photospheric surface by the FR. The source M is fixed, accounting for the initial background field, and S changes, playing the role of NEF. We introduce the channel function C to forecast the overall evolutionary behavior of the configuration. The location, polarity, and strength of NEF govern the evolutionary behavior of the FR before eruption. In the case of ∣S/M∣ < 1, with reconnection occurring between new and old fields, the configuration in equilibrium evolves to the critical state, invoking the catastrophe. In this case, if the polarities of the new and old fields are opposite, reconnection occurs as NEF is close to the FR, and if the polarities are the same, reconnection happens as NEF appears far from the FR. With different combinations of the relative polarity and the location, the evolutionary behavior of the system gets complex, and the catastrophe may not occur. If ∣S/M∣ > 1 and the two fields have opposite polarity, the catastrophe always takes place, but if the polarities are the same, the catastrophe occurs only as NEF is located far from the FR; otherwise, the evolution ends up either with a failed eruption or without a catastrophe at all.

Structure and function of the human mitochondrial MRS2 channel.

The human mitochondrial RNA splicing 2 protein (MRS2) has been implicated in Mg2+ transport across mitochondrial inner membranes, thus having an important role in Mg2+ homeostasis critical for mitochondrial integrity and function. However, the molecular mechanisms underlying its fundamental channel properties such as ion selectivity and regulation remain unclear. Here we present a structural and functional investigation of MRS2. Cryo-electron microscopy structures in various ionic conditions reveal a pentameric channel architecture and the molecular basis of ion permeation and potential regulation mechanisms. Electrophysiological analyses demonstrate that MRS2 is a Ca2+-regulated, nonselective channel permeable to Mg2+, Ca2+, Na+ and K+, which contrasts with its prokaryotic ortholog, CorA, operating as a Mg2+-gated Mg2+ channel. Moreover, a conserved arginine ring within the pore of MRS2 functions to restrict cation movements, thus preventing the channel from collapsing the proton motive force that drives mitochondrial adenosine triphosphate synthesis. Together, our results provide a molecular framework for further understanding MRS2 in mitochondrial function and disease.

Constitutive opening of the Kv7.2 pore activation gate causes KCNQ2-developmental encephalopathy

Pathogenic variants in KCNQ2 encoding Kv7.2 voltage-gated potassium channel subunits cause developmental encephalopathies (KCNQ2-encephalopathies), both with and without epilepsy. We herein describe the clinical, in vitro, and in silico features of two encephalopathy-causing variants (A317T, L318V) in Kv7.2 affecting two consecutive residues in the S6 activation gate that undergoes large structural rearrangements during pore opening; the disease-causing A356T variant in KCNQ3, paralogous to the A317T variant in KCNQ2, was also investigated. Currents through KCNQ2 mutant channels displayed increased density, hyperpolarizing shifts in activation gating, faster activation and slower deactivation kinetics, and resistance to changes in the cellular concentrations of phosphatidylinositol 4,5-bisphosphate (PIP2), a critical regulator of Kv7 channel function; all these features are consistent with a strong gain-of-function effect. An increase in the probability of single-channel opening, with no change in membrane abundance or single-channel conductance, was responsible for the observed gain-of-function effects. All-atom molecular dynamics simulations revealed that the mutations widened the inner pore gate and stabilized a constitutively open channel configuration in the closed state, with minimal effects on the open conformation. Thus, mutation-induced stabilization of the inner pore gate open configuration is a molecular pathogenetic mechanism for KCNQ2-related encephalopathies.

Towards in vivo Bronchoscopic Functional CFTR Assessment using a Short Circuit Current Measurement Probe.

The epithelial lining of luminal organs provides an immune barrier against external factors and regulates transport of nutrients, ions, and water into the body. Several conditions are associated with a breakdown or dysfunction of the epithelial lining. Short circuit current (Isc) measurement using a bulky, expensive, and hard to deploy system known as the Ussing chamber is the gold standard for evaluation of epithelial transport function but requires tissue excision. We demonstrated the ability of the Isc probe to measure Isc in normal wild type (WT) versus reduced CFTR function knockout (KO) rats as a relevant animal model for testing ion channel function.

