Channels (Austin, Tex.)最新文献

{"title":"Similarity of the ion occupations of K⁺ and Tl⁺ in the selectivity filter of a K⁺ channel, as verified by single-channel currents.","authors":"Lena Diederich, Jessica Múnera-Jaramillo, Ulf-Peter Hansen, Indra Schroeder","doi":"10.1080/19336950.2026.2623375","DOIUrl":"10.1080/19336950.2026.2623375","url":null,"abstract":"<p><p>Voltage-dependent gating in the selectivity filter of potassium channels is modulated by the permeating ions binding within the filter. In the viral Kcv channel, filter gating occurs on the sub-millisecond time scale. Crystallographic data from KcsA in the literature imply that ion occupation of the binding sites in the selectivity filter is equal for K⁺ and Tl⁺. Here, we verify this equivalence by electrophysiological experiments in Kcv_NTS and extend the finding to negative voltages up to -160 mV. The analysis is based on our previous work, which correlated the voltage dependence of ion occupation with the voltage dependence of the rate constant of channel closure. This equivalence of K⁺ and Tl⁺ is further supported by experiments in the mutant Kcv_NTS S42T. Additionally, measurements with Tl⁺ and K⁺ at opposite sides of the membrane show that the ion in the selectivity filter determines the rate constant of channel closure. Tl⁺ on the external side increases this rate constant by a constant factor but does not change voltage dependence. A similar influence of the ion species is found for the only weakly voltage-dependent rate constant of channel opening. Here, Tl⁺ on the external side increases the voltage-independent scaling factor whereas Tl⁺ on the cytosolic side decreases it.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"20 1","pages":"2623375"},"PeriodicalIF":3.2,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12940109/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147313240","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":"<i>Trpv1</i>-dependent <i>Cacna1b</i> gene inactivation reveals cell-specific functions of Ca_V2.2 channels <i>in vivo</i>.","authors":"Remy Y Meir, Martin S Sisti, Arturo Andrade, Diane Lipscombe","doi":"10.1080/19336950.2025.2594893","DOIUrl":"10.1080/19336950.2025.2594893","url":null,"abstract":"<p><p>Voltage-gated Ca_V2.2 channels underlie the N-type current, and they regulate calcium entry at many presynaptic nerve endings to control transmitter release. A role for Ca_V2.2 channels has been well established in the transmission of sensory signals including noxious information using pharmacological and global gene knockout mouse models. However, investigation of the cell-specific actions of Ca_V2.2 channels has been difficult due to the lack of gene-dependent knockout mouse models and particularly in dissecting behavioral responses that depend on Ca_V2.2 channel activity. Here, we show the importance of Ca_V2.2 channels in <i>Trpv1</i>-lineage neurons in behavioral responses to sensory stimuli using Cre-dependent inactivation of the <i>Cacna1b</i> gene. Our work shows the cell-type specificity of Ca_V2.2 channels in mediating rapidly developing heat hypersensitivity and the utility of Cre-dependent inactivation of <i>Cacna1b</i> to discern cell-specific Ca_V2.2 channel functions.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"20 1","pages":"2594893"},"PeriodicalIF":3.2,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12724195/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145812382","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":"TRPV1 from the TRP family: Structure, function, implication in autoimmune diseases and potential therapies.","authors":"Typhaine Bejoma, Yanna Pan, Qingjie Zhao","doi":"10.1080/19336950.2026.2616902","DOIUrl":"10.1080/19336950.2026.2616902","url":null,"abstract":"<p><p>The transient receptor potential vanilloid type 1 (TRPV1) channel, a member of the TRP ion channel family, plays a crucial role in both physiological and pathological processes. This review provides an overview of the structure, biological functions, and implications of TRPV1 in autoimmune diseases. The structural characteristics of TRPV1, including its transmembrane and intracellular domains, are examined to understand its activation and modulation. In addition to its well-known role as a thermosensor in nociceptive neurons, TRPV1 has been found to have functions in immune cells where it regulates lipid synthesis and inflammatory response. The investigation of TRPV1's involvement in autoimmune conditions such as systemic lupus erythematosus, multiple sclerosis, and rheumatoid arthritis highlights its potential as a therapeutic target. The search for selective agonists and antagonists for TRPV1 drugs is also discussed. A comprehensive understanding of TRPV1's structure, function, and role in autoimmune diseases lays the foundation for future studies and the development of innovative therapies targeting this channel.