Regulation Of Ion Channels Research Articles

Inositol Phosphates and Synthesizing Enzymes: Implications in Neurodegenerative Disorders

Inositol is a vital sugar molecule involved in numerous signaling pathways required for cellular homeostasis and cell survival. Myo-inositol and its phospho-derivatives, inositol phosphates (IPs), are the most prevalent forms of inositol found in living cells. They are involved in regulating ion channels, metabolic flux, stress response, and other key biological processes. While emerging research has highlighted the significant roles of inositol phosphates in immunity, cancer, and metabolic diseases, there is a lack of comprehensive reviews on their roles in psychiatric and neurological disorders. This review aims to fill that gap by analyzing the existing literature on the importance of inositol phosphates in severe psychiatric and neurological conditions such as Parkinson’s disease, Alzheimer’s disease, bipolar disorder, amyotrophic lateral sclerosis, schizophrenia, and Huntington’s disease, underscoring the potential to pave the way for new treatment regimens for these debilitating disorders targeting inositol pathways.

Dual role of cytosolic GSH in the ABA signaling pathway and plasma membrane ion channel regulation in guard cells of Vicia faba

Dual role of cytosolic GSH in the ABA signaling pathway and plasma membrane ion channel regulation in guard cells of Vicia faba

Chemiluminescence Resonance Energy Transfer for Targeted Photoactivation of Ion Channels in Living Cells.

The regulation of oxidative stress in living cells is essential for maintaining cellular processes and signal transduction. However, developing straightforward strategies to activate oxidative stress-sensitive membrane channels in situ poses significant challenges. In this study, we presented a chemiluminescence resonance energy transfer (CRET) system based on a conjugated oligomer, oligo(p-phenylenevinylene)-imidazole (OPV-Im), designed for the activation of transient receptor potential melastatin 2 (TRPM2) calcium channels in situ by superoxide anion (O2•-) without requiring external light sources. The OPV-Im oligomer, which targeted the cell membrane efficiently, leading to the activation of TRPM2 channels in situ by CRET process and subsequent intracellular calcium overload. This cascade resulted in mitochondrial damage and inhibition of autophagy, ultimately inducing cell apoptosis. Additionally, this strategy can be applied for the selective killing of tumor cells that overexpress TRPM2 ion channels and for inhibiting the growth of three-dimensional tumor cell spheroids. Compared to optogenetics and photodynamic therapy, our system offers a novel approach for regulating ion channel activity and oxidative stress in living cells.

Modeling ocular surface ion and water transport by generation of lipid- and mucin-producing human Meibomian gland and conjunctival epithelial cells.

Despite the importance of ocular surface in human physiology and diseases, little is known about ion channel expression, properties and regulation in ocular epithelial cells. Furthermore, human primary epithelial cells have rarely been studied in favor of rat, mouse and especially rabbit animal models. Here, we developed primary human Meibomian gland (hMGEC) and conjunctival (hConEC) epithelial cells. We show that hConEC and hMGEC produce MUC5AC and lipids, respectively. With cell cultures maintained at the air-liquid interface, we recorded transepithelial short-circuit currents by the Ussing chamber method. We identified in the apical membrane Na+, Cl- and K+ ion channels; amiloride-sensitive ENaC, cAMP-dependent CFTR, UTP-dependent TMEM16a, and chromanol 293B-sensitive KCNQ1. At the basolateral membrane we identified bumetanide-sensitive NKCC and barium-sensitive K+ channels. We also found that VIP, concentration-dependent (EC50 of 1-8 nM), stimulates the CFTR-dependent Isc in both cells. Western blot analysis confirms the expression in both cell cultures of βENaC subunit, CFTR, TMEM16a and KCNQ1 proteins. We recorded water influx by quantitative phase microscopy and identified a cAMP-dependent and mercury sensitive water flux and identified by western blot AQP3 and AQP5 proteins in hConEC and hMGEC. Taken together, we propose a model of the ion transports of human conjunctival and Meibomian gland epithelial cells that will set the stage for a future molecular dissection of the regulation of these transport proteins in the context of tear secretion and related diseases.