Calcium Channel Blocker Lacidipine Promotes Antitumor Immunity by Reprogramming Tryptophan Metabolism

AbstractDysfunction of calcium channels is involved in the development and progression of some cancers. However, it remains unclear the role of calcium channel inhibitors in tumor immunomodulation. Here, calcium channel blocker lacidipine is identified to potently inhibit the enzymatic activity and expression of indoleamine 2,3‐dioxygenase 1 (IDO1), a rate‐limiting enzyme in tryptophan metabolism. Lacidipine activates effector T cells and incapacitates regulatory T cells (Tregs) to augment the anti‐tumor effect of chemotherapeutic agents in breast cancer by converting immunologically “cold” into “hot” tumors. Mechanistically, lacidipine targets calcium channels (CaV1.2/1.3) to inhibit Pyk2‐JAK1‐calmodulin complex‐mediated IDO1 transcription suppression, which suppresses the kynurenine pathway and maintains the total nicotinamide adenine dinucleotide (NAD) pool by regulating NAD biosynthesis. These results reveal a new function of calcium channels in IDO1‐mediated tryptophan metabolism in tumor immunity and warrant further development of lacidipine for the metabolic immunotherapy in breast cancer.

Trametinib alters contractility of paediatric Noonan syndrome-associated hypertrophic myocardial tissue slices.

No curative treatment is available for RASopathy-associated childhood-onset hypertrophic cardiomyopathy (RAS-CM). Preclinical data and individual reports suggest a beneficial effect of small molecules targeting the RAS-mitogen-activated protein (MAP) kinase (MAPK) pathway in severely affected RAS-CM patients. The aim of this study was to evaluate the biophysical effects of trametinib, rapamycin and dasatinib on cultivated myocardial tissue slices of a paediatric RAS-CM patient using biomimetic cultivation chambers (BMCCs) and to correlate the findings with clinical data. Contracting right ventricular (RV) tissue slices were prepared from resected myocardium, cultivated in BMCCs and treated with distinct molecules directly and indirectly targeting the RAS-MAPK pathway (trametinib, rapamycin and dasatinib) or dimethyl sulfoxide (DMSO). Tissue biophysical properties were assessed using electrical stimulation protocols. Contractile function, force-frequency relationship and post-pause potentiation were compared before and after treatment. These parameters correlated to L-type Ca2+ channel function and sarcoplasmic Ca2+ loading. In vivo, off-label treatment with MAPK kinase (MEK) inhibitor trametinib of a child with severe RAS-CM resulted in a modest reduction of RV outflow tract (RVOT) obstruction (RVOT 151 to 122mmHg after 11weeks) and improved diastolic function (E/A 0.68 to 1.09 after 11weeks) and myocardial strain [RV global radial strain (RV-GRS) 25.94 to 42.76; RV global circumferential strain (RV-GCS) -15.26 to -18.61; and RV global longitudinal strain (RV-GLS) -10.31 to -16.78 at 11weeks], as determined by echocardiography and cardiac magnetic resonance tomography. In cultivated RV myocardial tissue slices, contraction force decreased after addition of trametinib and rapamycin but not after addition of DMSO and dasatinib. Improvement of Ca2+ handling, as depicted by a more positive force-frequency relationship and enhanced post-pause potentiation (31.2%), was noted in the trametinib-treated slice. The increase in post-pause potentiation was less pronounced in rapamycin-treated (26%) and absent in dasatinib-treated (<1%) slices. Ex vivo analysis of cultivated and electrically stimulated RV myocardial tissue slices of a patient with RAS-CM showed decreased contractility and improved sarcoplasmic reticulum function after addition of trametinib and in part after addition of rapamycin, but not after addition of dasatinib.