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"20 1","pages":"2616902"},"PeriodicalIF":3.2,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12834142/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146020513","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 for TREK-1 as a polymodal sensor and regulator of cell activity.","authors":"Alexander J Winkle, Aparna Odayil Muralidharan, Christian Renee McClenney, Kamellia Karimpour, Taukeed Muhammad Ashfaque, Shaihrum Qureshi, Thomas J Hund, Drew Nassal","doi":"10.1080/19336950.2026.2675071","DOIUrl":"10.1080/19336950.2026.2675071","url":null,"abstract":"<p><p>TREK-1 (KCNK2) is a polymodal two-pore domain potassium (K2P) channel that functions as a background K⁺ conductance and integrator of mechanical, chemical, and thermal stimuli across diverse cell types. Its unique structure enables sensitivity to membrane stretch, lipid composition, pH, temperature, pharmacologic agents, and intracellular signaling pathways. Beyond shaping resting membrane potential and excitability, TREK-1 engages in noncanonical signaling roles involving protein-protein interactions, trafficking, and modulation of intracellular signaling cascades such as MAPK and calcineurin pathways. TREK-1 is widely expressed in the nervous system, where it regulates neuronal firing, pain sensitivity, mood, and neuroprotection. In the heart, TREK-1 influences action potential duration, mechano-electric feedback, sinoatrial node function, and stress-induced remodeling, with mutations linked to arrhythmogenesis. In fibroblasts and fibroblast-like cells, TREK-1 acts as a mechanotransducer driving differentiation and fibrosis through MAPK signaling. TREK-1 also modulates immune activation, inflammasome signaling, adipogenesis, epithelial injury responses, vascular tone, and cancer cell proliferation. Across tissues, dysregulation of TREK-1 contributes to pathological excitability, fibrosis, inflammation, and degeneration. Given its multimodal regulation and broad impact on cellular function, TREK-1 represents a compelling therapeutic target, though challenges remain due to limited subtype-selective pharmacology and incomplete understanding of its nonionic signaling roles.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"20 1","pages":"2675071"},"PeriodicalIF":3.2,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13192137/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147977412","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":"One pocket to activate them all (?): Efforts on understanding the modulator pocket in K2P channels.","authors":"Edward Mendez-Otalvaro, Wojciech Kopec, Marcus Schewe, Bert L de Groot","doi":"10.1080/19336950.2025.2602975","DOIUrl":"10.1080/19336950.2025.2602975","url":null,"abstract":"<p><p>The modulator pocket is a cryptic site discovered in the TREK1 (K_2P2.1) K2P channel. This pocket, located close to the selectivity filter, accommodates agonists that enhance the channel's activity. Since its discovery, equivalent sites in other K2P channels have been shown to bind various ligands, both endogenous and exogenous. In this review, we attempt to elucidate how the modulator pocket contributes to K2P channel activation. To this end, we first describe the gating mechanisms reported in the literature and rationalize their modes of action. We then highlight previous experimental and computational evidence for agonists that bind to the modulator pocket, together with mutations at this site that affect gating. Finally, we elaborate how the activation signal arising from the modulator pocket is transduced to the gates in K2P channels. In doing so, we outline a potential common modulator pocket architecture across K2P channels: a largely amphipathic structure - consistent with the expected properties of a pocket exposed at the interface between a hydrophobic membrane and the aqueous solvent - but still with some important channel-sequence-variations. This architecture and its key differences can be leveraged for the design of new selective and potent modulators.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"20 1","pages":"2602975"},"PeriodicalIF":3.2,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12758241/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145822239","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":"Cholesterol inhibits capsaicin activation of the TRPV1 channel.","authors":"Tal Brandwine-Shemmer, Nicolas A Barbera, Irena Levitan, Baruch Minke","doi":"10.1080/19336950.2026.2630491","DOIUrl":"10.1080/19336950.2026.2630491","url":null,"abstract":"<p><p>TRPV1 is a polymodal ion channel activated by vanilloids, noxious heat, and pro-inflammatory signals. A recent cryo-EM structure of human TRPV1 bound to SAF312, a potent, selective, noncompetitive antagonist, revealed a cholesterol molecule occupying the vanilloid-binding pocket, a site well established