Channels (Austin, Tex.)最新文献

{"title":"Piezo1 in microglial cells: Implications for neuroinflammation and tumorigenesis.","authors":"Bo Yang, Zhenyu Li, Peiliang Li, Yuhan Liu, Xinghuan Ding, Enshan Feng","doi":"10.1080/19336950.2025.2492161","DOIUrl":"https://doi.org/10.1080/19336950.2025.2492161","url":null,"abstract":"<p><p>Microglia, the central nervous system (CNS) resident immune cells, are pivotal in regulating neurodevelopment, maintaining neural homeostasis, and mediating neuroinflammatory responses. Recent research has highlighted the importance of mechanotransduction, the process by which cells convert mechanical stimuli into biochemical signals, in regulating microglial activity. Among the various mechanosensitive channels, Piezo1 has emerged as a key player in microglia, influencing their behavior under both physiological and pathological conditions. This review focuses on the expression and role of Piezo1 in microglial cells, particularly in the context of neuroinflammation and tumorigenesis. We explore how Piezo1 mediates microglial responses to mechanical changes within the CNS, such as alterations in tissue stiffness and fluid shear stress, which are common in conditions like multiple sclerosis, Alzheimer's disease, cerebral ischemia, and gliomas. The review also discusses the potential of targeting Piezo1 for therapeutic intervention, given its involvement in the modulation of microglial activity and its impact on disease progression. This review integrates findings from recent studies to provide a comprehensive overview of Piezo1's mechanistic pathways in microglial function. These insights illuminate new possibilities for developing targeted therapies addressing CNS disorders with neuroinflammation and pathological tissue mechanics.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"19 1","pages":"2492161"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12005408/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144013533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biophysical and structural mechanisms of epilepsy-associated mutations in the S4-S5 Linker of KCNQ2 channels.","authors":"Inn-Chi Lee, Yen-Yu Yang, Hsueh-Kai Chang, Swee-Hee Wong, Shi-Bing Yang","doi":"10.1080/19336950.2025.2464735","DOIUrl":"10.1080/19336950.2025.2464735","url":null,"abstract":"<p><p>Mutations in <i>KCNQ2</i> are linked to various neurological disorders, including neonatal-onset epilepsy. The severity of these conditions often correlates with the mutation's location and the biochemical properties of the altered amino acid side chains. Two mutations affecting aspartate at position 212 (D212) in the S4-S5 linker of KCNQ2 have been identified. Interestingly, while the charge-conserved D212E mutation leads to severe neonatal-onset developmental and epileptic encephalopathy (DEE), the more dramatic substitution to glycine (D212G) results in self-limited familial neonatal epilepsy (SLFNE), a much milder pathology. To elucidate the underlying mechanisms, we performed electrophysiological studies and <i>in silico</i> simulations to investigate these mutations' biophysical and structural effects. Our findings reveal that the D212E mutation stabilizes the channel in the voltage sensor down-state and destabilizes the up-state, leading to a rightward shift in the voltage-dependent activation curve, slower activation kinetics, and accelerated deactivation kinetics. This disruption in KCNQ2 voltage sensitivity persists even in the more physiologically relevant KCNQ2/3 heterotetrameric channels. In contrast, the D212G mutation primarily destabilizes the up-state, but its impact on voltage sensitivity is significantly reduced in KCNQ2/3 heterotetrameric channels. These findings provide key insights into the biophysical and structural basis of <i>KCNQ2</i> D212 mutations and their contribution to epilepsy-related symptoms, offering a clearer understanding of how these mutations drive the varied clinical outcomes observed in patients.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"19 1","pages":"2464735"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11845087/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143460980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Electrophysiological characterization of sourced human iPSC-derived motor neurons.","authors":"Bohumila Jurkovicova-Tarabova, Robin N Stringer, Zuzana Sevcikova Tomaskova, Norbert Weiss","doi":"10.1080/19336950.2025.2480713","DOIUrl":"10.1080/19336950.2025.2480713","url":null,"abstract":"<p><p>Induced pluripotent stem cell (iPSC)-derived motor neurons provide a powerful platform for studying motor neuron diseases. These cells enable human-specific modeling of disease mechanisms and high-throughput drug screening. While commercially available iPSC-derived motor neurons offer a convenient alternative to time-intensive differentiation protocols, their electrophysiological properties and maturation require comprehensive evaluation to validate their utility for