Impaired Molecular Mechanisms Contributing to Chronic Pain in Patients with Hidradenitis Suppurativa: Exploring Potential Biomarkers and Therapeutic Targets

Hidradenitis suppurativa (HS) is a chronic skin condition that primarily affects areas with dense hair follicles and apocrine sweat glands, such as the underarms, groin, buttocks, and lower breasts. Intense pain and discomfort in HS have been commonly noted, primarily due to the lesions’ effects on nearby tissues. Pain is a factor that can influence DNA methylation patterns, though its exact role in HS is not fully understood. We aim to identify molecular markers of chronic pain in HS patients. We performed DNA methylome of peripheral blood DNA derived from a group of 24 patients with HS and 24 healthy controls, using Illumina methylation array chips. We identified 253 significantly differentially methylated CpG sites across 253 distinct genes regulating pain sensitization in HS, including 224 hypomethylated and 29 hypermethylated sites. Several genes with pleiotropic roles include transporters (ABCC2, SLC39A8, SLC39A9), wound healing (MIR132, FGF2, PDGFC), ion channel regulators (CACNA1C, SCN1A), oxidative stress mediators (SCN8A, DRD2, DNMT1), cytochromes (CYP19A, CYP1A2), cytokines (TGFB1, IL4), telomere regulators (CSNK1D, SMAD3, MTA1), circadian rhythm (IL1R2, ABCG1, RORA), ultradian rhythms (PHACTR1, TSC2, ULK1), hormonal regulation (PPARA, NR3C1, ESR2), and the serotonin system (HTR1D, HTR1E, HTR3C, HTR4, TPH2). They also play roles in glucose metabolism (POMC, IRS1, GNAS) and obesity (DRD2, FAAH, MMP2). Gene ontology and pathway enrichment analysis identified 43 pathways, including calcium signaling, cocaine addiction, and nicotine addiction. This study identified multiple differentially methylated genes involved in chronic pain in HS, which may serve as biomarkers and therapeutic targets. Understanding their epigenetic regulation is crucial for personalized pain management and could enhance the identification of high-risk patients, leading to better preventative therapies and improved maternal and neonatal outcomes.

Research Progress on Opioid Receptors and Ion Channels in Dorsal Root Ganglion Neurons

Dorsal root ganglion (DRG) neurons play a crucial role in the perception and modulation of pain signals, making them a critical focus in pain mechanism research. Opioid receptors, as classical analgesic targets, inhibit pain signals by regulating ion channels such as calcium channels, while ion channels are directly involved in the generation and transmission of pain signals. In recent years, the synergistic interaction between opioid receptors and ion channels has become a research hotspot, particularly under pathological pain conditions, where their complex interplay provides key insights into analgesic drug development. This paper systematically reviews the distribution and functional mechanisms of opioid receptors and ion channels in DRG neurons, explores their interaction in pain modulation, and discusses functional changes under inflammatory and neuropathic pain conditions. Additionally, it examines potential targeted therapeutic strategies based on their synergy and outlines their clinical application prospects.

Binding of LncDACH1 to dystrophin impairs the membrane trafficking of Nav1.5 protein and increases ventricular arrhythmia susceptibility.

Dystrophin is a critical interacting protein of Nav1.5 that determines its membrane anchoring in cardiomyocytes. Long noncoding RNAs (lncRNAs) are involved in the regulation of cardiac ion channels, while their influence on sodium channels remains unexplored. Our preliminary data showed that lncRNA-Dachshund homolog 1 (lncDach1) can bind to dystrophin, which drove us to investigate if lncDach1 can regulate sodium channels by interfering with dystrophin. Western blot and immunofluorescent staining showed that cardiomyocyte-specific transgenic overexpression of lncDach1 (lncDach1-TG) reduced the membrane distribution of dystrophin and Nav1.5 in cardiomyocytes. Meanwhile, peak INa was reduced in the hearts of lncDach1-TG mice than wild-type (WT) controls. The opposite data of western blot, immunofluorescent staining and patch clamp were collected from lncDach1 cardiomyocyte conditional knockout (lncDach1-cKO) mice. Moreover, increased ventricular arrhythmia susceptibility was observed in lncDach1-TG mice in vivo and ex vivo. The conservative fragment of lncDach1 inhibited membrane distribution of dystrophin and Nav1.5, and promoted the inducibility of ventricular arrhythmia. Strikingly, activation of Dystrophin transcription by dCas9-SAM system in lncDach1-TG mice rescued the impaired membrane distribution of dystrophin and Nav1.5, and prevented the occurrence of ventricular arrhythmia. Furthermore, lncDach1 was increased in transaortic constriction (TAC) induced failing hearts, which promoted the inducibility of ventricular arrhythmia. And the expression of lncDach1 is regulated by hydroxyacyl-CoA dehydrogenase subunit beta (hadhb), which binds to lncDach1 and decreases its stability. The human homologue of lncDACH1 inhibited the membrane distribution of Nav1.5 in human iPS-differentiated cardiomyocytes. The findings provide novel insights into the mechanism of Nav1.5 membrane targeting and the development of ventricular arrhythmias.

