Search Results (76)

Seizures in several epilepsy syndromes cluster within narrow windows of the sleep–wake cycle, even though the underlying molecular defects are present continuously. This narrative review asks how constitutive molecular pathologies give rise to state-dependent seizures. We integrated epilepsy genetics with sleep neurophysiology, drawing on literature retrieved from PubMed/MEDLINE across eleven concept blocks, and organized the evidence around four gene families: nicotinic acetylcholine receptor subunits, KCNT1, the GATOR1–mTOR complex, and thalamocortical calcium and HCN channels. Across these pathways, the genetic evidence ranges from well-established monogenic causation to susceptibility alleles of insufficient effect. We propose, as an integrative working model, that non-rapid eye movement (NREM) sleep converts continuous defects into state-bound seizures by strengthening thalamocortical coupling, withdrawing cholinergic tone and destabilizing arousal, with circadian phase adding a further layer of temporal control. In this model, sleep-state dependence may reflect the interaction between molecular lesions and vigilance states rather than the properties of any single gene. The strength of evidence for this link varies across gene families and is weakest for the GATOR1 pathway; much of the supporting evidence derives from animal, expression, and computational studies, whose extension to human syndromes remains inferential. Full article

Mastication is a fundamental rhythmic motor behavior controlled by a brainstem central pattern generator (CPG) located within the pontine and medullary reticular formations. Coordinated activation of jaw-opening and jaw-closing muscles is generated by this network and continuously refined through sensory feedback from periodontal mechanoreceptors and muscle spindles, together with descending inputs from the cortical masticatory area (CMA), basal ganglia, and cerebellum. Thus, mastication is regulated by distributed neural circuits rather than a single central locus. At the cellular level, the rhythmic activity of the masticatory CPG depends on the coordinated action of voltage-gated and ligand-gated ion channels. Recent electrophysiological and computational studies have identified candidate conductances that are proposed to underlie rhythm generation. Persistent sodium currents are proposed to facilitate burst initiation, whereas T-type calcium channels are thought to promote burst activation through post-inhibitory rebound. HCN channels may contribute to rhythmic timing, while calcium-activated potassium channels are thought to participate in burst termination. This review summarizes the hierarchical neural control of mastication and the biophysical mechanisms by which ion channels shape CPG rhythmogenesis. It also discusses the impact of channelopathies and neurodegenerative disorders on masticatory function, highlighting potential ion-channel-targeted therapeutic approaches for temporomandibular disorders, bruxism, and impaired mastication. Full article

Major depressive disorder (MDD) remains a leading cause of disability; however, monoaminergic models do not fully explain delayed treatment onset, incomplete remission, or rapid responses to glutamatergic interventions. In this study, we proposed a system-level ionic homeostasis framework for MDD. In this model, genetic susceptibility, chronic stress, metabolic burden, and neuroinflammation converge in neuronal and glial ion-channel systems, disrupting calcium, potassium, chloride, and purinergic homeostasis. These disturbances alter intrinsic excitability, synaptic integration, inhibitory tone, glial buffering, and neuron–glia signaling, thereby promoting excitation–inhibition imbalance, impaired plasticity, and corticolimbic network instability. We reviewed the evidence implicating the CACNA1C/Cav1.2, TREK-1, KCNQ, NKCC1/KCC2, HCN, transient receptor potential/acid-sensing ion channels, and glial mediators, including P2X7R, Kir4.1, and AQP4. We also discuss how ketamine-related mechanisms, chloride-restoring strategies, anti-inflammatory ion channel targeting, neuromodulation, EEG biomarkers, and AI/multiomics approaches support mechanism-informed precision therapeutics. MDD could be conceptualized as a distributed failure of ionic homeostasis that links neuroinflammation, E/I imbalance, network instability, and impaired adaptive plasticity. Full article

