Channels (Austin, Tex.)最新文献

{"title":"Mechanistic insights into Orai dynamics during pore opening.","authors":"Hadil Najjar, Veronika Aichner, Magdalena Prantl, Nora Müller, Heinrich Krobath, Isabella Derler","doi":"10.1080/19336950.2026.2624276","DOIUrl":"10.1080/19336950.2026.2624276","url":null,"abstract":"<p><p>Orai channels form highly Ca²⁺-selective pores in the plasma membrane (PM) and represent one of the two essential components of the Ca²⁺ release-activated Ca²⁺ (CRAC) channel. The second component is the Stromal Interaction Molecule (STIM) proteins, which is located in the endoplasmic reticulum (ER). Ca²⁺ influx through CRAC channels serves as the primary route of Ca²⁺ entry into the cell, playing a critical role in downstream signaling pathways such as gene transcription and cell proliferation. Activation of Orai channels is tightly coupled to the depletion of ER Ca²⁺ stores, which triggers STIM proteins to oligomerize and adopt an extended conformation that spans the ER-PM junction, enabling direct interaction with and activation of Orai. Several studies have shown that Orai activation is mediated by global conformational changes across the entire channel complex. In recent years, detailed functional analyses, structural investigations, genetic code expansion techniques, and molecular dynamics simulations have further refined our understanding of the molecular mechanisms underlying Orai1 pore opening and the associated amino acid-level conformational dynamics. In this review, we highlight proposed mechanisms, dynamic features, and functionally relevant contact sites across the Orai1 channel complex that contribute to gating and ion permeation, while also summarizing outstanding questions that remain to be resolved.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"20 1","pages":"2624276"},"PeriodicalIF":3.2,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12893689/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146144563","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 TRPV4 channels in high glucose-induced neurotoxicity in a neuronal-like cell model.","authors":"Andrés Mauricio García-Cuevas, Laura Victoria Muñoz-Rincón, Julio César Sánchez-Naranjo","doi":"10.1080/19336950.2026.2654636","DOIUrl":"10.1080/19336950.2026.2654636","url":null,"abstract":"<p><p>Neurological dysfunction caused by hyperglycemia has been linked to abnormal activity of the transient receptor potential vanilloid (TRPV) channel family, especially in diabetic neuropathy. TRPV4 functions as a sensor of oxidative stress related to acute high glucose toxicity in various models. However, the effects of acute high glucose on TRPV4 channels have not been studied in SH-SY5Y cells. The purpose of this study was to evaluate how a high glucose environment influences TRPV4 channels in SH-SY5Y cells. The MTT assay was used to evaluate cell viability in SH-SY5Y cells, and a dose-response curve was created to identify the glucose concentration that causes toxicity. To measure TRPV4 channel activity, calcium levels were analyzed using spectrofluorometry with FURA-2 AM in cell suspensions. Measurements lasted 100 seconds, with a TRPV4-selective agonist, GSK1016790A (100 nM), applied at 50 seconds. qPCR assays measured the effect of high glucose (HG) conditions on relative TRPV4 gene expression using the ΔΔCt method, and Western blot experiments assessed protein expression. Under HG conditions (45 mM, 24 hours), inhibition of TRPV4 with GSK2913874 (100 nM) significantly improved cell viability. HG conditions suppressed TRPV4-dependent calcium increase compared to basal conditions. A significant reduction in gene and protein expression of TRPV4 was observed in SH-SY5Y cells exposed to HG. Overall, these data indicate that HG environments decrease TRPV4 channel activity and expression, which can impair neuronal function by disrupting calcium signaling.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"20 1","pages":"2654636"},"PeriodicalIF":3.2,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147629220","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":"Postnatal refinement of Ca_V channel isoform composition, electrical activity, and insulin release in mouse pancreatic β-cells.","authors":"Tamara Theiner, Noelia Jacobo-Piqueras, Dorina Tota, Petronel Tuluc","doi":"10.1080/19336950.2026.2732550","DOIUrl":"10.1080/19336950.2026.2732550","url":null,"abstract":"<p><p>Pancreatic β-cell mass and glucose-stimulated insulin secretion strongly increase during postnatal development. Voltage-gated calcium channels (Ca_V) are the key determinants of pancreatic β-cell electrical activity, insulin granule exocytosis, β-cell proliferation and survival. Here we show that β-cells of 1-day-old mice have significantly smaller Ca_V currents compared to 14-day (juvenile) or 3-month-old (adult) mice, as well as a different Ca_V isoform composition. In neonates, P/Q-type channels contribute ~53% of the whole-cell current while L-type channels contribute only ~25%. The reduced L-type current is associated with a complete