Elucidating genetic intersections: Co-differentially expressed genes in myasthenia gravis and idiopathic inflammatory myopathies and their role in comorbid pathogenesis.

Myasthenia gravis (MG) and idiopathic inflammatory myopathies (IIM) are autoimmune disorders that can co-occur, complicating diagnosis and treatment. The molecular mechanisms underlying this comorbidity are not well understood. This study aims to identify common differentially expressed genes (co-DEGs) between MG and IIM to elucidate shared pathogenic pathways and potential therapeutic targets. Transcriptomic data from the Gene Expression Omnibus (GEO) were analyzed using the "limma" package in RStudio. Functional enrichment analyses were performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. A nomogram prediction model was developed, and receiver operating characteristic (ROC) analysis was used to evaluate its diagnostic potential. Four co-DEGs were identified between MG and IIM, associated with neurotransmitter transport and ion channel regulation. The nomogram model, incorporating three of these co-DEGs, showed high predictive accuracy for MG with IIM complications, with an area under the ROC curve of 0.94. Immune infiltration analysis revealed distinct patterns in MG and IIM, particularly involving gamma delta T cells and activated mast cells. The study identifies key genetic intersections between MG and IIM, providing insights into their shared pathogenesis and highlighting potential diagnostic and therapeutic targets. Further experimental validation is required to confirm these findings.

The Association of SUR1 Polymorphisms with Acute Infarct Size: The MRI-GENIE Study.

Background: The sulfonylurea receptor 1 (SUR1) is a known mediator of cerebral edema in large ischemic strokes, however, genetically induced response variability has yet to be evaluated. SUR1, encoded by the ABCC8 gene, is an ion channel regulator in ischemia-induced cerebral edema. Previous studies in severe traumatic brain injury demonstrated four tag single nucleotide polymorphisms (SNPs) of the ABCC8 gene to be associated with cerebral edema and functional outcome. We hypothesized that these four SNPs would also be associated with acute infarct size and functional outcome in non-lacunar ischemic stroke. Methods: Using 2,205 MRI–GENetics Interface Exploration (MRI-GENIE) study subjects with acute non-lacunar ischemic strokes, we evaluated the association between the 4 ABCC8 tag-SNPs and stroke infarct size (as measured in a standardized fashion from MRIs using diffusion-weighted imaging), adjusting for age, sex and population stratification. Modified Rankin scale (mRS) outcome was available at 3-months for a subset of 798 strokes in MRI-GENIE and was evaluated as a dichotomous variable (0-2 vs 3-6), adjusting for age, sex, stroke severity (baseline NIH Stroke Scale (NIHSS) score), and population stratification. Results: The candidate SNPs, rs7105832, rs2237982, rs11024286, rs4148622, were not statistically associated with DWI (beta= -0.065, -0.057, 0.037, 0.018; p=0.053, 0.078, 0.28, 0.61) or dichotomous mRS outcome (OR=0.80, 0.86, 1.14, 0.90; p=0.117, 0.289, 0.353, 0.502). Conclusion: rs7105832, rs2237982, rs11024286, rs4148622 polymorphisms of the ABCC8 gene did not demonstrate a significant effect on acute ischemic infarct size or 3-month functional outcome. Nonetheless, further studies with delayed imaging and more sensitive outcome measures remain warranted.

Clinical Insights Into Default Mode Network Abnormalities in Mild Traumatic Brain Injury: Unraveling Axonal Injury Through Functional, Structural, and Molecular Analyses.