as the activation locus for vanilloid agonists. This observation led us to test whether cholesterol functionally inhibits capsaicin-dependent TRPV1 activation. Using HEK293 cells heterologously expressing TRPV1, we found that membrane cholesterol enrichment markedly suppressed capsaicin-evoked currents at low agonist concentrations, whereas responses to saturating capsaicin were unaffected. The functional interaction between cholesterol and capsaicin was further supported by site-directed mutagenesis targeting the conserved Gly563, a residue within the S4-S5 linker of the vanilloid-binding pocket. The G563S mutation reduced the sensitivity to capsaicin and caused slow and incomplete deactivation; nevertheless, elevated cholesterol further suppressed capsaicin-evoked activity. Together, these findings support a model in which cholesterol competes with capsaicin at the vanilloid-binding pocket to inhibit activation of the TRPV1 channel.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"20 1","pages":"2630491"},"PeriodicalIF":3.2,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12915799/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146208571","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":"Research progress on the role and mechanism of STIM and Orai protein-mediated store-operated calcium entry in cardiovascular diseases.","authors":"Xin Liao, Chenglin Pan, Xueqing Guo, Jun Cheng","doi":"10.1080/19336950.2026.2709185","DOIUrl":"10.1080/19336950.2026.2709185","url":null,"abstract":"<p><p>Store-operated calcium entry (SOCE) mediated by STIM and Orai proteins is a fundamental Ca²⁺ influx mechanism that critically regulates intracellular calcium homeostasis and participates in cardiovascular pathophysiology. Upon endoplasmic reticulum Ca²⁺ store depletion, STIM1/2 activate plasma membrane Orai1/3 channels, initiating Ca²⁺ entry that drives vasoconstriction, smooth muscle proliferation, platelet activation, and cardiac hypertrophy. Dysregulated SOCE is closely associated with hypertension, atherosclerosis, pulmonary hypertension, and thromboembolic disorders. However, SOCE is not a simple binary pathway but operates within a complex regulatory network. Beyond the core STIM-Orai axis, auxiliary proteins including transient receptor potential canonical 1 (TRPC1), tetraspanin 18 (Tspan18), tropomyosin 3 (TPM3), SOCE-associated regulatory factor (SARAF), and A-kinase anchoring protein 79/150 (AKAP79/150) modulate SOCE amplitude, kinetics, and downstream signaling in a cell- and context-dependent manner. Moreover, the functional consequences of SOCE are highly heterogeneous: Orai1 protects adult cardiomyocytes but promotes pathological hypertrophy in neonatal cells, posing a therapeutic dilemma. Although preclinical studies have shown efficacy of SOCE inhibitors, clinical translation remains hindered by poor isoform selectivity, suboptimal pharmacokinetics, lack of tissue-specific delivery, disease-stage-dependent effects, and absence of validated biomarkers. Importantly, recent evidence has definitively ruled out amlodipine-induced CRAC channel activation at therapeutic concentrations, confirming it as an experimental artifact. This review systematically summarizes the molecular complexity, functional diversity, and translational barriers of STIM/Orai-mediated SOCE, aiming to inform precision therapeutic strategies for cardiovascular diseases.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"20 1","pages":"2709185"},"PeriodicalIF":3.2,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13418705/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148594757","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":"Transient receptor potential canonical (TRPC) channels in diabetes and associated complications.","authors":"Yi Wu, Shengming Chen, Xiaolu Xia","doi":"10.1080/19336950.2026.2672357","DOIUrl":"10.1080/19336950.2026.2672357","url":null,"abstract":"<p><p>TRPC channels are widely expressed in various tissues and cell types, and accumulating evidence indicates that they play critical roles in pancreatic β cell function, including the regulation of insulin secretion. Moreover, TRPC channels have been implicated in the pathogenesis of type 2 diabetes mellitus (T2DM) and its associated complications, underscoring their potential as therapeutic targets. Despite this, there remains a lack of comprehensive, up-to-date reviews summarizing the distribution and functional roles of TRPC channels in diabetes and its complications. In addition, the expression patterns and physiological significance of certain TRPC subtypes remain controversial. This review, therefore, aims to provide a thorough overview of current research, starting with general aspects of TRPC channel structure and function, and progressing to their physiological and pathological roles, with particular emphasis on their involvement in insulin secretion, insulin resistance, diabetes, and diabetic complications.