Search Results (225)

Infrasound, physically defined as sound at frequencies below 20 Hertz, can travel long distances with minimal attenuation and permeate biological tissues due to its marked particle displacement and deep penetration. Generated by both natural phenomena and human-made systems, infrasound has drawn increasing scientific and public attention regarding its potential physiological and psychological effects. Experimental studies demonstrate that infrasound can modulate mechanosensitive structures at the cellular level, particularly pressure-sensitive ion channels such as PIEZO1 and TRPV4, leading to intracellular calcium influx, oxidative stress, altered intercellular communication, and in some settings, apoptosis. These responses vary according to sound pressure levels, frequencies, exposure duration, and tissue type. In the cardiovascular system, higher sound pressures have been associated with mitochondrial injury and fibrosis, whereas low sound pressures may exert context-dependent protective effects. In animal models, prolonged or intense exposure to infrasound has been shown to induce neuroinflammatory responses and memory impairment. Short-term studies in humans at moderate intensities have reported minimal physiological changes, with psychological and contextual factors influencing symptom perception. Occupational environments such as factories and agricultural settings may contain elevated levels of infrasound, underscoring the importance of systematic measurements and exposure assessments. At the same time, controlled infrasound stimulation has shown potential as an adjunct modality in bone repair and tissue regeneration, highlighting its dual capacity as both a biological stressor and a possible therapeutic tool. Overall, existing data indicate that infrasound may be harmful at chronic exposure depending on intensity and frequency, yet beneficial when precisely regulated. Future research should standardize exposure metrics, refine measurement technologies, and clarify dose–response relationships to better define the health risks and therapeutic applications of infrasound. Full article

Exposure to microgravity results in cardiovascular deconditioning, with endothelial cell apoptosis recognized as a pivotal initiating event. However, the mechanosensitive mechanisms underlying this process remain poorly understood. Here, we demonstrate that the expression of mechanosensitive ion channel protein PIEZO1 is upregulated in human umbilical vein endothelial cells (HUVECs) under simulated microgravity. Functional studies revealed that PIEZO1 activation promotes endothelial apoptosis under simulated microgravity conditions. Proteomic analysis following PIEZO1 knockdown revealed extensive alterations in biological processes associated with apoptosis. Furthermore, we found that PIEZO1 activation triggers calcium influx, leading to elevated expression of the HMGA2. Moreover, we identify that PIEZO1 activation induces calcium influx, which subsequently elevates the expression of HMGA2. The knockdown of HMGA2 significantly mitigated microgravity-induced endothelial apoptosis, indicating its role in PIEZO1-mediated apoptosis. These findings reveal a novel PIEZO1–Ca²⁺–HMGA2 axis critical for microgravity-induced endothelial apoptosis, providing mechanistic insight into cardiovascular adaptation to spaceflight and potential therapeutic targets for countermeasure development. Full article

Acid-sensing ion channels (ASICs), activated under acidic conditions, play a critical role in ischemic brain injury, but the detailed mechanisms and signaling pathways remain unclear. Our previous studies have shown that activation of ASIC1a channels contributes to acidosis-induced neuronal injury, partially mediated by increased calcium influx. In this study, we provide evidence that activation of ASIC2a-containing channels induces zinc influx. In cultured mouse cortical neurons, ASIC currents that were insensitive to PcTx1 inhibition were potentiated by extracellular zinc. In Chinese Hamster Ovary cells transfected with different ASIC subunits, large inward currents were recorded upon a pH drop from 7.4 to 5.0 in cells expressing homomeric ASIC1a, ASIC2a, or heteromeric ASIC1a/2a channels when normal Na⁺-rich extracellular fluid (ECF) was used. However, when ECF was modified to one containing zinc as the primary cation, the same pH drop induced an inward current only in cells expressing homomeric ASIC2a or heteromeric ASIC1a/2a, but not homomeric ASIC1a. Fluorescence imaging revealed rapid zinc influx in cells expressing ASIC2a but not ASIC1a when zinc was applied with the acidic ECF. Additionally, at pH values where ASIC2a-containing channels were activated, acid-mediated neurotoxicity was exacerbated by zinc. Thus, ASIC2a-containing channels may represent a novel pathway for zinc entry and activation of these channels might contribute to zinc-mediated neurotoxicity. Full article