Mild traumatic brain injury (mTBI) frequently results in persistent cognitive, emotional, and functional impairments, closely linked to disruptions in the default mode network (DMN). Understanding the mechanisms driving these network abnormalities is critical for advancing diagnostic and therapeutic strategies. This study adopted a multimodal approach, combining functional connectivity (FC) analysis, diffusion tensor imaging (DTI), and gene expression profiling to investigate DMN disruptions in mTBI. A primary focus was placed on the middle cingulate cortex (MCC), a region consistently identified with increased connectivity. We explored the structural and molecular changes underlying this phenomenon. Receiver operating characteristic (ROC) curve analysis was utilized to assess the diagnostic potential of DTI-derived metrics, while white matter tractography was employed to explore structural connectivity between the MCC and the dorsolateral prefrontal cortex (DLPFC). Our findings revealed significant disruptions in DMN connectivity, with the MCC prominently involved in mTBI pathology. DTI analyses identified pronounced axonal injury in the MCC, characterized by decreased fractional anisotropy (FA) and axial diffusivity (AD), alongside increased isotropy (ISO), indicating compromised white matter integrity and diffuse axonal injury. Gene expression profiling revealed the upregulation of pathways related to synaptic transmission, ion channel regulation, and axonal injury response. ROC analysis demonstrated that ISO serves as a particularly effective biomarker for mTBI, showing high diagnostic accuracy (AUC = 0.871). White matter tractography further confirmed strong structural connectivity between the MCC and the DLPFC, identifying potential therapeutic targets for neuromodulation. This study provides robust evidence that diffuse axonal injury plays a pivotal role in DMN abnormalities observed in mTBI. The integration of FC, DTI, and gene expression profiling offers a comprehensive framework for understanding mTBI's impact on brain networks. Our findings also highlight the DLPFC as a promising target for therapeutic interventions aimed at addressing cognitive and emotional deficits associated with mTBI.

Multi‐omics assessment of genotype and sex‐specific effects of organochlorine pesticide DDT in humanized APOE mice

AbstractBackgroundThe Apolipoprotein‐E (APOE) ε4 gene variant is the strongest genetic risk factor for late‐onset Alzheimer’s Disease, but is not entirely predictive. Emerging evidence suggests environmental factors contribute to disease etiology, with epidemiological studies associating pesticide exposure with lower cognitive scores. Dichlorodiphenyltrichloroethane (DDT), a pesticide used extensively in the US until 1972, persists in trace amounts due to its long half‐life, bioaccumulation, and existing dumpsites. We have previously reported that DDT induces AD pathology in multiple models and also shown increased serum levels of DDE, the primary metabolite of DDT, in AD patients, where APOE genotype modified MMSE scores and contributed a ∼4‐fold increase in AD risk. Here, we sought to identify the mechanism(s) by which APOE4 genotype alters pathological response to DDT by a multi‐omics approach.MethodTo assess the effects of DDT exposure, three‐month‐old male and female APOE3 (E3) and APOE4 (E4) mice were exposed to 3 mg/kg DDT by oral gavage every 3 days for 5 months. Hippocampus was dissected out and frozen for RNA‐sequencing and metabolomic analysis, while serum was collected for metabolomic analysis and biomarker measurement.ResultRNA‐sequencing analysis between genotypes of female DDT‐exposed mice indicated significantly downregulated pathways and functions (p<0.05) in the hippocampus of E4‐females, including phosphatidylserine decarboxylase activity and neuron projection. Similarly, DDT‐exposed E4‐males indicated downregulation of ion channel regulator activity, nucleotide binding, cell‐cell and synaptic signaling, and neuron projection. Further, untargeted metabolomic analysis of DDT‐exposed mice was compared. Top pathways (p<0.05) altered in E4 vs. E3 female‐DDT hippocampus were carnitine shuttle and glycolysis‐gluconeogenesis, while serum changes included TCA cycle and tryptophan metabolism. In E4 vs. E3 male‐DDT, hippocampal alterations included purine metabolism, fatty acid mitochondrial beta‐oxidation, TCA cycle, glycolysis, and carnitine shuttle, while serum changes involved cholesterol biosynthesis, TCA cycle, and glycolysis‐gluconeogenesis. Finally, DDT increased serum neurofilament light chain (NfL) levels, a biomarker for neurodegeneration, by 1.9 and 2.1‐fold in E4‐male and E4‐female mice compared to respective controls. NfL was 1.4‐fold higher in DDT‐exposed E4‐females compared to E4‐males.ConclusionThese data demonstrate gene‐by‐environment interactions modified by sex, providing a platform to investigate mechanisms in AD‐related neurodegeneration and corroborating previous epidemiological findings.