Major depressive disorder remains a leading cause of disability, and decades of monoamine-centered pharmacology have yielded delayed and often incomplete relief. Rapid-acting antidepressants reshaped the field by linking swift symptom improvement to glutamatergic plasticity, yet durable benefit depends on how newly reconfigured circuits are stabilized and tuned. This review synthesizes evidence that antidepressant efficacy arises from the coordinated engagement of synaptic plasticity, spanning induction and consolidation, and intrinsic excitability, which provides gain control, and proposes an integrated framework to guide future discovery. It first outlines induction through N-methyl-D-aspartate receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), exemplified by ketamine and esketamine, followed by consolidation mediated by tropomyosin receptor kinase B (TrkB) signaling, translational disinhibition via eukaryotic elongation factor 2 kinase (eEF2K), and presynaptic stabilization indexed by synaptic vesicle glycoprotein 2A (SV2A); together, these processes transform transient potentiation into persistent network change. It then highlights intrinsic excitability, emphasizing voltage-gated potassium channel subfamily Q (Kv7), hyperpolarization-activated cyclic nucleotide-gated (HCN), and G protein-gated inwardly rectifying potassium (GIRK) channels as circuit-level governors that normalize firing and limit relapse-prone hyperexcitability. Finally, it presents the Induction–Consolidation–Maintenance (ICM) framework as a hypothesis-generating roadmap for future studies, with SV2A positron emission tomography (PET), electroencephalography (EEG), and functional magnetic resonance imaging (fMRI) biomarkers discussed as candidate tools rather than validated guides for treatment timing or patient selection. The proposed contribution is not another list of plasticity pathways, but a phase-specific model that links synaptic induction, consolidation, and excitability-based maintenance to distinct therapeutic windows, biomarkers, and relapse-prevention strategies. Full article

Grape pomace extract (GPE) from Vitis vinifera L. cv. Aglianico is rich in polyphenols with recognized cardioprotective properties, yet its direct electrophysiological effects on spontaneous cardiac activity have not been previously investigated. Here, we examined the chronotropic effects of GPE using two complementary models: HL-1 cardiomyocytes, assessed by whole-cell patch-clamp and intracellular Ca²⁺ imaging, and the Drosophila melanogaster larval heart tube, evaluated by optical recording. In HL-1 cells, chronic treatment with 25 µg/mL GPE for 48 h significantly reduced potential spontaneous action frequency and selectively prolonged the diastolic depolarization phase without altering action potential morphology, depolarization-activated currents, or cytosolic Ca²⁺ homeostasis. GPE reduced the hyperpolarization-activated funny current (I_f) density without shifting its voltage dependence. GPE-treated cells retained cAMP sensitivity, as both isoproterenol and intracellular 8-Br-cAMP significantly increased I_f amplitude, while ELISA quantification confirmed that global cAMP levels were unaffected by GPE. In Drosophila larvae, a cAMP-independent myogenic preparation, GPE administered in the diet significantly reduced heart rate. These findings demonstrate that Aglianico GPE exerts a negative chronotropic effect through a mechanism that reduces functional I_f density without altering cAMP availability or HCN channel voltage dependence, and reveal a cAMP-independent component of action conserved across phylogenetically distant species. Full article

Bladder cancer is one of the most common malignancies of the urinary system. Identifying new potential therapeutic targets and exploring molecular mechanisms are crucial for improving treatment and prognosis. The hyperpolarization-activated cyclic nucleotide-gated (HCN) channel 2, known to play a key role in various physiological and pathological processes, has an unclear function and mechanism of action in bladder cancer. We employed bioinformatics analysis and immunohistochemistry to assess the role of HCN2 in bladder cancer, integrating in vitro and in vivo models to evaluate the impact of HCN2 on cell behavior. Molecular interactions were characterized using immunoprecipitation, chromatin immunoprecipitation, and dual-luciferase reporter assays. Our investigation revealed a significant upregulation of HCN2 in bladder cancer tissues, which was predictive of a poorer clinical outcome. Functionally, HCN2 knockdown in bladder cancer impeded cell proliferation, induced apoptosis, and curtailed migration and invasion. Mechanistically, the overexpression of HCN2 contributed to the translocation of the REST transcription factor into the nucleus and facilitated its binding to the BGN promoter for transcriptional activation of its expression. This regulatory mechanism was shown to suppress ferroptosis, a form of regulated cell death, thereby enhancing the proliferative and tumorigenesis of bladder cancer cells. This study uncovers the novel mechanism by which HCN2 regulates ferroptosis via the REST-BGN axis, affecting bladder cancer cell behavior, and provides new perspectives and strategies for future clinical treatment. Full article