Hereditary spherocytosis (HS) is the most common inherited red blood cell (RBC) membrane disorder and has traditionally been attributed to defects in cytoskeletal proteins such as spectrin, ankyrin, band 3, and protein 4.2. Growing evidence, however, shows that disturbances in ion transport also contribute to HS pathophysiology. This review summarizes current understanding of HS by integrating membrane structural defects with abnormalities in ion homeostasis and highlights the diagnostic value of osmotic gradient ektacytometry (OGE). Beyond membrane instability, HS erythrocytes exhibit increased cation permeability with abnormal Na⁺ influx and K⁺ loss, leading to cellular dehydration, elevated mean corpuscular hemoglobin concentration (MCHC), and reduced deformability. Dysregulation of mechanosensitive and Ca²⁺-activated K⁺ channels (PIEZO1, KCNN4) may modulate disease expression. OGE—now the reference functional test for RBC deformability—identifies reproducible phenotypes reflecting hydration status, including dehydrated (HS1) and partially hydrated (HS2) HS profiles. When combined with next-generation sequencing (NGS), OGE improves differentiation between HS and overlapping membranopathies such as hereditary xerocytosis or stomatocytosis. In conclusion, HS is a multifactorial disorder resulting from the interplay between cytoskeletal fragility, oxidative stress, and dysregulated ion transport. Integrated diagnostic strategies that combine hematologic indices, OGE, and targeted NGS enhance diagnostic accuracy, support genotype–phenotype interpretation, and guide individualized clinical management. Future efforts should focus on ion-channel modulation and wider adoption of functional assays in precision hematology. Full article

Fibrosis manifests as an excessive accumulation of fibrillar collagen in tissues where secreted collagen exceeds degradation. Myofibroblasts are important contributors to the excessive collagen seen in fibrotic lesions. Accordingly, targeting signaling pathways that enhance collagen degradation and subdue myofibroblast differentiation has the potential to optimize collagen remodeling and improve organ fibrosis. One of the most promising molecular targets for therapeutic development is the G protein-coupled receptor (GPCR) family, which is diverse, cell-type-specific, multi-pass transmembrane receptors that participate in the regulation of extracellular matrix remodeling. GPCRs are categorized into multiple subclasses, some of which activate signaling cascades that can augment or reduce pro-fibrotic processes, depending on which Gα class is activated. Specifically, activation of Gαs GPCR stimulates production of the second messenger, cyclic adenosine monophosphate (cAMP), which generally inhibits pro-fibrotic mediators. A related, second approach for control of fibrosis is the blockade of a specific mechanosensitive, Ca²⁺-permeable channel that is implicated in fibrosis and contributes to myofibroblast differentiation, the transient receptor potential vanilloid type 4 (TRPV4). In health, TRPV4 activation regulates collagen remodeling, but when dysregulated, it promotes pro-fibrotic gene expression through mechanosensitive transcription factors. In this review, we focus on the functions of the Gαs GPCR pathway and TRPV4 activation through the interplay of the second messengers cAMP and Ca²⁺ ions. Ca²⁺ influx modulates cAMP levels by regulating phosphodiesterases and adenylyl cyclases. We consider evidence that Gαs GPCR and TRPV4 signaling pathways interact antagonistically to either promote collagen degradation or to increase the formation of myofibroblasts through signaling that involves cAMP and Ca²⁺ conductance. Coordinated activation of the Gαs GPCR pathway and inhibition of TRPV4 could provide a novel, bimodal approach to control tissue fibrosis. Full article

Transient receptor potential melastatin 2 (TRPM2) channel is a Ca²⁺-permeable, redox-activated cardiac ion channel protective in ischemia–reperfusion, but whether it regulates atrial endocrine output under stress is unclear. Here, we investigated whether TRPM2 contributes to the atrial natriuretic peptide (ANP) response during β-adrenergic stimulation. We compared how male C57BL/6J wild-type (WT) and TRPM2 knockout (TRPM2^−/−) mice (8–12 weeks old) respond to β-adrenergic stress induced by isoproterenol (ISO) using echocardiography, histology, RT-PCR, electrophysiology, Ca²⁺ imaging, ELISA, and atrial RNA-seq. We detected abundant Trpm2 transcripts in WT atria and measured ADP-ribose (ADPr)-evoked currents and hydrogen peroxide (H₂O₂)-induced Ca²⁺ influx characteristic of TRPM2; these were absent in TRPM2^−/− cells. Under the ISO-induced hypertrophic model, TRPM2^−/− mice developed greater cardiac hypertrophy, fibrosis, and systolic dysfunction compared with WT mice. Atrial bulk RNA-seq showed significant induction of Nppa (ANP precursor gene) in WT + ISO, accompanied by higher circulating ANP; TRPM2^−/− + ISO showed blunted Nppa and ANP responses. ISO-treated TRPM2^−/− mice exhibited more blunt responses, in both Nppa transcripts and circulating ANP levels. Exogenous ANP attenuated ISO-induced dysfunction, hypertrophy, and fibrosis in TRPM2^−/− mice, suggesting that TRPM2 is needed for the cardioprotective endocrine response via ANP to control stress-induced β-adrenergic remodeling. Full article