absence of β-cell-specific glucose-induced excitability even though the β-cells depolarize at a lower glucose threshold. By postnatal day 14, the L-type contribution increases to ~44%, reaching ~50% in adults, and P/Q-type currents decrease to ~20%. Nevertheless, the total β-cell calcium influx density is largest in juvenile mice consistent with a lower-threshold glucose dependence of the electrical activity compared to adults. Despite the larger calcium influx, the islets of 14-day-old mice show significantly reduced vesicle exocytosis, insulin release and insulin content. Our data show extensive postnatal remodeling in β-cell mass and glucose sensitivity, and an age-dependent refinement of Ca_V isoform composition, electrical activity, and insulin release. The cumulative increase in β-cell mass and insulin release causes a ~ 7-fold increase in plasma insulin levels between 14-day- and 3-month-old mice.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"20 1","pages":"2732550"},"PeriodicalIF":3.2,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13580498/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148979012","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":"Functional evidence of Hv1-mediated proton flux in cardiac mitochondria.","authors":"Rayen De Fazio, Clara Ventura, Paulina Finochietto, Ernesto A Aiello, Carolina Jaquenod De Giusti, Verónica Milesi","doi":"10.1080/19336950.2026.2728231","DOIUrl":"10.1080/19336950.2026.2728231","url":null,"abstract":"<p><p>Mitochondria are essential for cardiac myocyte function, providing the continuous ATP supply required for contraction and cellular homeostasis. Regulation of the proton motive force, which is critical for ATP synthesis, depends on multiple ion transport mechanisms, including those mediating H⁺ flux. The voltage-gated proton channel (Hv1), encoded by the <i>Hvcn1</i> gene, is known to regulate cytosolic pH and membrane potential in several cell types. Here, using isolated mouse cardiac mitochondria, we demonstrate for the first time that Hv1 is functionally expressed in cardiac mitochondria. Pharmacological inhibition of Hv1 enhanced matrix alkalinization and induced mitochondrial hyperpolarization during succinate-driven mitochondrial energization. Importantly, a similar hyperpolarization was also observed under basal conditions in intact cardiac myocytes.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"20 1","pages":"2728231"},"PeriodicalIF":3.2,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13577268/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148964094","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":"An update on regulation of the polymodal TRPV4 channel by protein phosphorylation.","authors":"Aravind Parthasarathy, David X Zhang","doi":"10.1080/19336950.2025.2611698","DOIUrl":"10.1080/19336950.2025.2611698","url":null,"abstract":"<p><p>TRPV4 is a polymodal Ca²⁺-permeable cation channel activated by diverse stimuli via various pathways and has been one of the difficult membrane proteins to comprehend, like other TRP channels. However, a broad range of functions and pathological conditions associated with these channels continues to fascinate researchers to study them. One of the major regulatory pathways of these channels is through protein phosphorylation catalyzed by various kinases (e.g. PKC, PKA, SGK1, and Src kinase) in a stimulus-specific manner. Several sites of protein phosphorylation have been identified in both N- and C-terminal tails located in the cytosolic region of the channel. One critical phosphorylation-mediated regulatory pathway involves the C-terminal phosphorylation of Ser-824 residue, which has been implicated in activation/sensitization of the channel and its functioning in cells. Due to the lack of structural evidence on the N- and C-terminal tails (largely intrinsically disordered), it remains a challenge to understand the molecular mechanisms involved in their regulation of the TRPV4 channel. However, recent studies have provided new insights into the potential mechanisms of phosphorylation regulation of the channel and helped unravel the complexity of TRPV4 regulation pathways. This review provides an updated summary of the regulatory role of post-translational regulation through phosphorylation, the kinases and residues involved in phosphorylation of the TRPV4 channel. Furthermore, we discuss the importance and potential mechanisms of the C-terminal domain, harboring the Ser-824 residue, in the regulation of channel activation and proper functioning.