Spatial differences in gene expression across the dorsal raphe nucleus in a model of early Alzheimer's disease.

Persons with Alzheimer's disease (AD) present with changes in mood, sleep, and arousal that may precede the clinical manifestation of cognitive decline. These early symptoms can be driven by changes in the serotonergic (5-HT) nuclei of the brainstem, particularly the dorsal raphe nucleus (DRN). It is unclear why all 5-HT neurons do not simultaneously develop AD pathology that progresses at the same rate. We sought to identify any underlying genetic components associated with susceptibility or resistance of 5-HT neurons to AD pathology. The Visium Spatial Gene Expression platform was used to identify transcriptomic changes across the DRN in a preclinical model of early AD, human tau-overexpressing mice (htau mice). We further used RNAscope and immunohistochemical assessment to validate findings of primary interest. We find that the DRN of htau mice differentially expresses AD-related genes, including those related to kinase binding, ion channel activity, ligand-receptor interactions, and regulation of serine/threonine kinases. We further find that computational sub-clustering of the DRN is consistent with previous circuitry-driven characterizations, allowing for spatial bounding of distinct subregions within the DRN. Of these, we find the dorsolateral DRN is preferentially impacted by 5-HT neuron loss and development of tau pathology, which coincides with increased expression of the long noncoding RNA Map2k3os. Map2k3os may serve regulatory roles relevant for tau phosphorylation and warrants further investigation to characterize its interactions. Overall, this report demonstrates the power of large-scale spatial transcriptomics technologies, while underscoring the need for convergent-data validation to overcome their limitations.

A novel mouse model for developmental and epileptic encephalopathy by Purkinje cell-specific deletion of Scn1b.

Loss of function variants of SCN1B are associated with a range of developmental and epileptic encephalopathies (DEEs), including Dravet syndrome. These DEEs feature a wide range of severe neurological disabilities, including changes to social, motor, mood, sleep, and cognitive function which are notoriously difficult to treat, and high rates of early mortality. While the symptomology of SCN1B -associated DEEs indicates broad changes in neural function, most research has focused on epilepsy-related brain structures and function. Mechanistic studies of SCN1B / Scn1b have delineated diverse roles in development and adult maintenance of neural function, via cell adhesion, ion channel regulation, and other intra- and extra-cellular actions. However, use of mouse models is limited as knockout of Scn1b , globally and even in some cell-specific models (e.g., Parvalbumin+ interneuron-specific knockout) in adult mice, leads to severe and progressive epilepsy, health deterioration, and 100% mortality within weeks. Here, we report findings of a novel transgenic mouse line in which Scn1b was specifically deleted in cerebellar Purkinje cells. Unlike most existing models, these mice did not show failure to thrive or early mortality. However, we quantified marked decrements to Purkinje cell physiology as well as motor, social, and cognitive dysfunction. Our data indicate that cerebellar Purkinje cells are an important node for dysfunction and neural disabilities in SCN1B -related DEEs, and combined with previous work identify this as a potentially vital site for understanding mechanisms of DEEs and developing therapies that can treat these disorders holistically.

Effects of CFTR-ENaC on spinal cord edema after spinal cord injury.