Artificial Ion Transporters as Potent Therapeutics for Channelopathies.

Ion channels are essential for the selective transport of ions, playing a fundamental role in critical physiological processes. Dysfunctions in these channels, often arising from genetic mutations or environmental factors, give rise to a class of disorders collectively known as channelopathies. In recent years, artificial ion transporters have been developed to mimic the essential function of natural channels, offering potential therapeutic approaches for these conditions. Although significant progress has been made in improving the activity and selectivity of these synthetic transporters, their application in treating diseases associated with ion transport dysregulation remains in its infancy. This concept provides an overview of recent advancements in artificial ion transporters for treating channelopathies, while highlighting the key challenges and prospects in translating these developments into practical therapies.

The genetic and molecular basis of a connexin-linked skin disease.

Erythrokeratodermia variabilis et progressiva (EKVP) is a rare hereditary skin disorder characterized by hyperkeratotic plaques and erythematous patches that progressively worsen with age. This disorder has been associated with variants in three connexin encoding genes (GJA1, GJB3, GJB4) and four unrelated genes (KRT83, KDSR, TRPM4, PERP). Most cases of connexin-linked EKVP exhibit an autosomal dominant mode of inheritance, with rare autosomal recessive cases. Collectively, evidence suggests that connexin variants associated with EKVP elicit a plethora of molecular defects including impaired gap junction (GJ) formation, dysregulated hemichannel and/or GJ channel function, cytotoxicity, dominant disruption of co-expressed connexins, and/or altered turnover kinetics. Here, we review the progress made in understanding the genetic and molecular basis of EKVP associated with connexin gene variants. We also discuss the landscape of treatment options used for this disorder and the future directions for research into this rare condition.

A structural analysis of the splice-specific functional impact of the pathogenic familial hemiplegic migraine type 1 S218L mutation on Cav2.1 P/Q-type channel gating

P/Q-type (Cav2.1) calcium channels mediate Ca2+ influx essential for neuronal excitability and synaptic transmission. The CACNA1A gene, encoding the Cav2.1 pore forming subunit, is highly expressed throughout the mammalian central nervous system. Alternative splicing of Cav2.1 pre-mRNA generates diverse channel isoforms with distinct biophysical properties and drug affinities, which are differentially expressed in nerve tissues. Splicing variants can also affect channel function under pathological conditions although their phenotypic implication concerning inherited neurological disorders linked to CACNA1A mutations remains unknown. Here, we quantified the expression of Cav2.1 exon 24 (e24) spliced transcripts in human nervous system samples, finding different levels of expression within discrete regions. The corresponding Cav2.1 variants, differing by the presence (+) or absence (Δ) of Ser-Ser-Thr-Arg residues (SSTR) in the domain III S3-S4 linker, were functionally characterized using patch clamp recordings. Further, the + /ΔSSTR isoforms were used to demonstrate the differential impact of the Familial Hemiplegic Migraine Type 1 (FHM-1) S218L mutation, located in the domain I S4-S5 linker, on the molecular structure and electrophysiological properties of Cav2.1 isoforms. S218L has a prominent effect on the voltage-dependence of activation of +SSTR channels when compared to ΔSSTR, indicating a differential effect of the mutation depending on splice-variant context. Structural modeling based upon Cav2.1 cryo-EM data provided further insight reflecting independent contributions of amino acids in distant regions of the channel on gating properties. Our modelling indicates that by increasing hydrophobicity the Leu218 mutation contributes to stabilizing a structural conformation in which the domain I S4-S5 linker is oriented alongside the inner plasma membrane, similar to that occurring when S4 is translocated upon activation.The SSTR insertion appears to exert an influence in the local electric field of domain III due to an change in the distribution of positively charged regions surrounding the voltage sensing domain, which we hypothesize impacts its movement during the transition to the open state. In summary, we reveal molecular changes correlated with distinct functional effects provoked by S218L FHM-1 mutation in hCav2.1 splice isoforms whose differential expression could impact the manifestation of the neurological disorder.