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"20 1","pages":"2611698"},"PeriodicalIF":3.2,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12818809/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146004660","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":"TRPV4 regulates intraocular pressure through trabecular meshwork contractility and fibrosis.","authors":"Juš Žavbi, Sarah N Redmon, David Križaj","doi":"10.1080/19336950.2025.2611702","DOIUrl":"10.1080/19336950.2025.2611702","url":null,"abstract":"<p><p>Intraocular pressure (IOP) is dynamically regulated by the contractility and viscoelasticity of the trabecular meshwork (TM). Two recent studies identified the polymodal cation channel TRPV4 as a central mechanosensor that integrates mechanical, biochemical, and circadian signals to set the IOP levels. Pharmacological TRPV4 inhibition, global Trpv4 knockout, and conditional deletion of Trpv4 attenuated pathological ocular hypertension induced by corticosteroids, TGFβ2, or angle occlusion, as well as physiological nocturnal IOP elevation. Conversely, the selective TRPV4 agonist GSK1016790A raised IOP when injected intracamerally but lowered it when applied topically, indicating compartment-specific action. TRPV4 activation induced actomyosin contractility and ECM deposition in cultured TM cells and increased outflow resistance in biomimetic 3D scaffolds and hydrogels, with the impact reversed by TRPV4 inhibition and gene deletion. TGFβ2 strongly upregulated transcription and functional expression of TRPV4, revealing a feed-forward fibrotic loop that may contribute to myofibroblast transdifferentiation of the stressed TM. Collectively, these findings established TRPV4 as an essential mediator of TM contractility, stiffness, and IOP homeostasis. Its expression in key pressure-regulating tissues (TM, Schlemm's canal, ciliary body, and ciliary muscle) positions the channel as a convergence point for diverse glaucoma risk factors that regulate aqueous fluid production and drainage, and thus as a promising therapeutic target to lower IOP without global disruption of actin polymerization.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"20 1","pages":"2611702"},"PeriodicalIF":3.2,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12795293/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145946980","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":"mTORC2-Na_v1.2 signaling drives early hyperexcitability in Alzheimer's disease mouse model.","authors":"Nolan M Dvorak, Jeffrey L Noebels","doi":"10.1080/19336950.2026.2687246","DOIUrl":"10.1080/19336950.2026.2687246","url":null,"abstract":"<p><p>Hyperexcitability is a biomarker of early-stage Alzheimer's Disease (AD) and hastens cognitive decline later in its course. Mechanistic target of rapamycin (mTOR) signaling contributes to the slope of this trajectory, as evidenced by early increased brain expression and the rescue of hyperexcitability by genetic deletion of mTOR complex 2 (mTORC2); however, a molecular mechanism directly linking mTOR signaling to membrane hyperexcitability in early-stage AD remains elusive. Here, we show that hyperactive mTOR signaling stimulates the voltage-gated Na⁺ channel 1.2 (Na_v1.2), a previously identified downstream phosphorylation target of mTORC2 and a key regulator of membrane electrogenesis. Augmented Na_v1.2 channel function induced by hyperactive mTOR signaling requires the action of mTORC2 and is selective among major brain Na_v channel isoforms. In a murine AD model, neocortical pyramidal neurons display augmented Na_v1.2 channel function and hyperexcitability through a mechanism that requires mTORC2 activity. These results highlight the mTORC2-Na_v1.2 interaction as a therapeutic target for attenuating pathogenic hyperexcitability in early-stage AD.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"20 1","pages":"2687246"},"PeriodicalIF":3.2,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13290088/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148297653","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":"Regulated degradation of KCC2, a potassium-chloride co-transporter required for synaptic transmission and neurodevelopment.","authors":"Morgan Kok, Elias Aizenman, Christopher J Guerriero, Jeffrey L Brodsky","doi":"10.1080/19336950.2025.2607247","DOIUrl":"10.1080/19336950.2025.2607247","url":null,"abstract":"<p><p>Neuronal function requires fine-tuned and coordinated activity of several ion channels and transporters. One member of this ensemble is the KCC2 potassium-chloride cotransporter. Because KCC2 expression is required for GABA-dependent inhibitory synaptic transmission, mutations in the gene encoding KCC2 (<i>SLC12A5</i>) have been linked to several diseases that also arise from defects in GABA signaling, including epilepsy, schizophrenia, and autism spectrum disorders. Although characterization of the corresponding mutant proteins is ongoing, KCC2 mutants may reside at the cell surface but lack function, they may remain trapped intracellularly and are thus unable to function at the cell surface, or they may be readily degraded. In this article, we summarize these data and emphasize the importance of protein degradation and protease activity during KCC2 quality control, i.e. the pathway that ensures only properly folded and mature KCC2 can traffic to and function at the cell surface. We also highlight how proteolysis regulates the amount of active KCC2 at the cell surface, i.e. KCC2 quantity control. Finally, because previously unidentified KCC2 mutants are continuously being discovered, we discuss the use of predictive pathogenicity algorithms to provide researchers with information on potential disease outcomes.