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"20 1","pages":"2672357"},"PeriodicalIF":3.2,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13166186/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147876597","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 mediates macrophage polarization involved in inflammatory root resorption induced by mechanical pressure.","authors":"Xuanchen Su, Min Jin, Yue Chen, Wenjun Cai, Meng Wang, Lizhiyi Liu, Zhi Zhou, Yali Liu","doi":"10.1080/19336950.2026.2660014","DOIUrl":"10.1080/19336950.2026.2660014","url":null,"abstract":"<p><p>In clinical orthodontic treatment, mechanical pressure applied to the tooth root triggers orthodontically induced inflammatory root resorption (OIIRR). An elevated M1/M2 macrophage polarization ratio is a key factor in OIIRR on the pressure side. However, the pathways through which macrophages perceive mechanical pressure stimuli remain unclear. The transient receptor potential vanilloid 4 channel, which is upregulated on the pressure side during orthodontic treatment, is a mechanically sensitive calcium ion channel protein that may play a crucial role in orthodontic periodontal mechanical signal transduction. Nevertheless, whether TRPV4 is involved in macrophage perception of and response to orthodontic force under mechanical pressure, thereby influencing macrophage polarization, requires further investigation. This study aims to explore the mechanism by which TRPV4 mediates mechanical pressure in regulating macrophage polarization, with the objective of providing new insights and strategies for mitigating OIIRR in clinical orthodontic practice. Studies have shown that resorption lacunae are present on the compressed root surface, with macrophages localized at the sites of root resorption. Mechanical pressure significantly upregulated intracellular Ca²⁺ concentration and macrophage expression levels of TRPV4, iNos, and CD86, while significantly downregulating the expression levels of Arg-1 and CD206. Treatment with the TRPV4 inhibitor GSK2193874 resulted in a significant downregulation of intracellular Ca²⁺ concentration and expression levels of iNos and CD86, and a significant upregulation of Arg-1 and CD206 expression levels. Therefore, our study demonstrates that TRPV4 senses mechanical pressure by promoting Ca²⁺ influx and upregulates the M1/M2 macrophage polarization ratio. In conclusion, our findings indicate that TRPV4 serves as a critical mediator in mechanical pressure-regulated macrophage polarization during OIIRR.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"20 1","pages":"2660014"},"PeriodicalIF":3.2,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13089922/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147700940","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":"Physiological 17β-oestradiol inhibits K_V7.4 currents via GPER1-dependent PLC/PKC signalling.","authors":"Elif Karabatak, Skye Lau, Samantha C Salvage, Thomas A Jepps, Iain A Greenwood, Samuel N Baldwin","doi":"10.1080/19336950.2026.2729646","DOIUrl":"10.1080/19336950.2026.2729646","url":null,"abstract":"<p><p>K_V7.4 channels are important regulators of membrane potential and excitability in multiple tissues and are emerging as key effectors of steroid hormone signaling. Here, 17β-estradiol (E2) was examined as a modulator of recombinant K_V7.4 channels expressed in HEK293 cells. Whole-cell patch-clamp recordings showed that acute application of E2 reduced K_V7.4 current density. At nanomolar concentrations, both E2 and the alternate GPER1 agonist aldosterone inhibited K_V7.4 currents only when G protein-coupled estrogen receptor 1 (GPER1) was co-expressed, indicating a receptor-dependent mechanism. Pharmacological inhibition showed that phospholipase C (PLC) and protein kinase C (PKC), but not adenylyl cyclase, contribute to GPER1-mediated inhibition of K_V7.4. In contrast, equivalent experiments performed with K_V7.5 channels showed no significant effect of E2 despite GPER1 co-expression, suggesting subtype-selective regulation within the K_V7 family. Surface biotinylation experiments suggest that GPER1 co-expression reduced surface K_V7.4 expression, with a further reduction observed following E2 treatment. Finally, both E2 and aldosterone negatively regulate the sensitivity of K_V7.2-5 activator ML213-mediated relaxation in arteries from female rats. Together, these findings identify K_V7.4 as a downstream effector of rapid GPER1-dependent estrogen signaling and suggest that steroid status may influence K_V7-targeted therapeutic responses.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"20 1","pages":"2729646"},"PeriodicalIF":3.2,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13568567/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148921966","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}