Channels (Austin, Tex.)最新文献

{"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}

{"title":"Transient receptor potential channels in <i>Flaviviridae</i> infection: A comprehensive review.","authors":"Fuchun Jiang, Xiaoqiang Yao, Chang-Bo Zheng","doi":"10.1080/19336950.2026.2665540","DOIUrl":"10.1080/19336950.2026.2665540","url":null,"abstract":"<p><p>Diseases caused by <i>Flaviviridae</i> viruses exert profound global health and economic burdens due to their high incidence and associated mortality. Infection by the <i>Flaviviridae</i> 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 <i>Flaviviridae</i> 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 <i>Flaviviridae</i> 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 <i>Flaviviridae</i> 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 <i>Flaviviridae</i> infection and to guide future research on antiviral strategies. Future directions should highlight the potential utility of TRP channel research for advancing anti-<i>Flaviviridae</i> therapies and clarifying their underlying mechanisms.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"20 1","pages":"2665540"},"PeriodicalIF":3.2,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13154987/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147846811","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":"Association of the chemerin-CMKLR1 with atrial potassium current dysregulation and atrial fibrillation in obese mice.","authors":"Yating Chen, Bin Li, Jie Liu, Jiaqi Liu, Chuanbin Liu, Yacong Zhu, Mengting Shen, Zhuhui Lin, Jiancheng Zhang, Yang Li","doi":"10.1080/19336950.2025.2611704","DOIUrl":"10.1080/19336950.2025.2611704","url":null,"abstract":"<p><p>Obesity is an established risk factor for atrial fibrillation (AF) and is associated with hypersecretion of the adipokine chemerin. Chemerin has been linked to the AF initiation and progression predominantly through Chemokine-like receptor 1(CMKLR1)-mediated signaling. This study aimed to elucidate how activation of the chemerin-CMKLR1 contributes to atrial potassium current dysregulation in obesity-related AF. Male C57BL/6J mice were divided into high-fat diet (HFD) and low-fat diet (LFD) group. Action potentials and potassium currents were recorded by whole-cell patch-clamp electrophysiology. HFD mice exhibited significantly increased susceptibility to AF. Atrial myocytes from HFD mice showed marked shortening of action potential duration, primarily due to an increase in peak repolarizing potassium current (<i>I</i>_k,peak). The rise in <i>I</i>_K,peak density was attributed to concurrent remodeling of its components, the transient outward potassium current (<i>I</i>_to) and the ultrarapid delayed rectifier potassium current (<i>I</i>_KUr). <i>I</i>_to density increased from 30.13 ± 0.76 <i>pA/pF</i> to 35.42 ± 0.70 <i>pA/pF</i> at +70 mV, accompanied by a leftward shift of steady-state activation, a rightward shift of steady-state inactivation, faster recovery from inactivation, and upregulated Kv4.3 and KChIP2 expression. <i>I</i>_KUr density increased from 23.95 ± 1.95 <i>pA/pF</i> to 30.24 ± 0.97 <i>pA/pF</i> at +70 mV, consistent with elevated Kv1.5 expression. These electrophysiological changes were paralleled by upregulated protein abundance of chemerin and its receptor CMKLR1 in atrial myocytes, suggesting activation of the chemerin-CMKLR1 in obese mice. Obesity-associated activation of the chemerin-CMKLR1 promotes pathological potassium current remodeling, shortens atrial APD, and contributes to obesity-related AF.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"20 1","pages":"2611704"},"PeriodicalIF":3.2,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12773632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907297","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":"Protein sorting and proteostasis mechanisms in CFTR-related exocrine pancreas dysfunction: A systematic narrative review.","authors":"Aime Patrick Niyomugabo, Leopold Ntakirutimana, Abdullateef Isiaka Alagbonsi","doi":"10.1080/19336950.2026.2731660","DOIUrl":"10.1080/19336950.2026.2731660","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"20 1","pages":"2731660"},"PeriodicalIF":3.2,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13577266/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148957428","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":"Bladder under stress: Pathological and adaptive shifts in channel expression.","authors":"Karl Swärd, Karl-Erik Andersson, Bengt Uvelius","doi":"10.1080/19336950.2026.2652649","DOIUrl":"10.1080/19336950.2026.2652649","url":null,"abstract":"<p><p>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 <i>CLIC4</i>, <i>CLCN3</i>, <i>TPCN1</i> and <i>ANO10</i>. 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, <i>Gja1</i>, <i>Piezo1</i> and <i>Ano1</i>, 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.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"20 1","pages":"2652649"},"PeriodicalIF":3.2,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147635141","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":"Role of NADPH oxidase 2-derived reactive oxygen species in cardiac electrophysiological disorders.","authors":"Bin Li, Ying Dong, Yating Chen, Chuanbin Liu, Yang Li","doi":"10.1080/19336950.2026.2696810","DOIUrl":"10.1080/19336950.2026.2696810","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"20 1","pages":"2696810"},"PeriodicalIF":3.2,"publicationDate":"2026-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13348922/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148392663","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":"Inhibition of lipolysis in visceral adipose tissue from obese mice and humans prevents impairment of endothelial Kir2.1 channels.","authors":"Emma C Hudgins, Erica J Johnson, Sabita Rokka, Bhaswati Kashyap, Arielle Mahugu, Thanh Nguyen, Anthony