Calmodulin (CaM) plays a central role in cardiac excitation–contraction coupling by regulating ion channels, including the L-type calcium (Ca²⁺) channel Ca_v1.2 and the voltage-gated potassium (K⁺) channel K_v7.1. Mutations in CaM are linked to severe arrhythmogenic disorders such as Long QT syndrome (LQTS), yet the molecular mechanisms remain incompletely understood. Here, we investigate the structural and functional consequences of the arrhythmia-associated CaM variant D133H. Biophysical analysis revealed that D133H destabilises Ca²⁺ binding at the C-terminal lobe of CaM, altering its Ca²⁺-dependent conformational changes. Electrophysiological recordings demonstrated that CaM D133H impairs Ca²⁺-dependent inactivation (CDI) of Ca_v1.2, prolonging Ca²⁺ influx, while also reducing activation of K_v7.1, thereby limiting repolarising K⁺ currents. Together, these dual defects converge to prolong action potential duration, providing a mechanistic basis for arrhythmogenesis in LQTS. Our findings establish that CaM D133H perturbs both Ca²⁺ and K⁺ channel regulation, highlighting a shared pathway by which calmodulinopathy mutations disrupt cardiac excitability. Full article

Endometrial cancer is one of the most common malignancies of the female reproductive system, with incidence rising globally due to population ageing and life-style-related risk factors. Calcium (Ca²⁺) is a ubiquitous second messenger regulating diverse physiological processes, and its dysregulation has been increasingly implicated in carcinogenesis, including endometrial. Altered expression and function of Ca²⁺ channels, pumps, exchangers, and binding proteins disrupt the finely tuned balance of Ca²⁺ influx, efflux, and intracellular storage, leading to aberrant signalling that promotes tumour proliferation, migration, survival, and metastasis. This review summarises current knowledge on the molecular “Ca²⁺ toolkit” in the human uterus, highlighting the role of voltage-gated calcium channels (VGCCs), transient receptor potential (TRP) channels, store-operated calcium entry (SOCE) components, Na⁺/Ca²⁺ exchangers, purinergic receptors, P-type ATPases (SERCA, SPCA, PMCA), ryanodine (RyR) and inositol 1,4,5-trisphosphate (IP₃R) receptors, and mitochondrial Ca²⁺ uniporter (MCU) complexes in endometrial cancer progression. Multiple Ca²⁺-handling proteins, including CACNA1D, CACNA2D1, TRPV4, TRPV1, TRPM4, MCU, and RyR1, exhibit cancer-associated overexpression or functional changes, correlating with poor prognosis and aggressive disease features. Emerging evidence supports the therapeutic potential of targeting Ca²⁺ homeostasis using small-molecule inhibitors, ion channel modulators or gene-silencing strategies. These interventions may restore Ca²⁺ balance, induce apoptosis or autophagy, and suppress metastatic behaviour. While no clinical trials have yet explicitly focused on Ca²⁺ modulation in endometrial cancer, the diversity of dysregulated Ca²⁺ pathways offers a rich landscape for novel therapeutic strategies. Targeting key components of the Ca²⁺ signalling network holds promise for improving outcomes in endometrial cancer. Full article