Serotonergic projections innervate both the dorsal and ventral cochlear nuclei; however, the electrophysiological consequences of serotonergic input in the ventral cochlear nucleus (VCN) remain incompletely understood. This study aimed to identify the serotonin receptor subtypes involved in serotonergic modulation of stellate cells in the mouse anteroventral cochlear nucleus (AVCN) and to determine the underlying ion channel mechanisms. Whole-cell patch-clamp recordings were performed in acute brain slices obtained from postnatal day 12–17 mice. Bath application of serotonin (25 µM) induced membrane depolarization (~5 mV) and increased action potential firing. Pharmacological experiments demonstrated that antagonists of 5-HT1A, 5-HT2A, and 5-HT2C receptors partially reversed the depolarization and reduced serotonin-induced inward currents, indicating that multiple receptor subtypes contribute to serotonergic excitation. Blockade of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels with extracellular Cs⁺ suppressed approximately 95% of the serotonin-induced depolarization and inward current, implicating HCN channel-mediated Ih as a principal ionic mechanism. Serotonin significantly increased Ih amplitude. Analysis of steady-state activation revealed no statistically significant shift in V0.5; however, under near-resting membrane potential conditions, serotonin significantly reduced the slope factor of the activation curve, consistent with altered voltage sensitivity of Ih gating. Immunohistochemical analysis confirmed the presence of 5-HT1A, 5-HT2A, and 5-HT2C receptors in the AVCN. Together, these findings indicate that serotonergic excitation of AVCN stellate cells is mediated by coordinated activation of multiple 5-HT receptor subtypes and primarily involves modulation of HCN-dependent subthreshold membrane dynamics. Full article

Glucagon is an endogenous peptide that is produced in the pancreas. Via glucagon receptors, glucagon increases the beating rate in cultured rat neonatal cardiomyocytes and also in isolated right atrial preparations from adult rats. Moreover, in living adult mice, injections of glucagon can elevate the heart rate. It is unknown whether these effects of glucagon in living adult mice are mediated via central glucagon receptors or via a direct effect on cardiac glucagon receptors. Thus, we tested the hypothesis that glucagon can exert a direct positive chronotropic effect in the adult mouse heart. We measured the contractile effects of cumulatively increasing concentrations of glucagon (0.1–100 nM) in isolated paced (1 Hz) left atrial preparations, in isolated spontaneously beating right atrial preparations and in isolated spontaneously beating retrogradely perfused whole hearts. We detected in isolated right atrial preparations time- and concentration-dependent positive chronotropic effects of glucagon that were reversed by the glucagon receptor antagonists SC203972 and desglucagon. The positive chronotropic effects of glucagon were also attenuated by 1 µM of ivabradine, an inhibitor of the hyperpolarization-activated cation channels (HCN), but not by 100 nM rolipram, a phosphodiesterase 4 inhibitor, nor by 10 µM of propranolol, a β-adrenoceptor antagonist. Moreover, the positive chronotropic effects of glucagon were also attenuated by stimulation of the A₁-adenosine receptor or muscarinic receptors. Glucagon decreased the force of contraction in right atrial preparations. In left atrial preparations, glucagon failed to alter the force of contraction. In isolated adult mouse hearts perfused in the Langendorff mode, 10 nM of glucagon increased the beating rate and reduced left ventricular force of contraction. The gene expression of the glucagon receptors was lowest in the left atrium, higher in the ventricle and highest in the right atrium of adult mice. In summary, glucagon exerted a positive chronotropic effect in the mouse heart via glucagon receptors, mediated, at least in part, via HCN channels in the sinus node. Full article

The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in the kidney participate in reabsorbing potassium (K⁺) and ammonium (NH₄⁺) in the nephron, contributing to the acid–base balance. Acidosis is a metabolic condition of renal tubular acidosis and chronic kidney disease. Acidosis stimulates the production of mitochondrial reactive oxygen species (mROS), activating protective mechanisms dependent on mitochondrial membrane potential (Δψm) such as autophagy. The HCN3 channel is expressed in the plasma membrane, mitochondria (mitoHCN3), and lysosomes (lysoHCN3) of the rat proximal tubule. In this work we aimed to investigate the role of HCN3 in autophagy, mROS production, and Δψm in cultured rat proximal tubule cells (NRK-52E) exposed to ammonium chloride (NH₄Cl). NH₄Cl arrested autophagic flux and produced extracellular acidosis and, under this condition, mitoHCN3 and lysoHCN3 were up-regulated. NH₄Cl or/and ZD7288, a specific blocker of HCN channels, enhanced mROS. ZD7288 in NH₄Cl conditions at 24 h stimulated autophagy by reducing Beclin1, LC3BII, p62, and Parkin in an mROS- or Δψm independent pathway. Therefore, ZD7288 reverted NH₄Cl inhibited autophagy through lysoHCN3 inhibition. Oxidative stress induced by H₂O₂ up-regulated mitoHCN3 expression, while Tiron had the opposite effect. In conclusion, inhibition of mito- and lysoHCN3 channels by ZD7288 can protect against mitochondrial oxidative stress and stimulate the lysosome–autophagy pathway in response to NH₄Cl treatment. Full article