research and therapeutic applications. In this study, we characterized the electrophysiological properties of commercially available iPSC-derived motor neurons. Immunofluorescence confirmed the expression of motor neuron-specific biomarkers, indicating successful differentiation and maturation. Electrophysiological recordings revealed stable passive membrane properties, maturation-dependent improvements in action potential kinetics, and progressive increases in repetitive firing. Voltage-clamp analyses confirmed the functional expression of key ion channels, including high- and low-voltage-activated calcium channels, TTX-sensitive and TTX-insensitive sodium channels, and voltage-gated potassium channels. While the neurons exhibited hallmark features of motor neuron physiology, high input resistance, depolarized resting membrane potentials, and limited firing capacity suggest incomplete electrical maturation. Altogether, these findings underscore the potential of commercially available iPSC-derived motor neurons as a practical resource for MND research, while highlighting the need for optimized protocols to support prolonged culture and full maturation.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"19 1","pages":"2480713"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11938304/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143702178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural and functional mapping of ion access pathways in the human K⁺-dependent Na⁺/Ca²⁺ exchanger NCKX2 using cysteine scanning mutagenesis, thiol-modifying reagents, and homology modelling.","authors":"Robert T Szerencsei, Shitian Cai, Hristina R Zhekova, Ali H Jalloul, D Peter Tieleman, Paul P M Schnetkamp","doi":"10.1080/19336950.2025.2513268","DOIUrl":"10.1080/19336950.2025.2513268","url":null,"abstract":"<p><p>K⁺-dependent Na⁺/Ca²⁺ exchanger proteins (NCKX) are members of the CaCA superfamily with critical roles in vision, skin pigmentation, enamel formation, and neuronal functions. Despite their importance, the structural pathways governing cation transport remain unclear. To address this, we conducted a systematic study using cysteine scanning mutagenesis of human NCKX2 combined with the thiol-modifying reagents MTSET and MTSEA to probe the accessibility and functional significance of specific residues. We used homology models of outward-facing and inward-facing NCKX2 states and molecular dynamics (MD) simulations to compare and investigate residue accessibility in human NCKX2 based on the published structures of the archaeal NCK_Mj Na⁺/Ca²⁺ exchanger and the human NCX1 Na⁺/Ca²⁺ exchanger. Mutant NCKX2 proteins expressed in HEK293 cells revealed diverse effects of MTSET and MTSEA on Ca²⁺ transport. Of the 146 cysteine substitutions analyzed, 35 exhibited significant changes in Ca²⁺ transport activity upon treatment with MTSET, with 16 showing near-complete inhibition and six demonstrating increased activity. Residues within the cation binding sites and extracellular access channels were sensitive to modification, consistent with their critical role in ion transport, whereas intracellular residues showed minimal accessibility to MTSET but were inhibited by membrane-permeable MTSEA. Water accessibility maps from MD simulations corroborated these findings, providing a high-resolution view of water-accessible pathways. This study provides a comprehensive structural and functional map of NCKX2 ion access pathways, offering insights into the molecular basis of ion selectivity and transport. These findings highlight the key residues critical for cation binding and transport, advancing our understanding of the structural dynamics of NCKX2.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"19 1","pages":"2513268"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12150658/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144259512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the potential for gene therapy in Cav1.4-related retinal channelopathies.","authors":"Matthias Ganglberger, Alexandra Koschak","doi":"10.1080/19336950.2025.2480089","DOIUrl":"10.1080/19336950.2025.2480089","url":null,"abstract":"<p><p>The visual process begins with photon detection in photoreceptor outer segments within the retina, which processes light signals before transmission to the thalamus and visual cortex. Cav1.4 L-type calcium channels play a crucial role in this process, and dysfunction of these channels due to pathogenic variants in corresponding genes leads to specific manifestations in visual impairments. This review explores the journey from basic research on Cav1.4 L-type calcium channel complexes in retinal physiology and pathophysiology to their potential as gene therapy targets. Moreover, we provide a concise overview of key findings from studies using different animal models to investigate retinal diseases. It will critically examine the constraints these models present when attempting to elucidate retinal channelopathies. Additionally, the paper will explore potential strategies for addressing Cav1.4 channel dysfunction and discuss the current challenges facing gene therapy approaches in this area of research.