Dominant negative variants in ITPR3 impair T cell Ca2+ dynamics causing combined immunodeficiency.

The importance of calcium (Ca2+) as a second messenger in T cell signaling is exemplified by genetic deficiencies of STIM1 and ORAI1, which abolish store-operated Ca2+ entry (SOCE) resulting in combined immunodeficiency (CID). We report five unrelated patients with de novo missense variants in ITPR3, encoding a subunit of the inositol 1,4,5-trisphosphate receptor (IP3R), which forms a Ca2+ channel in the endoplasmic reticulum (ER) membrane responsible for the release of ER Ca2+ required to trigger SOCE, and for Ca2+ transfer to other organelles. The patients presented with CID, abnormal T cell Ca2+ homeostasis, incompletely penetrant ectodermal dysplasia, and multisystem disease. Their predominant T cell immunodeficiency is characterized by significant T cell lymphopenia, defects in late stages of thymic T cell development, and impaired function of peripheral T cells, including inadequate NF-κB- and NFAT-mediated, proliferative, and metabolic responses to activation. Pathogenicity is not due to haploinsufficiency, rather ITPR3 protein variants interfere with IP3R channel function leading to depletion of ER Ca2+ stores and blunted SOCE in T cells.

Trpv1-lineage neuron-expressing Kcnq4 channel modulates itch sensation in mice.

Voltage-gated potassium channel subfamily q member 4 (Kcnq4) is predominantly expressed by hair cells and auditory neurons and regulates the neuronal excitability in the auditory pathway. Although it is further detected in myelinated large-diameter dorsal root ganglia (DRG) neurons in the periphery, the expression and function of Kcnq4 channel in nociceptors remains unknown. Here we showed that Kcnq4 is substantially expressed by unmyelinated small-diameter DRG neurons in both human and mouse. In spite of a dispensable role in acute pain and chronic skin inflammation, Kcnq4 is specifically involved in the regulation of scratching behavior through controlling action potential firing properties, evidenced by the increased neuronal excitability in small-diameter DRG neurons isolated from Kcnq4 deficient mice. Moreover, genetic ablation of Kcnq4 in Trpv1-positive neurons exacerbates both acute and chronic itch behavior in mice. Taken together, our results uncover a functional role of Trpv1-lineage neuron-expressing Kcnq4 channel in the modulation of itch-specific neuronal excitation in the periphery.

Interleukin-6 Modulates the Expression and Function of HCN Channels: A Link Between Inflammation and Atrial Electrogenesis.

Inflammatory cytokines, including interleukin 6 (IL6), are associated with ion channel remodeling and enhance the propensity to alterations in cardiac rhythm generation and propagation, in which the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play a crucial role. Hence, we investigated the consequences of exposure to IL6 on HCN channels in cell models and human atrial biopsies. In murine atrial HL1 cells and in cardiomyocytes derived from human induced pluripotent stem cells (hiPS-CMs), IL6 elicited STAT3 phosphorylation, a receptor-mediated downstream signaling. Downregulation of HCN1,2,4 by IL6 was observed after 24-48 h; in hiPS-CMs, this effect was reverted by 24 h of application of tocilizumab, a human IL6 receptor antagonist. In parallel, hiPS-CM action potentials (APs) showed a reduced spontaneous frequency. Moreover, we assessed IL6 and HCN expression in dilated left atrial samples from patients with mitral valve disease, an AF-prone condition. IL6 levels were increased in dilated atria compared to controls and positively correlated with echocardiographic atrial dimensions. Interestingly, the highest IL6 transcript levels and the lowest HCN4 and HCN2 expression were in these samples. In conclusion, our data uncovered a novel link between IL6 and cardiac HCN channels, potentially contributing to atrial electrical disturbances and a higher risk of dysrhythmias in conditions with elevated IL6 levels.

Ligand distances as key predictors of pathogenicity and function in NMDA receptors.