To explore the role of cystic fibrosis transmembrane conduction regulator (CFTR)-Epithelial sodium channel (ENaC) in spinal cord edema after spinal cord injury (SCI) and the related mechanism. Lipopolysaccharide (LPS)-treated M1830 astrocytes were applied as the SCI in vitro model. Immunohistochemistry, real-time PCR, and Western blotting were utilized to detect CFTR and ENaC expression. Enzyme-linked immunosorbent assay was used to measure inflammatory cytokines including TNF-α, IL-1β, IL-6, and IL-18. Transmission electron microscope examined ultrastructure changes, while CFTR-172 or Capsazepine treatment assessed their effects on edema and inflammation. Western blot analysis was employed to evaluate the PI3K, p-PI3K, AKT, and p-AKT signaling pathways in treated cells. LPS-treated M1830 cells exhibited increased levels of CFTR and pro-inflammatory cytokines, including TNF-α, IL-1β, IL-6, and IL-18, alongside decreased ENaC expression and suppressed p-PI3K/PI3K and p-AKT/AKT levels. Degeneration of the myelin sheath and axons was observed in LPS-treated M1830, while changes in ultrastructural were recovered after adding CFTR-172 or Capsazepine. The level of CFTR, TNF-α, IL-1β, IL-6, and IL-18 was decreased, while the level of ENaC, p-PI3K/PI3K, and p-AKT/AKT was increased obviously in LPS-treated M1830 with CFTR-172, Capsazepine, or IGF-1. Down-regulation of CFTR and up-regulation of ENaC can attenuate inflammation in SCI by activating the PI3K/AKT signaling pathway, highlighting a new therapeutic approach for SCI treatment. These findings address a critical gap in current SCI treatments and suggest a novel intervention strategy targeting ion channel regulation.

Role of Neurotransmitters (Biomediators) in Plant Responses to Stress.

Plants possess a complex signaling system that enables them to sense and adapt to various environmental stressors, including abiotic factors like extreme temperatures, drought, salinity, and toxic heavy metals. While the roles of hormones and signaling molecules in plant stress responses are well established, the involvement of neurotransmitters-traditionally linked to animal nervous systems-in plant stress physiology is a relatively underexplored area. Recent findings indicate that neurotransmitters such as gamma-aminobutyric acid, glutamate, serotonin, and dopamine play crucial roles in several physiological processes within plants. They regulate ion channels, adjust stomatal movements, modulate the production of reactive oxygen species, and influence gene expression. Evidence suggests that these neurotransmitters enhance antioxidant defense mechanisms and regulate stress-responsive pathways vital for plant stress tolerance. Additionally, under stressful conditions, neurotransmitters have been shown to impact plant growth, development, and reproductive activities. This review aims to illuminate the emerging understanding of neurotransmitters as key biomediators in plant responses to abiotic stress.

SUMO Regulation of Ion Channels in Health and Disease.

The small ubiquitin-like modifier (SUMO) protein pathway governs a panoply of vital biological processes including cell death, proliferation, differentiation, metabolism, and signal transduction by diversifying the functions, half-lives, and partnerships of target proteins in situ. More recently, SUMOylation has emerged as a key regulator of ion homeostasis and excitability across multiple tissues due to the regulation of a plethora of ion channels expressed in a range of tissue subtypes. Altogether, the balance of SUMOylation states among relevant ion channels can result in graded biophysical effects that tune excitability and contribute to a range of disease states including cardiac arrhythmia, epilepsy, pain transmission, and inflammation. Here, we consolidate these concepts by focusing on the role of ion channel SUMOylation in the central nervous system, peripheral nervous system, and cardiovascular system. In addition, we review what is known about the enigmatic factors that regulate the SUMO pathway and consider the emerging role of small molecule SUMO modulators as potential therapeutics in a range of diseases.

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.

Magnesium (Mg2+): Essential Mineral for Neuronal Health: From Cellular Biochemistry to Cognitive Health and Behavior Regulation.