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"19 1","pages":"2480089"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11938310/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143702190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The GluN3-containing NMDA receptors.","authors":"Kunlong Xiong, Shulei Lou, Zuoyu Lian, Yunlin Wu, Zengwei Kou","doi":"10.1080/19336950.2025.2490308","DOIUrl":"https://doi.org/10.1080/19336950.2025.2490308","url":null,"abstract":"<p><p>N-methyl-D-aspartate receptors (NMDARs) are heterotetrameric ion channels that play crucial roles in brain function. Among all the NMDAR subtypes, GluN1-N3 receptors exhibit unique agonist binding and gating properties. Unlike \"conventional\" GluN1-N2 receptors, which require both glycine and glutamate for activation, GluN1-N3 receptors are activated solely by glycine. Furthermore, GluN1-N3 receptors display faster desensitization, reduced Ca²⁺ permeability, and lower sensitivity to Mg²⁺ blockage compared to GluN1-N2 receptors. Due to these characteristics, GluN1-N3 receptors are thought to play critical roles in eliminating redundant synapses and pruning spines in early stages of brain development. Recent studies have advanced pharmacological tools for specifically targeting GluN1-N3 receptors and provided direct evidence of these glycine-activated excitatory receptors in native brain tissue. The structural basis of GluN1-N3 receptors has also been elucidated through cryo-EM and artificial intelligence. These findings highlight that GluN1-N3 receptors are not only involved in essential brain functions but also present potential targets for drug development.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"19 1","pages":"2490308"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12005412/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144059965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Calcium handling remodeling in dilated cardiomyopathy: From molecular mechanisms to targeted therapies.","authors":"Yuhan Wang, Tingting Zhou, Jiajing Zhao, Hongjun Zhu, Xiaodong Tan, Jiahao Chen, Zhuojun Zhang, Lijuan Shen, Shu Lu","doi":"10.1080/19336950.2025.2519545","DOIUrl":"https://doi.org/10.1080/19336950.2025.2519545","url":null,"abstract":"<p><p>Calcium ions play a crucial role in cardiac excitation-contraction (EC) coupling, and disruptions in Ca²⁺ homeostasis are a key factor in the development of dilated cardiomyopathy (DCM). This review aims to systematically analyze how structural and functional remodeling of Ca²⁺-handling proteins drives DCM progression and to evaluate therapeutic strategies targeting these pathways. The movement of intracellular Ca²⁺, which is regulated by transporters like SERCA2a, ryanodine receptor 2 (RYR2), and L-type Ca²⁺ channels, affects the heart's contraction and relaxation. In DCM, both structural and functional changes in the Ca²⁺-handling machinery-including t-tubule remodeling, modifications to RYR2, and dysregulation of SERCA2a and phospholamban (PLN)-disrupt Ca²⁺ cycling, worsening systolic dysfunction and ventricular dilation. For instance, reduced affinity of SERCA2a for Ca²⁺ due to imbalances in the PLN-SERCA2a interaction impairs the heart's ability to reuptake Ca²⁺ during diastole. Meanwhile, abnormalities in RYR2 contribute to arrhythmogenic Ca²⁺ leaks. Targeting these pathways for treatment has two main challenges: too much Ca²⁺ modulation can cause arrhythmias, while insufficient correction may fail to improve heart contractility. Precision interventions demand structurally resolved targets, such as stabilizing RYR2 closed states or enhancing SERCA2a activity via gene therapy, to address DCM's heterogeneous pathophysiology. Emerging strategies leveraging t-tubule restoration or isoform-specific L-type channel modulation show promise in normalizing Ca²⁺ transients and halting adverse remodeling. This review compiles evidence that connects changes in EC coupling components to the progression of DCM and emphasizes the potential benefits of restoring Ca²⁺ balance as a treatment. By integrating molecular insights with clinical phenotypes, structurally informed Ca²⁺-targeted therapies could pave the way for personalized DCM management, balancing efficacy with minimized off-target effects.