Channels (Austin, Tex.)最新文献

{"title":"Inwardly rectifying potassium channels: Critical insights for insect species and Apis mellifera.","authors":"Fabien Sourisseau, Craig A Doupnik, Pierre Charnet, Mohamed Chahine","doi":"10.1080/19336950.2025.2529250","DOIUrl":"https://doi.org/10.1080/19336950.2025.2529250","url":null,"abstract":"<p><p>Kir (inwardly rectifying potassium) channels that play key roles in maintaining potassium homeostasis, neuronal excitability, and osmoregulation have been cloned and characterized in a variety of insects. In <i>Drosophila melanogaster</i>, three Kir channels (dKir1 dKir2, and dKir3) have been cloned and characterized, and share significant homology with mammalian Kir channels. The dKir channels are essential for various developmental processes, such as wing patterning, by modulating bone morphogenetic protein signaling pathways. Electrophysiological studies have confirmed that <i>Drosophila</i> Kir channels function in a way analogous to their mammalian counterparts, indicating that their roles in cellular and developmental signaling have been evolutionarily conserved. Several Kir channels have also been identified and characterized in mosquitoes (<i>Aedes aegypti</i> and <i>Anopheles gambiae</i>). Interestingly, insect Kir channel orthologs cluster into three gene \"clades\" or subfamilies (Kir1, Kir2, Kir3) that are distinct from mammal Kir channels based on sequence comparisons. Insect Kir channel paralogs range from two to eight Kir channel genes per species genome representing separate gene duplication events. These differences may be attributed to distinct physiological adaptations associated with their respective taxonomic groups. The honeybee <i>Apis mellifera</i> genome contains two Kir channel genes, AmKir1 and AmKir2, producing six Kir channel isoforms via alternative splicing, which have been cloned and expressed in heterologous systems to study their electrophysiological properties. This review provides a comprehensive overview of current knowledge about Kir channel structures, activities, and gating as well as of their roles in insects, including evolutionary genomic aspects, molecular biology, physiological roles, and pharmacological targeting.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"19 1","pages":"2529250"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144610454","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":"A rare HCN4 variant combined with sick sinus syndrome, left ventricular noncompaction, and complex congenital heart disease.","authors":"Fengxiao Zhang, Ning Zhao, Lin Wang, Hua Peng, Ying Jiang, Min Cheng, Feng Zhu","doi":"10.1080/19336950.2025.2517851","DOIUrl":"10.1080/19336950.2025.2517851","url":null,"abstract":"<p><p>The hyperpolarization-activated cyclic nucleotide-gated potassium channel 4 (HCN4) gene has been reported to regulate the spontaneous depolarization of sinoatrial node cells. A novel HCN4 mutation (c.2036 G>A) may lead to sick sinus syndrome. The green fluorescent protein (GFP) and either the wild-type (WT) or C679Y mutant (mut) were co-transfected into HEK293 cells to investigate the impact of the mutation on HCN4 channel function. The whole-cell patch-clamp approach was utilized to record HCN4 currents. According to electrophysiological recording, the current amplitude and density generated by mut-C679Y HCN4 channels were much lower than those generated by WT channels. HCN4 channel current activation was not significantly affected by the C679Y mutation. Because of the little current, analyzing the mut channel deactivation kinetic was challenging. Thus, we have identified a novel HCN4 gene mutation that is connected to bradycardia, left ventricular noncompaction, and diverse valve-related heart conditions.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"19 1","pages":"2517851"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12233691/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144562139","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 crucial role of potassium ion channels in diabetes mellitus and its complications: A review.","authors":"Xiangdong Yang, Yan Yang","doi":"10.1080/19336950.2025.2531949","DOIUrl":"https://doi.org/10.1080/19336950.2025.2531949","url":null,"abstract":"<p><p>Potassium ion channel (K⁺ channel) is a crucial transmembrane protein found on cell membranes that plays a pivotal role in regulating various physiological processes such as cell membrane potential, action potential formation, and cellular excitability. Diabetes, a chronic metabolic disorder characterized by elevated blood glucose levels, can cause abnormal changes in the sensitivity and functioning of K⁺ channels over time. This can lead to an increase in intracellular K⁺ and Ca²⁺, disrupting normal cellular function and metabolism and resulting in a range of physiological and metabolic issues. Recent studies have uncovered the collaborative relationship between K⁺ channels auxiliary SUR1 and Kir6.2 gating, as well as the impact of K+ channel mutations such as KCNK11 Leu114Pro, KCNQ1Arg397Trp, KCNJ11Arg136Cys, KCNK16 Leu114Pro, and KCNMA1 Gly356Arg on diabetes mellitus and associated complications. Specifically, issues such as impaired cardiac repolarization, K_ATP, Kir, TALK, and K_V channel remodeling and a higher risk of arrhythmia have been emphasized. Furthermore, structural and dysfunctional K⁺ channels (K_Ca, K_V and Kir) can also affect the function of vascular endothelial and smooth muscle cells, leading to impaired vasomotor function, abnormal cell growth, and increased inflammation. These abnormalities can result in cardiovascular damage and lesions, and increase the risk of cardiovascular disease in diabetic individuals. These findings serve as a crucial foundation for a better understanding and addressing cardiovascular issues in patients with diabetes. Moreover, different drugs and treatments targeting the K⁺ channel may yield varying effects, offering promising prospects for preventing and managing diabetes and its related complications.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"19 1","pages":"2531949"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144621497","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":"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":"Astrocytic abnormalities in brain-specific <i>Cacna1c</i>-deficient mice: Implications for BBB impairment in neuropsychiatric diseases associated with <i>CACNA1C</i> mutations.","authors":"Yeojung Koh, Maria Noterman-Soulinthavong, Anusha Bangalore, Uapingena P Kandjoze, Zea Bud, Kamryn L Noel, Hami Lee, Kathryn Franke, Coral J Cintrón-Pérez, Anjali M Rajadhyaksha, Eric B Taylor, Andrew A Pieper","doi":"10.1080/19336950.2025.2523788","DOIUrl":"10.1080/19336950.2025.2523788","url":null,"abstract":"<p><p>Intronic genetic variants within the <i>CACNA1C</i> gene, which encodes the pore-forming alpha 1c subunit of the Ca_v1.2 L-type calcium channel, are significant risk factors for a multitude of neuropsychiatric disorders. In most cases, these intronic SNPs have been associated with reduced <i>CACNA1C</i> expression. Here, we demonstrate that targeted genetic deletion of <i>Cacna1c</i> in mouse brain leads to increased astrocyte reactivity, increased expression of aquaporin 4 (AQP4) in astrocytes adjacent to the blood-brain barrier (BBB), and neuroinflammation, including changes in the levels of brain chemokines and inflammatory cytokines. Astrocytes are vital for maintaining BBB integrity, with AQP4 predominantly expressed in astrocytic endfeet where it regulates water balance in the brain. This function is critical to brain health, and deterioration of the BBB is a major feature of virtually all forms of neuropsychiatric disease. Our results highlight a previously unrecognized role for <i>CACNA1C</i> in astrocytes at the BBB, which could be a major factor in how intronic <i>CACNA1C</i> SNPs broadly increase the risk of multiple forms of major neuropsychiatric disease.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"19 1","pages":"2523788"},"PeriodicalIF":0.0,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12218471/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144509826","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}