Oxidative stress mediated by NADPH oxidase 2 (NOX2), a major source of reactive oxygen species in the myocardium, is an important mechanism that underlies cardiac arrhythmias. NOX2 is activated by the precise assembly of multiple protein subunits. It plays a critical role in initiating and sustaining atrial fibrillation and ventricular arrhythmias by disrupting calcium homeostasis, differentially regulating ion channel function, and inducing structural remodeling. Notably, a close association between NOX2 and arrhythmias is well-established, and interventions targeting NOX2 have demonstrated therapeutic potential. However, the signaling pathways through which NOX2 modulates myocardial electrophysiology under different pathological states remain unclear. Moreover, the dynamic coupling of NOX2 with upstream risk factors, such as abnormal cardiac load and metabolic diseases, remains poorly characterized. In this review, we summarize the structure, activation mechanisms, arrhythmogenic mechanisms, and targeted strategies of NOX2, providing a comprehensive reference for understanding its role in cardiac electrical remodeling and developing antiarrhythmic therapies.

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 (Nav1.2), a previously identified downstream phosphorylation target of mTORC2 and a key regulator of membrane electrogenesis. Augmented Nav1.2 channel function induced by hyperactive mTOR signaling requires the action of mTORC2 and is selective among major brain Nav channel isoforms. In a murine AD model, neocortical pyramidal neurons display augmented Nav1.2 channel function and hyperexcitability through a mechanism that requires mTORC2 activity. These results highlight the mTORC2-Nav1.2 interaction as a therapeutic target for attenuating pathogenic hyperexcitability in early-stage AD.

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.

Long QT Syndrome Type 2 (LQT2) is a cardiac disorder caused by Loss of Function (LOF) mutations in the KCNH2 gene that encodes the K[+] channel hERG (Kv11.1). 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.

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.

Diseases caused by Flaviviridae viruses exert profound global health and economic burdens due to their high incidence and associated mortality. Infection by the Flaviviridae family often leads to severe acute or chronic illnesses, including hemorrhagic systemic diseases caused by dengue virus (DENV) and yellow fever virus, neurological complications associated with West Nile virus and Zika virus (ZIKV) infection, as well as liver damage and hepatocellular carcinoma resulting from hepatitis C virus (HCV) infection. Accumulating evidence indicates that a hallmark of Flaviviridae infection is to hijack calcium (Ca2+) signaling of the host cells, consequently facilitating viral entry, RNA replication, viral assembly, and release. Transient receptor potential (TRP) channels, a superfamily of nonselective cation channels, are central regulators of intracellular Ca2+ homeostasis. Recent studies reveal that TRP channels are closely involved in Flaviviridae infection. This comprehensive review synthesizes current findings on the role of TRP channels (e.g. TRPC, TRPV, TRPA, TRPM, and TRPML) in the pathogenesis of Flaviviridae viruses such as DENV, ZIKV, HCV, and Japanese encephalitis virus. Moreover, this review summarizes virus-TRP channel interaction mechanisms and discusses the potential of targeting TRP channels for host-directed antiviral therapies. This review aims to establish a conceptual framework for understanding TRP channel biology in Flaviviridae infection and to guide future research on antiviral strategies. Future directions should highlight the potential utility of TRP channel research for advancing anti-Flaviviridae therapies and clarifying their underlying mechanisms.

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 Ca[2+] 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 Ca[2+] 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 Ca[2+] 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.

Membrane channels are central to bladder function, yet current understanding is shaped disproportionately by a few well-studied families such as TRPA1 and TRPV1. To provide a more balanced view, this review analyzed emerging human transcriptomic datasets to identify the channels most highly expressed in the urinary bladder and examined how they remodel in bladder outlet obstruction and denervation. Sixty-seven channels were prominently expressed at the mRNA level in GTEx bladder tissue, with correlation analyses and protein expression data assigning many to smooth muscle, urothelial, endothelial, or neuronal compartments. Several abundant channels remain largely unstudied in urological contexts, including CLIC4, CLCN3, TPCN1 and ANO10. Disease-associated remodeling revealed shared and model-specific patterns. Outlet obstruction produced marked upregulation of L-type Ca2+ channel auxiliary subunits and robust changes in CLIC-family channels, whereas denervation induced broader channel downregulation not explained by nerve loss alone. Three channels, Gja1, Piezo1 and Ano1, were concordantly altered in both conditions, suggesting coordinated changes within interstitial cell networks and mechanotransductive pathways. These findings highlight a diverse and incompletely explored bladder "channel-ome." Expanding research beyond traditional targets may uncover new mechanisms underlying storage and voiding dysfunction and provide opportunities for therapeutic innovation in lower urinary tract disease.

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.

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 KcvNTS 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 KcvNTS 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.

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.

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.

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.

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.

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.