Gallic acid (GA), a polyphenol extensively used in the food, wine, and pharmaceutical industries, is known for its inhibitory effects on soil microbial activity. Photocatalytic degradation offers an environmentally friendly solution for GA removal from water. In this work, graphitic carbon nitride (g-C₃N₄) photocatalysts were synthesized by two methods: thermal exfoliation (CN-E) and supramolecular assembly via hydrothermal processing (HCN-II). Structural analyses by XRD, FTIR, and XPS confirmed the formation of the g-C₃N₄ framework, while SEM revealed that CN-E consisted of folded and curled nanosheets, whereas HCN-II displayed a polyhedral–nanosheet hybrid architecture with internal channels. Both materials achieved approximately 80% GA degradation within 180 min under visible-light irradiation, yet HCN-II exhibited a superior apparent rate constant (k = 0.01156 min⁻¹) compared with CN-E. Radical trapping experiments demonstrated that O₂•⁻ and h⁺ were the primary reactive oxygen species involved, with OH• making a minor contribution. The enhanced performance of HCN-II is attributed to its higher surface area, improved light harvesting, and efficient charge separation derived from supramolecular assembly. These findings highlight the potential of engineered g-C₃N₄ nanostructures as efficient, metal-free photocatalysts for the degradation of recalcitrant organic pollutants in water treatment applications. Full article

This review explores the advantages of ivabradine in the management of cardiac surgery patients, particularly highlighting its heart rate (HR)-reducing properties, its role in minimizing the impact of atrial fibrillation, and its contributions to improving left ventricular diastolic function, as well as reducing pain, stress, and anxiety. In parallel, studies provide evidence that ivabradine influences endothelial inflammatory responses through mechanisms such as biomechanical modulation. Unlike traditional beta-blockers that may induce hypotension, ivabradine selectively inhibits hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, allowing for effective HR reduction without compromising blood pressure stability. This characteristic is particularly beneficial for patients at risk of atrial fibrillation post-surgery, where HR control is crucial for cardiovascular stability. This is an area in which ivabradine appears to play a role prophylactically, possibly in combination with beta-blockers. Furthermore, ivabradine has been associated with enhanced diastolic parameters in left ventricular function, reflecting its potential to improve surgical outcomes in patients with compromised heart function. In addition to its cardiovascular benefits, it appears to alleviate psychological stress and anxiety, common in postoperative settings, by moderating the neuroendocrine response to stress, thereby reducing stress-induced hormone levels. Furthermore, it has notable analgesic properties, contributing to pain management through its action on HCN channels in both the peripheral and central nervous systems. Collectively, these findings indicate that ivabradine may serve as a valuable therapeutic agent in the perioperative care of cardiac surgery patients, addressing both physiological and psychological challenges during recovery. Full article

Cardioprotection against ischemia is achieved using openers of mitochondrial ATP-sensitive K⁺ (mitoKATP) channels such as diazoxide (DZX), leading to pharmacological preconditioning (PPC). We previously reported that PPC decreases the abundance of ventricular Cav1.2 channels, but PPC’s effects on other channels remain largely unexplored. In this study, we hypothesized that DZX regulates the expression of hyperpolarization-activated cyclic nucleotide potassium channel 4 (HCN4) channels in sinoatrial node cells (SANCs), the specialized cardiomyocytes that generate the heartbeat. DZX increased the heart rate in intact adult rats. Patch-clamp experiments revealed an increase in the magnitude of ionic currents through HCN4 channels, which was abolished by the reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) and the selective mitoKATP channel inhibitor 5-hydroxydecanoate (5-HD). Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and Western blot assays showed that DZX increased HCN4 channel expression at the mRNA and protein levels. Immunofluorescence analyses revealed that PPC increased HCN4 fluorescence, which was abolished by NAC. DZX increased nuclear translocation of c-Fos and decreased protein abundance of RE1 silencing transcription factor (REST)/neuron-restrictive silencer factor (NRSF), suggesting the involvement of these factors. Our results suggest that PPC increases the heart rate by upregulating HCN4 channel expression through a mechanism involving c-Fos, REST, and ROS. Full article