R Tascone, Elizabeth McCarthy, Caitlin Halbert, Ibra S Fancher","doi":"10.1080/19336950.2025.2564651","DOIUrl":"10.1080/19336950.2025.2564651","url":null,"abstract":"<p><p>Accumulation of abdominal visceral adipose tissue (VAT) is a major risk factor for cardiovascular disease. Obesity-induced endothelial dysfunction is a precursor to severe disease, and we and others have shown that arteries embedded in VAT, but not subcutaneous adipose tissue, exhibit robust endothelial dysfunction. Using a mouse model of diet-induced obesity, we recently linked VAT from obese mice to the impairment of endothelial Kir2.1, a critical regulator of endothelial function. However, the mechanism by which VAT impairs Kir2.1 is unclear. As Kir2.1 impairment is dependent on endothelial CD36, we hypothesized that lipolytic VAT induces Kir2.1 impairment through fatty acids (FA). To test this, we first treated endothelial cells with palmitic acid (PA) to determine whether the addition of exogenous FAs recapitulated our original finding of Kir2.1 dysfunction when challenged with VAT. PA inhibited Kir2.1 assessed via whole-cell patch-clamp electrophysiology, an effect that was dependent on endothelial CD36. To determine whether inhibiting VAT lipolysis prevents Kir2.1 dysfunction in the presence of VAT in obese mice and humans, VAT was pretreated with small molecule inhibitors of adipose triglyceride lipase prior to incubating endothelial cells with adipose tissue. This approach also prevented VAT-induced impairment of endothelial Kir2.1 suggesting that VAT-derived FAs may play a role. Furthermore, inhibition of lipolysis in the VAT of obese mice and humans significantly reduced endothelial FA uptake, similar to that observed when CD36 was downregulated. These findings advance our understanding of the relationship between VAT and endothelial Kir2.1 impairment and place VAT-derived FAs as potential paracrine mediators.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"19 1","pages":"2564651"},"PeriodicalIF":3.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12477883/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145151961","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":"Sclareol and cinnarizine are non-selective inhibitors of voltage-gated Cav1.3 L-type Ca²⁺ channels.","authors":"Lucia Zanetti, Ferenc Török, Luisa Leitzbach, Holger Stark, Jörg Striessnig","doi":"10.1080/19336950.2025.2556101","DOIUrl":"10.1080/19336950.2025.2556101","url":null,"abstract":"<p><p>A growing body of preclinical evidence indicates that the inhibition of voltage-gated Cav1.3 L-type Ca²⁺ channels could be a therapeutic concept for the therapy of treatment-resistant hypertension, spinal injury and for neuroprotection in early Parkinson's disease (PD). However, available Ca²⁺-channel blockers are potent inhibitors of vascular Cav1.2 L-type channels which can cause low blood pressure as an adverse drug reaction. Therefore, Cav1.3-selective inhibitors are needed to further investigate the therapeutic potential of Cav1.3 as drug target in vivo. The bicyclic diterpene alcohol sclareol has recently been reported to exert neuroprotective properties in a mouse PD model by blocking Cav1.3 L-type channels. This study investigates the proposed Cav1.3-selectivity of sclareol compared to Cav1.2 and to other voltage-gated Ca²⁺ channels in whole-cell patch-clamp experiments. Various stimulation protocols, including dopamine neuron-like firing patterns show that sclareol is neither a subtype-selective nor a potent blocker of heterologously expressed Cav1.3 and inhibits also Cav2.3 channels. Therefore, the contribution of Cav1.3 channel inhibition for the previously reported neuroprotective effects of sclareol in a mouse PD model remains unclear. In addition, cinnarizine, a vertigo therapeutic also under investigation for inhibition of Cav1.3-mediated aldosterone-secretion, inhibits Cav1.3 channels in a frequency-dependent manner, but also without relevant selectivity with respect to Cav1.3.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"19 1","pages":"2556101"},"PeriodicalIF":3.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12445503/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145076584","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":"A rare HCN4 variant combined with sick sinus syndrome, left ventricular noncompaction, and complex congenital heart disease.","authors":"Fengxiao Zhang, Ning Zhao, Lin Wang, Hua Peng, Ying Jiang, Min Cheng, Feng Zhu","doi":"10.1080/19336950.2025.2517851","DOIUrl":"10.1080/19336950.2025.2517851","url":null,"abstract":"<p><p>The hyperpolarization-activated cyclic nucleotide-gated potassium channel 4 (HCN4) gene has been reported to regulate the spontaneous depolarization of sinoatrial node cells. A novel HCN4 mutation (c.2036 G>A) may lead to sick sinus syndrome. The green fluorescent protein (GFP) and either the wild-type (WT) or C679Y mutant (mut) were co-transfected into HEK293 cells to investigate the impact of the mutation on HCN4 channel function. The whole-cell patch-clamp approach was utilized to record HCN4 currents. According to electrophysiological recording, the current amplitude and density generated by mut-C679Y HCN4 channels were much lower than those generated by WT channels. HCN4 channel current activation was not significantly affected by the C679Y mutation. Because of the little current, analyzing the mut channel deactivation kinetic was challenging. Thus, we have identified a novel HCN4 gene mutation that is connected to bradycardia, left ventricular noncompaction, and diverse valve-related heart conditions.</p>","PeriodicalId":72555,"journal":{"name":"Channels (Austin, Tex.)","volume":"19 1","pages":"2517851"},"PeriodicalIF":3.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12233691/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144562139","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}