Genetic variants in the genes GRIN1, GRIN2A, GRIN2B, and GRIN2D, which encode subunits of the N-methyl-D-aspartate receptor (NMDAR), have been associated with severe and heterogeneous neurologic and neurodevelopmental disorders, including early onset epilepsy, developmental and epileptic encephalopathy, intellectual disability, and autism spectrum disorders. Missense variants in these genes can result in gain or loss of the NMDAR function, requiring opposite therapeutic treatments. Computational methods that predict pathogenicity and molecular functional effects of missense variants are therefore crucial for therapeutic applications. We assembled 223 missense variants from patients, 631 control variants from the general population, and 160 missense variants characterized by electrophysiological readouts that show whether they can enhance or reduce the function of the receptor. This includes new functional data from 33 variants reported here, for the first time. By mapping these variants onto the NMDAR protein structures, we found that pathogenic/benign variants and variants that increase/decrease the channel function were distributed unevenly on the protein structure, with spatial proximity to ligands bound to the agonist and antagonist binding sites being a key predictive feature for both variant pathogenicity and molecular functional consequences. Leveraging distances from ligands, we developed two machine-learning based predictors for NMDA variants: a pathogenicity predictor which outperforms currently available predictors and the first molecular function (increase/decrease) predictor. Our findings can have direct application to patient care by improving diagnostic yield for genetic neurodevelopmental disorders and by guiding personalized treatment informed by the knowledge of the molecular disease mechanism.

Comprehensive gene expression analysis in gallbladder mucosal epithelial cells of dogs with gallbladder mucocele.

Gallbladder mucocele (GBM) is a common disease in the canine gallbladder. Although the pathogenesis of GBM remains unclear, we recently reported that the excessive accumulation of mucin in the gallbladder is not a result of overproduction by gallbladder epithelial cells (GBECs). Changes in the function of GBECs other than the production of mucin are associated with the pathogenesis of GBM. We performed an RNA sequencing (RNA-seq) analysis to comprehensively search for abnormalities in gene expression profiles of GBECs in dogs with GBM. Fifteen dogs with GBM and 8 dogs euthanized for reasons other than gallbladder disease were included. The GBECs were isolated from gallbladder tissues to extract RNA. The RNA-seq analysis was performed using the samples from 3 GBM cases and 3 dogs with normal gallbladders, and the gene expression profiles were compared between the 2 groups. Differences in mRNA expression levels of the extracted differentially expressed genes (DEGs) were validated by quantitative reverse transcription polymerase chain reaction (RT-qPCR) using samples of 15 GBM cases and 8 dogs with normal gallbladders. Comparison of gene expression profiles by RNA-seq extracted 367 DEGs, including ANO1, a chloride channel associated with changes in mucin morphology, and HTR4, which regulates the function of chloride channels. The ANO1 and HTR4 genes were confirmed to be downregulated in the GBM group by RT-qPCR. Our results suggest that GBM may be associated with decreased function of chloride channels expressed in GBECs.

Abstract 4138514: From Treatment to Trigger: A Case of Atomoxetine-Induced Brugada Pattern