Pain, or the ability to feel pain and express the unpleasantness caused by peripheral injuries, are functions of the central nervous system. From peripheral sensory nerve terminals to certain cortical regions of the brain, activation of related neural networks underlies the sensory process. Recently, our knowledge of pain has been increasing dramatically, due to the advancement of scientific approaches. We no longer see the brain as a random matrix for pain but, rather, we are able to identify the step-by-step selective signaling proteins, neurons, and networks that preferentially contribute to the process of chronic pain and its related negative emotions, like anxiety and fear. However, there is still lacking the selective and effective drugs and methods for the treatment of chronic pain clinically. While first-line drugs for acute pain and mental diseases are also applied for the clinical management of chronic pain, their prolonged usage always causes serious side effects. In this short review, we will update and summarize the recent progress in this field and mainly focus on the roles of neural networks and synaptic mechanisms in chronic neuropathic pain. Furthermore, potential drug targets (such as plasticity-related signaling molecules, ionic channels, cytokines, and neuropeptides) and methods for the management of chronic neuropathic pain will be discussed as well. We hope this review can provide new, valuable insight into the treatment of chronic neuropathic pain. Full article

Induced pluripotent stem cell (iPSC)-derived biological pacemakers have emerged as an alternative to traditional electronic pacemakers for managing cardiac arrhythmias. While effective, electronic pacemakers face challenges such as device failure, lead complications, and surgical risks, particularly in children. iPSC-derived pacemakers offer a promising solution by mimicking the sinoatrial node’s natural pacemaking function, providing a more physiological approach to rhythm control. These cells can differentiate into cardiomyocytes capable of autonomous electrical activity, integrating into heart tissue. However, challenges such as achieving cellular maturity, long-term functionality, and immune response remain significant barriers to clinical translation. Future research should focus on refining gene-editing techniques, optimizing differentiation, and developing scalable production processes to enhance the safety and effectiveness of these biological pacemakers. With further advancements, iPSC-derived pacemakers could offer a patient-specific, durable alternative for cardiac rhythm management. This review discusses key advancements in differentiation protocols and preclinical studies, demonstrating their potential in treating dysrhythmias. Full article

In vitro experiments performed on dissociated dorsal root ganglion (DRG) neurons suggest the involvement of the hyperpolarization-activated cation current (I_h) in enhancing neuronal excitability, potentially contributing to neuropathic pain. However, the more confirmative in vivo information about how nerve injury interacts with I_h is lacking. In this study, I_h was recorded in vivo using the dynamic single-electrode voltage clamp (dSEVC) technique on L5 DRG neurons of normal rats and those seven days after spinal nerve axotomy (SNA). Compared to normal rats, SNA unexpectedly inhibited the activity of I_h channels on A-fiber DRG neurons: (a) the I_h current magnitude, density, and conductance were consistently diminished; and (b) the I_h activation velocity was slowed and the voltage for I_h activation was hyperpolarized. The half-activation voltage (V_0.5) exhibited a negative shift, and the time constant for I_h activation was prolonged across all test potentials, indicating the reduced availability of I_h after SNA. To further investigate the mechanisms of SNA on I_h, the underlying HCN channels and the correlated mRNA were quantified and compared. The mRNA expression level of HCN1-4 was uniformly enhanced after SNA, which might have contributed to the increased cytoplasmic HCN1 intensity observed in both medium- and large-sized DRG neurons. This finding contradicted the functional reduction of I_h after SNA. Surprisingly, the HCN labeling pattern was altered after SNA: the labeling area of HCN1 and HCN2 at the membranous ring region of the axotomized large neurons became significantly thinner or absent. We concluded that the diminished ring immunoreactivity for HCN1 and HCN2 correlated with a reduced availability of I_h channels, elucidating the observed decrease in I_h in axotomized A-fiber neurons. Full article