Channels (Austin, Tex.)最新文献

{"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":"Genetic silencing of K_Ca3.1 inhibits atherosclerosis in ApoE null mice.","authors":"P Alam, D L Tharp, H J Bowles, L A Grisanti, H Bui, S B Bender, D K Bowles","doi":"10.1080/19336950.2025.2538864","DOIUrl":"10.1080/19336950.2025.2538864","url":null,"abstract":"<p><p>Increased expression of K_Ca3.1 has been found in vascular smooth muscle cells (SMC), macrophages, and T cells in atherosclerotic lesions from humans and mice. Pharmacological inhibition of K_Ca3.1 in limiting atherosclerosis has been demonstrated in mice and pigs, however direct, loss-of-function, i.e. gene silencing, studies are absent. Therefore, we generated K_Ca3.1^-/-Apoe^-/- (DKO) mice and assessed lesion development in the brachiocephalic artery (BCA) of DKO versus Apoe^-/- mice on a Western diet for 3 months. In BCAs of DKO mice, lesion size and relative stenosis were reduced by ~70% compared to Apoe^-/- mice, with no effect on medial or lumen area. Additionally, DKO mice exhibited a significant reduction in macrophage content within plaques compared to Apoe^-/- mice, independent of sex. <i>In vitro</i> migration assays showed a significant reduction in migration of bone marrow-derived macrophages (BMDMs) from DKO mice compared to those from Apoe^-/- mice. <i>In vitro</i> experiments using rat aortic smooth muscle cells revealed inhibition of PDGF-BB-induced MCP1/Ccl2 expression upon K_Ca3.1 inhibition, while activation of K_Ca3.1 further enhanced MCP1/Ccl2 expression. Both <i>in vivo</i> and <i>in vitro</i> analyses showed that silencing K_Ca3.1 had no significant effect on the collagen content of plaque. RNAseq analysis of BCA samples from DKO and Apoe^-/- mice revealed PPAR-dependent signaling as a potential key mediator of the reduction in atherosclerosis due to K_Ca3.1 silencing. Overall, this study provides the first genetic evidence that K_Ca3.1 is a critical regulator of atherosclerotic lesion development and composition and provides novel mechanistic insight into the link between K_Ca3.1 and atherosclerosis.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"19 1","pages":"2538864"},"PeriodicalIF":3.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12320860/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144777049","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}

{"title":"Mechanotransduction mechanisms in human erythrocytes: Fundamental physiology and clinical significance.","authors":"Lennart Kuck, Lars Kaestner, Stéphane Egée, Virgilio L Lew, Michael J Simmonds","doi":"10.1080/19336950.2025.2556105","DOIUrl":"10.1080/19336950.2025.2556105","url":null,"abstract":"<p><p>The hallmarks of mechanosensitive ion channels have been observed for half a century in various cell lines, although their mechanisms and molecular identities remained unknown until recently. Identification of the bona fide mammalian mechanosensory Piezo channels resulted in an explosion of research exploring the translation of mechanical cues into biochemical signals and dynamic cell morphology responses. One of the Piezo isoforms - Piezo1 - is integral in the erythrocyte (red blood cell; RBC) membrane. The exceptional flexibility of RBCs and the absence of intracellular organelles provides a unique mechanical and biochemical environment dictating specific Piezo1-functionality. The Piezo1-endowed capacity of RBCs to sense the mechanical forces acting upon them during their continuous traversal of the circulatory system has solidified a brewing step-change in our fundamental understanding of RBC biology in health and disease; that is, RBCs are not biologically inert but rather capable of complex dynamic cellular signaling. Although several lines of investigation have unearthed various regulatory mechanisms of signaling pathway activation by RBC-Piezo1, these independent studies have not yet been synthesized into a cohesive picture. The aim of the present review is to thus summarize the progress in elucidating how Piezo1 functions in the unique cellular environment of RBCs, challenge classical views of this enucleated cell, and provoke developments for future work.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"19 1","pages":"2556105"},"PeriodicalIF":3.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12427448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145034825","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":"Graded activation of mutant K41C-KCNE1:KCNQ1 channel complexes by mefenamic acid.","authors":"Yundi Wang, Magnus Chan, Marc Pourrier, Jodene Eldstrom, David Fedida","doi":"10.1080/19336950.2025.2539494","DOIUrl":"10.1080/19336950.2025.2539494","url":null,"abstract":"<p><p>The <i>I</i>_<i>Ks</i> current formed by the co-assembly of KCNE1 and KCNQ1 plays an important role in cardiac repolarization. Mefenamic acid, an NSAID, is known to enhance <i>I</i>_<i>Ks</i> currents and has in turn been suggested as a therapeutic starting point for the development of compounds for the treatment of long QT syndrome. Our previous examinations of mefenamic acid's action revealed that residue K41 on KCNE1 was critical for mefenamic acid's activating effect on fully KCNE1 saturated, and partially saturated <i>I</i>_<i>Ks</i> channel complexes. The present study extends our previous work by incorporating the K41C-KCNE1 mutation into individual subunits to destabilize local mefenamic acid binding and explore how many of the remaining mefenamic acid-bound WT KCNE1-KCNQ1 subunits are required to support the activating action of the drug. Our results show that the potency of mefenamic acid action is reduced by the presence of K41C-KCNE1 subunits in a graded and stoichiometric, but non-linear manner. Modeling results are consistent with the idea that WT <i>I</i>_<i>Ks</i> subunits, in the presence of mefenamic acid, precede activation of K41C-<i>I</i>_<i>Ks</i> subunits due to their augmented voltage sensor kinetics.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"19 1","pages":"2539494"},"PeriodicalIF":3.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12309529/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144746321","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":"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":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12184125/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144310832","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":"Expression of Concern.","authors":"","doi":"10.1080/19336950.2025.2570092","DOIUrl":"10.1080/19336950.2025.2570092","url":null,"abstract":"","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"19 1","pages":"2570092"},"PeriodicalIF":3.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12520125/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145253855","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":"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}