Magnesium (Mg2+) is a crucial mineral involved in numerous cellular processes critical for neuronal health and function. This review explores the multifaceted roles of Mg2+, from its biochemical interactions at the cellular level to its impact on cognitive health and behavioral regulation. Mg2+ acts as a cofactor for over 300 enzymatic reactions, including those involved in ATP synthesis, nucleic acid stability, and neurotransmitter release. It regulates ion channels, modulates synaptic plasticity, and maintains the structural integrity of cell membranes, which are essential for proper neuronal signaling and synaptic transmission. Recent studies have highlighted the significance of Mg2+ in neuroprotection, showing its ability to attenuate oxidative stress, reduce inflammation, and mitigate excitotoxicity, thereby safeguarding neuronal health. Furthermore, Mg2+ deficiency has been linked to a range of neuropsychiatric disorders, including depression, anxiety, and cognitive decline. Supplementation with Mg2+, particularly in the form of bioavailable compounds such as Magnesium-L-Threonate (MgLT), Magnesium-Acetyl-Taurate (MgAT), and other Magnesium salts, has shown some promising results in enhancing synaptic density, improving memory function, and alleviating symptoms of mental health disorders. This review highlights significant current findings on the cellular mechanisms by which Mg2+ exerts its neuroprotective effects and evaluates clinical and preclinical evidence supporting its therapeutic potential. By elucidating the comprehensive role of Mg2+ in neuronal health, this review aims to underscore the importance of maintaining optimal Mg2+ levels for cognitive function and behavioral regulation, advocating for further research into Mg2+ supplementation as a viable intervention for neuropsychiatric and neurodegenerative conditions.

Acquired long QT interval syndrome as a predictor of sudden cardiac death: Causes, diagnostic criteria, and management strategy

Despite medical advances in diagnosis and treatment, cardiovascular disease remains the leading cause of death worldwide. Sudden cardiac death, an extreme and irreversible outcome of cardiac arrest, is observed in 50% of cases and is often the first suddenly detected pathology. Long QT syndrome is a variant of electrical heart disease resulting from both congenital and acquired dysfunction and/or regulation of cardiomyocyte ion channels, accompanied by impaired depolarization and repolarization of the ventricular myocardium and characterized by QT prolongation and T abnormalities on the electrocardiogram, clinically accompanied by syncope, bidirectional spindle ventricular tachycardia of the “pirouette” type (torsade de pointes), associated with a high risk of sudden cardiac death or sudden arrhythmic death syndrome. Effective management of these patients requires an individualized approach: careful examination, calculation of corrected QT, determination of typology (hereditary or acquired syndrome), risk assessment using the Tisdale scale, and selection of optimal therapy. Treatment should be comprehensive and include pharmacological (beta-adrenergic blockers, correction of electrolyte balance) and surgical (implantable cardioverter-defibrillator and left-sided thoracic sympathetic denervation of the heart), lifestyle (avoidance of drugs that contribute to prolongation of the QT interval, avoidance of specific arrhythmia triggers (active swimming, exposure to loud noises)) and regular consultation with a cardiologist. Early diagnosis and a comprehensive approach are key to successful prevention of sudden cardiac death in patients with Long QT syndrome.

Voltage- and Ca2+-inducible PLC activity for analyzing PI(4,5)P2 sensitivity of ion channels in Xenopus oocytes

Phosphatidylinositol 4,5-bisphosphate (PIP2) is a key membrane lipid regulating various ion channel activities. Currently, several molecular tools are used to modulate PIP2 levels, each of which has distinct advantages and drawbacks. In this study, we proposed a novel methodology using heterologous Xenopus oocytes to precisely manipulate PIP2 levels using phospholipase C (PLC)-ζ, which hydrolyzes PIP2. Xenopus oocytes injected with PLCζ exhibited notable hyperpolarization-induced Ca2+ influx driven by the increased driving force of Ca2+. High Ca2+ sensitivity of PLCζ facilitated hyperpolarization-induced PLC activity in Xenopus oocytes that was voltage- and Ca2+-dependent. This study demonstrated the regulatory capacity of PLCζ in modulating PIP2-sensitive ion channels, such as the KCNQ2/3 and GIRK channels, in a voltage- and Ca2+-dependent manner. Moreover, activation pathway of PLCζ only requires a two-electrode voltage clamp setup, making it a convenient molecular tool to manipulate PIP2 levels in combination with a voltage-sensing phosphatase (VSP). PLCζ has distinct characteristics and advantages compared to VSP: (1) Hyperpolarization, but not depolarization, reduced the PIP2 levels, (2) PIP2 levels were decreased without any increase in phosphatidylinositol 4-monophosphate (PIP) levels, and (3) PIP2 levels were reduced by Ca2+ administration. Therefore, PLCζ effectively supports understanding how PIP2 regulates ion channels, alongside VSP. Overall, this study highlights the unique characteristics of PLCζ and its distinct advantages in analyzing ion channel regulation by PIP2 and the PLC pathway in Xenopus oocytes.