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"20 1","pages":"2607247"},"PeriodicalIF":3.2,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12758278/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145822256","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":"Utero-placental calcium and magnesium ion channels: A systematic review of obstetric implications of their alterations.","authors":"Gaudence Ndinganire, Aime Patrick Niyomugabo, Daniel Udofia Owu, Makinde Vincent Olubiyi, David Chibuike Ikwuka, Alphonse Niyodusenga, Mayowa Jeremiah Adeniyi, Muluken Walle, Onyinye Cynthia Okeke, Abdul-Rahuf Aderemi Feyitimi, Ejike Daniel Eze, Akaninyene Ubong Ime, Elemi John Ani, Abdulazeez Jimoh, Abdullahi Hussein Umar, Diresebachew Wondimu Haile, Abdullateef Isiaka Alagbonsi, Olufunke Onaadepo","doi":"10.1080/19336950.2026.2724674","DOIUrl":"10.1080/19336950.2026.2724674","url":null,"abstract":"<p><p>Despite the established roles of calcium (Ca²⁺) and magnesium (Mg²⁺) in placental function and uterine contractility, limited information exists on how dysregulation of major ion channels contributes to poor pregnancy outcomes. We synthesized data on the consequences of Ca²⁺ and Mg²⁺ channelopathies in uterine and placental functions. Using PubMed, Wiley Online, AJOL, and Web of Science databases for article search, a systematic review of forty-nine papers published between 2000 and March 2026 was carried out and reported in accordance with the PRISMA 2020 guideline. Based on the PICO framework, eligible studies involving human, animal, and in vitro designs were chosen and subjected to narrative analysis. L-type and T-type voltage-gated Ca²⁺ channels, together with transient receptor potential channels, emerged as principal mediators of placental Ca²⁺ transport and myometrial contractility. Mechanosensitive Piezo1 channels mediate stretch-activated Ca²⁺ influx, while store-operated Ca²⁺ entry pathways involving STIM1-Orai1 sustain intracellular Ca²⁺ homeostasis. Potassium-Ca²⁺ coupling channels modulated membrane hyperpolarization and anti-labor effects, and intracellular regulators such as PMCA and RYR1 fine-tuned Ca²⁺ homeostasis. The Mg²⁺ transporters are essential for preserving Mg²⁺ homeostasis and regulating Ca²⁺-dependent excitability. Dysregulation of these ion channel systems was consistently linked to abnormal uterine contractility, preterm birth, preeclampsia, fetal growth restriction, and adverse pregnancy outcomes. Both Ca²⁺ and Mg²⁺ ion channelopathies represent both a potential therapeutic target and a mechanistic factor underlying key obstetric complications.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"20 1","pages":"2724674"},"PeriodicalIF":3.2,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13523982/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148820402","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":"Quantitative analysis of trafficking defects induced by heterozygous expression of hERG voltage sensor domain variants.","authors":"Yihong Zhang, Joseph Carr, Jules C Hancox, Stephen C Harmer, Christopher E Dempsey","doi":"10.1080/19336950.2026.2672228","DOIUrl":"10.1080/19336950.2026.2672228","url":null,"abstract":"<p><p>Long QT Syndrome Type 2 (LQT2) is a cardiac disorder caused by Loss of Function (LOF) mutations in the <i>KCNH2</i> gene that encodes the K⁺ channel hERG (K_v11.1). Mistrafficking of hERG LOF variants is the dominant cause of LQT2. We recently characterized greatly attenuated cell surface trafficking in eight natural variants in a region of the hERG voltage sensor domain identified using evolutionary analysis. Here we have used quantitative On/In-Cell western assays to characterize trafficking of these variants under heterozygous conditions more relevant to the clinical circumstance. Dominant-negative effects of variant on wild-type (WT) cell surface expression and WT rescue of variant mistrafficking were separately assessed in co-expressions in which only WT or variant carried the HA-tag used to detect cell surface expression. Co-expression of all variants reduced cell surface expression and exhibited dominant-negative effects on trafficking. However, when compared to previous studies that utilized hERG glycosylation status as a measure of trafficking efficiency, the heterozygous effects on trafficking were smaller than expected. An identified relationship between pharmacological rescue of variant trafficking by the hERG blocker E-4031 and by co-expression with WT hERG indicated that inherent \"rescuability\" of variants might be characterized in advance of efforts to identify non-blocking trafficking rescuers.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"20 1","pages":"2672228"},"PeriodicalIF":3.2,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13182972/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147950346","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}