The spatiotemporal regulatory mechanism underlying silicon (Si)-mediated cadmium (Cd) detoxification in rice (Oryza sativa L.) was investigated using non-invasive micro-test technology (NMT), combined with physiological and biochemical analyses. The results revealed the following: (1) Si significantly inhibited Cd²⁺ influx into rice roots, with the most pronounced reductions in ion flux observed under moderate Cd stress (Cd50, 50 μmol·L⁻¹), reaching 35.57% at 7 days and 42.30% at 14 days. Cd accumulation in roots decreased by 34.03%, more substantially than the 28.27% reduction observed in leaves. (2) Si application enhanced photosynthetic performance, as evidenced by a 14.21% increase in net photosynthetic rate (Pn), a 32.14% increase in stomatal conductance (Gs), and a marked restoration of Rubisco activity. (3) Si mitigated oxidative damage, with malondialdehyde (MDA) and hydrogen peroxide (H₂O₂) levels reduced by 11.29–21.88%, through the upregulation of antioxidant enzyme activities (SOD, APX, CAT increased by 15.34–38.33%) and glutathione metabolism (GST activity and GSH content increased by 60.78% and 51.35%, respectively). (4) The mitigation effects of Si were found to be spatiotemporally specific, with stronger responses under Cd50 than Cd100 (100 μmol·L⁻¹), at 7 days (d) compared to 14 d, and in roots relative to leaves. Our study reveals a coordinated mechanism by which Si modulates Cd uptake, enhances photosynthetic capacity, and strengthens antioxidant defenses to alleviate Cd toxicity in rice. These findings provide a scientific basis for the application of Si in mitigating heavy metal stress in agricultural systems. Full article

Although hypergravity may influence cardiac mechanosensitivity, the effects on specific ion channels remain inadequately understood. This research examined the effects of long-term hypergravity on the functional activity and transcriptional expression of mechanosensitive channels (MSCs) in rat ventricular cardiomyocytes. After 14 days of exposure to 4g, rats were subjected to molecular and electrophysiological analyses. Significant remodeling of MSC-encoding genes was revealed by RNA-seq. Trpm7 (+41.23%, p = 0.0073) and Trpc1 (+68.23%, p = 0.0026) were significantly upregulated among non-selective cation channels, while Trpv2 (−62.19%, p = 0.0044) and Piezo2 (−57.58%, p = 0.0079) were significantly downregulated. Kcnmb1 (−47.84%, p = 0.0203) was suppressed, whereas Traak/K2P4.1 showed a strong increase (+239.48%, p = 0.0092), among K⁺-selective MSCs. Furthermore, Kir6.1 was significantly downregulated (−75.8%, p = 0.0085), whereas Kir6.2 was significantly upregulated (+38.58%, p = 0.0317). These results suggest targeted transcriptional reprogramming that suppresses pathways associated with maladaptive Ca²⁺ influx while enhancing Ca²⁺-permeable mechanosensitive channels alongside stabilized K⁺ conductance. At the structural level, cardiomyocytes from hypergravity exposure showed a 44% increase in membrane capacitance, consistent with hypertrophic remodeling, and sarcomere elongation (p < 0.001). Functionally, stretch-activated current (I_SAC) was markedly hypersensitive in patch-clamp analysis: currents were induced at very small displacements (1–2 µm) and were significantly larger under 4–10 µm stretch (222–107% of control values). These findings indicate that chronic hypergravity induces coordinated molecular, structural, and functional remodeling of cardiomyocytes, characterized by increased membrane excitability, compensatory stabilizing mechanisms, and enhanced Ca²⁺ signaling. This demonstrates the flexibility of cardiac mechanotransduction under prolonged gravitational stress, with potential implications for understanding cardiovascular risks, arrhythmias, and hypertrophy associated with altered gravity environments. Full article