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"19 1","pages":"2519545"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144310832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of the C-terminal domain in modifying pH-dependent regulation of Ca_v1.4 Ca²⁺ channels.","authors":"Juan de la Rosa Vázquez, Amy Lee","doi":"10.1080/19336950.2025.2473074","DOIUrl":"10.1080/19336950.2025.2473074","url":null,"abstract":"<p><p>In the retina, Ca²⁺ influx through Ca_v1.4 Ca²⁺ channels triggers neurotransmitter release from rod and cone photoreceptors. Changes in extracellular pH modify channel opening, enabling a feedback regulation of photoreceptor output that contributes to the encoding of color and contrast. However, the mechanisms underlying pH-dependent modulation of Ca_v1.4 are poorly understood. Here, we investigated the role of the C-terminal domain (CTD) of Ca_v1.4 in pH-dependent modulation of Ba²⁺ currents (<i>I</i>_<i>Ba</i>) in HEK293T cells transfected with the full length Ca_V1.4 (FL) or variants lacking portions of the CTD due to alternative splicing (Δe47) or a disease-causing mutation (K1591X). While extracellular alkalinization caused an increase in <i>I</i>_<i>Ba</i> for each variant, the magnitude of this increase was significantly diminished (~40-50%) for both CTD variants; K1591X was unique in showing no pH-dependent increase in maximal conductance. Moreover, the auxiliary α₂δ-4 subunit augmented the pH sensitivity of <i>I</i>_<i>Ba</i>, as compared to α₂δ-1 or no α₂δ, for FL and K1591X but not Δe47. We conclude that the CTD and α₂δ-4 are critical determinants of pH-dependent modulation of Ca_v1.4 and may influence the processing of visual information in normal and diseased states of the retina.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"19 1","pages":"2473074"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11934190/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143671726","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The research progress into cellular mechanosensitive ion channels mediating cancer pain.","authors":"Chang Liu, Haiyan Li, Lihua Hang","doi":"10.1080/19336950.2025.2517109","DOIUrl":"10.1080/19336950.2025.2517109","url":null,"abstract":"<p><p>Cellular mechanotransduction refers to the process through which cells perceive mechanical stimuli and subsequently translate them into biochemical signals. Key mechanosensitive ion channels encompass PIEZO, TREK-1, and TRESK. These mechanosensitive ion channels are crucial in regulating specific pathophysiological conditions, including fibrosis, tumor progression, and cellular proliferation and differentiation. Recent research indicates that PIEZO, TREK-1, and TRESK are significant contributors to various types of cancer pain by sensing mechanical stimuli, which subsequently activate internal signaling pathways. Here concentrates on advancements in research concerning PIEZO, TREK-1, and TRESK in cancer pain research, aiming to lay the groundwork for creating new therapeutic drugs that address mechanosensitive ion channels for treating cancer pain.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"19 1","pages":"2517109"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12169045/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role and mechanism of vascular wall cell ion channels in vascular fibrosis remodeling.","authors":"Xiaolin Zhang, Hai Tian, Cheng Xie, Yan Yang, Pengyun Li, Jun Cheng","doi":"10.1080/19336950.2024.2418128","DOIUrl":"10.1080/19336950.2024.2418128","url":null,"abstract":"<p><p>Fibrosis is usually the final pathological state of many chronic inflammatory diseases and may lead to organ malfunction. Excessive deposition of extracellular matrix (ECM) molecules is a characteristic of most fibrotic tissues. The blood vessel wall contains three layers of membrane structure, including the intima, which is composed of endothelial cells; the media, which is composed of smooth muscle cells; and the adventitia, which is formed by the interaction of connective tissue and fibroblasts. The occurrence and progression of vascular remodeling are closely associated with cardiovascular diseases, and vascular remodeling can alter the original structure and function of the blood vessel. Dysregulation of the composition of the extracellular matrix in blood vessels leads to the continuous advancement of vascular stiffening and fibrosis. Vascular fibrosis reaction leads to excessive deposition of the extracellular matrix in the vascular adventitia, reduces vessel compliance, and ultimately alters key aspects of vascular biomechanics. The pathogenesis of fibrosis in the vasculature and strategies for its reversal have become interesting and important challenges. Ion channels are widely expressed in the cardiovascular system; they regulate blood pressure, maintain cardiovascular function homeostasis, and play important roles in ion transport, cell differentiation, proliferation. In blood vessels, different types of ion channels in fibroblasts, smooth muscle cells and endothelial cells may be relevant mediators of the development of fibrosis in organs or tissues. This review discusses the known roles of ion channels in vascular fibrosis remodeling and discusses potential therapeutic targets for regulating remodeling and repair after vascular injury.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"18 1","pages":"2418128"},"PeriodicalIF":0.0,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11492694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}