Pancreatic β-cell mass and glucose-stimulated insulin secretion strongly increase during postnatal development. Voltage-gated calcium channels (CaV) 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 CaV currents compared to 14-day (juvenile) or 3-month-old (adult) mice, as well as a different CaV 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 CaV 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.

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 Hvcn1 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.

The pancreas consists of exocrine and endocrine compartments. In the exocrine pancreas, cystic fibrosis transmembrane conductance regulator (CFTR) functions mainly in ductal epithelial cells as a chloride and bicarbonate channel. Its activity depends on proper protein folding, trafficking, and localization to the apical membrane. This systematic narrative review aims to synthesize the available evidence on the role of protein sorting machinery in CFTR channelopathies and its contribution to exocrine pancreatic dysfunction. A thorough search was conducted using PRISMA criteria on PubMed, Wiley Online Library, and Scopus for studies published in English between January 2000 and November 2025. Twenty studies that met the inclusion criteria were included in this review. Pathogenic CFTR variants impair protein folding, endoplasmic reticulum (ER) exit, and endosomal recycling, resulting in reduced apical membrane expression and stability. These defects disrupt the localization of associated transporters and secretory proteins, impair ductal bicarbonate secretion, alter zymogen handling, and promote acinar injury, although these claims are supported mainly by indirect experimental models and therefore require clinical confirmation. CFTR channelopathies in the exocrine pancreas encompass both ion transport defects and broader disruptions of protein sorting machinery. CFTR may contribute to the assembly, stabilization, or localization of selected apical transport complexes, and its loss can secondarily alter epithelial organization. Therapeutic approaches targeting both channel correction and intracellular trafficking may improve pancreatic function and mitigate disease progression.

KV7.4 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 KV7.4 channels expressed in HEK293 cells. Whole-cell patch-clamp recordings showed that acute application of E2 reduced KV7.4 current density. At nanomolar concentrations, both E2 and the alternate GPER1 agonist aldosterone inhibited KV7.4 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 KV7.4. In contrast, equivalent experiments performed with KV7.5 channels showed no significant effect of E2 despite GPER1 co-expression, suggesting subtype-selective regulation within the KV7 family. Surface biotinylation experiments suggest that GPER1 co-expression reduced surface KV7.4 expression, with a further reduction observed following E2 treatment. Finally, both E2 and aldosterone negatively regulate the sensitivity of KV7.2-5 activator ML213-mediated relaxation in arteries from female rats. Together, these findings identify KV7.4 as a downstream effector of rapid GPER1-dependent estrogen signaling and suggest that steroid status may influence KV7-targeted therapeutic responses.

Despite the established roles of calcium (Ca[2+]) and magnesium (Mg[2+]) 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 Ca[2+] and Mg[2+] 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 Ca[2+] channels, together with transient receptor potential channels, emerged as principal mediators of placental Ca[2+] transport and myometrial contractility. Mechanosensitive Piezo1 channels mediate stretch-activated Ca[2+] influx, while store-operated Ca[2+] entry pathways involving STIM1-Orai1 sustain intracellular Ca[2+] homeostasis. Potassium-Ca[2+] coupling channels modulated membrane hyperpolarization and anti-labor effects, and intracellular regulators such as PMCA and RYR1 fine-tuned Ca[2+] homeostasis. The Mg[2+] transporters are essential for preserving Mg[2+] homeostasis and regulating Ca[2+]-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 Ca[2+] and Mg[2+] ion channelopathies represent both a potential therapeutic target and a mechanistic factor underlying key obstetric complications.

Store-operated calcium entry (SOCE) mediated by STIM and Orai proteins is a fundamental Ca[2+] influx mechanism that critically regulates intracellular calcium homeostasis and participates in cardiovascular pathophysiology. Upon endoplasmic reticulum Ca[2+] store depletion, STIM1/2 activate plasma membrane Orai1/3 channels, initiating Ca[2+] 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.

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 (Ca[2+]) 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 Ca[2+] 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 Ca[2+] 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.