During the pathological process of spinal cord injury (SCI), ferroptosis is closely related to mitochondrial homeostasis. Following the occurrence of SCI, the interruption of local blood supply leads to mitochondrial damage within cells and a reduction in Adenosine triphosphate (ATP) production. This results in the loss of transmembrane ion gradients, causing an influx of Ca²⁺ into the cells, which in turn generates a significant amount of Reactive oxygen species (ROS) and reactive nitrogen species. This leads to severe mitochondrial dysfunction and an imbalance in mitochondrial homeostasis. Ferroptosis is a form of programmed cell death that differs from other types of apoptosis, as it is dependent on the accumulation of iron and lipid peroxides, along with their byproducts. The double bond structures in intracellular polyunsaturated fatty acids (PUFA) are particularly susceptible to attack by ROS, leading to the formation of lipid alkyl free radicals. This accumulation of lipid peroxides within the cells triggers ferroptosis. After SCI, the triggering of ferroptosis is closely associated with the “death triangle”—a core network that catalyzes cell death through the interaction of three factors: local iron overload, collapse of antioxidant defenses, and dysregulation of PUFA metabolism (where PUFA are susceptible to attack by reactive ROS leading to lipid peroxidation). These three elements interact to form a central network driving cell death. In the pathological cascade of SCI, mitochondria serve as both a major source of ROS and a primary target of their attack, playing a crucial role in the initiation and execution of cellular ferroptosis. Mitochondrial homeostasis imbalance is not only a key inducer of the “death triangle” (such as the intensification of lipid peroxidation by mitochondrial ROS), but is also reverse-regulated by the “death triangle” (such as the destruction of mitochondrial structure by lipid peroxidation products). Through the cascade reaction of this triangular network, mitochondrial homeostasis imbalance and the “death triangle” jointly drive the progression of secondary damage. This study aims to synthesize the mechanisms by which various therapeutic approaches mitigate SCI through targeted regulation of mitochondrial homeostasis and inhibition of ferroptosis. Unlike previous research, we integrate the bidirectional regulatory relationship between “mitochondrial homeostasis disruption” and “ferroptosis” in SCI, and emphasize their importance as a synergistic therapeutic target. We not only elaborate in detail how mitochondrial homeostasis—including biogenesis, dynamics, and mitophagy—modulates the initiation and execution of ferroptosis, but also summarize recent strategies that simultaneously target both processes to achieve neuroprotection and functional recovery. Furthermore, this review highlights the translational potential of various treatments in blocking the pathological cascade driven by oxidative stress and lipid peroxidation. These insights provide a novel theoretical framework and propose combinatory therapeutic approaches, thereby laying the groundwork for designing precise and effective comprehensive treatment strategies for SCI in clinical settings. Full article

Schwann cells (SCs) are central players in peripheral nerve repair, facilitating axonal regrowth, remyelination, and modulation of the regenerative microenvironment. A pivotal driver of these functions is intracellular Ca²⁺ signaling, regulated by both endogenous Ca²⁺-permeable ion channels and engineered optogenetic actuators. Recent developments in optogenetics, particularly the application of Ca²⁺-permeable channelrhodopsins such as CapChR2, have enabled precise, light-controlled activation of SCs, allowing for targeted investigation of Ca²⁺-dependent pathways in non-neuronal cells. This review synthesizes emerging evidence demonstrating that optogenetically or endogenously induced Ca²⁺ influx in SCs leads to the release of a diverse set of neurotrophic and regulatory factors. These Ca²⁺-triggered secretomes modulate SC phenotypes and surrounding neurons, orchestrating axon regeneration and myelin repair via autocrine and paracrine mechanisms. We further discuss the roles of key endogenous Ca²⁺ channels—including transient receptor potential (TRP) channels and store-operated Ca²⁺ entry (SOCE; STIM/Orai)—in orchestrating SC activation under physiological and injury-induced conditions. By integrating insights from optogenetic manipulation and intrinsic signaling biology, this review proposes a conceptual framework in which Ca²⁺-triggered SC secretomes act as structural and functional scaffolds for nerve repair. We highlight how SC-derived factors shape the regenerative niche, influence adjacent neurons and glia, and modulate repair processes in peripheral and autonomic nerves. Full article

The epidermal growth factor receptor (EGFR), as an important target protein for inhibiting and intervening in osteoporosis, is associated with cell migration, proliferation, and apoptosis. Peptides derived from food have been shown to have a strong affinity for EGFR, thereby regulating downstream cellular-signaling pathways and participating in stimulating bone formation. However, it is still a “black box” as to how active peptides affect the conformational changes in the EGFR-binding domain when interacting with its ligand EGF. To shed light on the roles, peptides in EGFR binding, which is involved in the osteoblast differentiation, a high EGFR affinity soybean peptide (HEP) was isolated and purified from soy yogurt. Firstly, the osteogenic activity of HEP was identified through cellular alkaline-phosphatase (ALP) and calcium influx. HEP promoted ALP activity from 0.01897 ± 0.00165 to 0.04051 ± 0.00402 U/mg after 100 μM of peptide treatment, and free intracellular calcium ions and calcium deposition both increased in a dose-dependent manner at 1–100 μg/mL. Secondly, the interaction between HEP and EGFR was detected by bioinformatics, spectroscopy analysis, and Western blot. The Molecular docking results showed that HEP (VVELLKAFEEKF) exhibited high affinity among all the peptides, with -CDOCKER energy values of 184.077 kcal/mol on one EGFR. Moreover, a different loop conformation has been detected in HEP, comparing it to that of EGF, which influences HEP interactions with EGFR. GlU3, LEU4, and LEU5 (HEP) match GLU40, LEU26, and GLU40 (EGF). Moreover, the CD data showed that HEP could interact with extracellular domain protein of EGFR, but the secondary structure did not change after HEP was mixed with Mutant extracellular domain protein. Furthermore, treatment with HEP increased the expression of EGFR and the activation of the PI3K-RUNX2-signaling pathway. These results suggested that HEP may have the function of promoting bone remodeling, which could promote the binding between EGF and EGFR and may be used as a potential active factor for functional food development to prevent osteoporosis. Full article

Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) tend to show a mixed population of action potential (AP) types, including atrial-like (A-like) and ventricular-like (V-like) APs. In the present study, we investigated the membrane currents underlying these two AP types in hESC-CMs. These were generated using standard (Std) and retinoic acid (RA)-based differentiation protocols. Patch clamp methodology was used to correlate AP morphology with major cardiac ion currents by applying alternating current and voltage clamp protocols to each cell, and to measure L-type Ca²⁺ current (I_Ca,L) and Na⁺-Ca²⁺ exchange current (I_NCX) in detail, whereas Ca²⁺ transients were measured ratiometrically using Indo-1. A- and V-like APs were found in both Std and RA-treated hESC-CMs and the AP plateau amplitude (AP_plat), as a measure of fast phase-1 repolarization, appeared the best AP criterion to separate these two AP types. Traditional voltage clamp experiments revealed a significantly smaller I_Ca,L density in RA-treated hESC-CMs, as well as larger densities of the transient outward and delayed rectifier K⁺ currents (I_to1 and I_K, respectively), without changes in the inward rectifier K⁺ current (I_K1). The AP_plat showed strong and moderate correlations with the densities of I_Ca,L and I_K, respectively, in the absence of a clear-cut correlation with the density of I_to1. Using pre-recorded, typical A- and V-like APs, AP clamp demonstrated that the I_Ca,L-mediated Ca²⁺ influx during the V-like AP in Std hESC-CMs is 3.15 times larger than the influx during the A-like AP in RA-treated hESC-CMs. Ca²⁺ transients of A-like hESC-CMs have a lower diastolic and systolic level, as well as a lower amplitude, than those of Std hESC-CMs, while their duration is shorter due to enhanced SERCA activity. In conclusion, I_Ca,L is an important determinant of the differently shaped A- and V-like APs in hESC-CMs. Furthermore, the Ca²⁺ homeostasis differs between A- and V-like hESC-CMs due to the smaller I_Ca,L and enhanced SERCA activity during A-like APs, resulting in a strongly reduced Ca²⁺ influx, which will cause a substantial reduction in I_NCX, further contributing to the shorter A-like APs. Full article

The GABA_A receptors, through a short-term interaction with a mediator, induce hyperpolarization of the membrane potential (V_m) via the passive influx of chloride ions (Cl⁻) into neurons. The massive (or intense) activation of the GABA_ARs by the agonist could potentially lead to depolarization/excitation of the V_m. Although the ionic mechanisms of GABA_A-mediated depolarization remain incompletely understood, a combination of the outward chloride current and the inward bicarbonate current and the resulting pH shift are the main reasons for this event. The GABA_A responses are determined by the ionic gradients—neuronal pH/bicarbonate homeostasis is maintained by carbonic anhydrase and electroneutral/electrogenic bicarbonate transporters and the chloride level is maintained by secondary active cation–chloride cotransporters. Massive activation can also induce the rundown effect of the receptor function. This rundown effect partly involves phosphorylation, Ca²⁺ and the processes of receptor desensitization. In addition, by various methods (including fluorescence and optical genetic methods), it has been shown that massive activation of GABA_ARs during pathophysiological activity is also associated with an increase in [Cl⁻]_i and a decline in the pH and ATP levels in neurons. Although the relationship between the neuronal changes induced by massive activation of GABAergic signaling and the risk of developing neurodegenerative disease has been extensively studied, the molecular determinants of this process remain somewhat mysterious. The aim of this review is to summarize the data on the relationship between the massive activation of inhibitory signaling and the ionic changes in neurons. The potential role of receptor dysfunction during massive activation and the resulting ionic and metabolic disruption in neurons during the manifestation of network/seizure activity will be considered. Full article