Introduction: Brugada syndrome is an inherited cardiac disorder characterized by specific ECG patterns, notably the coved-type ST-segment elevation in the right precordial leads (V1-V3), leading to an increased risk of sudden cardiac death. This condition often stems from mutations in the SCN5A gene, which impair cardiac sodium channel function. The manifestation of Brugada Pattern, showing typical ECG findings without clinical criteria like sudden cardiac arrest or syncope, is significant. We highlight a case where atomoxetine, a selective norepinephrine reuptake inhibitor used for ADHD, unveiled a type 1 Brugada pattern. Case Presentation: A 26-year-old male with a history of ADHD on atomoxetine only presented to the emergency department with sudden substernal chest pain radiating to his left arm. His initial ECG showed right bundle branch block and type 1 Brugada pattern (Figure.1). Despite normal troponin levels and a negative coronary CT angiography, the patient's ECG abnormalities raised concerns. With no personal or familial history of arrhythmia or SCD and no other medications, atomoxetine was suspected as the trigger. Upon discontinuation, the patient's ECG type 1 Brugada pattern resolved (Figure. 2), and he remained asymptomatic with a normal Holter monitor at a 1-month follow-up. Discussion: Brugada syndrome is marked by dynamic ECG abnormalities, which can surface due to triggers like fever, certain medications, and electrolyte imbalances. Atomoxetine, an ADHD treatment and selective norepinephrine reuptake inhibitor, affects the human cardiac sodium channel (hNav1.5), encoded by the SCN5A gene. This interaction can disrupt heart action potentials, leading to conditions like long QT syndrome and Brugada pattern, by slowing cardiomyocyte depolarization and conduction. Its effect on hNav1.5 resembles that of antidepressants like Fluoxetine, increasing the risk of Brugada pattern. In our case, a patient's type 1 Brugada pattern, with no underlying heart disease or family history, pointed to atomoxetine as the cause. Discontinuing the drug resolved the ECG abnormalities. Conclusion: This case emphasizes the importance of assessing cardiovascular risk before prescribing atomoxetine, especially in individuals at risk for cardiac sodium channel dysfunctions. Immediate intervention and monitoring are critical to prevent severe arrhythmias.

Biochemical, biophysical, and structural investigations of two mutants (C154Y and R312H) of the human Kir2.1 channel involved in the Andersen-Tawil syndrome.

Inwardly rectifying potassium (Kir) channels play a pivotal role in physiology by establishing, maintaining, and regulating the resting membrane potential of the cells, particularly contributing to the cellular repolarization of many excitable cells. Dysfunction in Kir2.1 channels is implicated in several chronic and debilitating human diseases for which there are currently no effective treatments. Specifically, Kir2.1-R312H and Kir2.1-C154Y mutations are associated with Andersen-Tawil syndrome (ATS) in humans. We have investigated the impact of these two mutants in the trafficking of the channel to the cell membrane and function in Xenopus laevis oocytes. Despite both mutations being trafficked to the cell membrane at different extents and capable of binding PIP2 (phosphatidylinositol-4,5-bisphosphate), the main modulator for channel activity, they resulted in defective channels that do not display K+ current, albeit through different molecular mechanisms. Coexpression studies showed that R312H and C154Y are expressed and associated with the WT subunits. While WT subunits could rescue R312H dysfunction, the presence of a unique C154Y subunit disrupts the function of the entire complex, which is a typical feature of mutations with a dominant-negative effect. Molecular dynamics simulations showed that Kir2.1-C154Y mutation induces a loss in the structural plasticity of the selectivity filter, impairing the K+ flow. In addition, the cryo-EM structure of the Kir2.1-R312H mutant has been reconstructed. This study identified the molecular mechanisms by which two ATS-causing mutations impact Kir2.1 channel function and provide valuable insights that can guide potential strategies for the development of future therapeutic interventions for ATS.

Mechanisms of lipid-mediated regulation of the pore-forming activity of antimicrobial agents: studies on planar lipid bilayers

Planar lipid bilayers are unique tools designed for modeling cell membranes and electrophysiological studies of incorporated ion channels. Such model systems are designed to limit the number of components taking part in the functioning of biological membranes in order to characterize in detail the occurring processes under well-controlled experimental conditions. Planar lipid bilayers make it possible to record single events with a measured current of more than a tenth of a picoampere. The relative simplicity of the method, the ability to observe single molecular events, and the high reproducibility of the results obtained determines the unprecedented effectiveness of using planar lipid bilayers to identify key physical and chemical factors responsible for regulating the functioning of ion channels. This review represents an analysis of literature data concerning the mechanisms of lipid-associated regulation of ion channels formed by various antimicrobial agents. The examination allows us to consider the lipids as molecular chaperones that ensure the formation of pores in target membranes by antimicrobials.