{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:41:48Z","timestamp":1760146908114,"version":"build-2065373602"},"reference-count":78,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2024,12,29]],"date-time":"2024-12-29T00:00:00Z","timestamp":1735430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Grant Agency of the Ministry of Education, Research, Development and Youth of the Slovak Republic and the Slovak Academy of Sciences","award":["VEGA 2\/0018\/21","VEGA 2\/0160\/21","APVV-22-0061"],"award-info":[{"award-number":["VEGA 2\/0018\/21","VEGA 2\/0160\/21","APVV-22-0061"]}]},{"DOI":"10.13039\/501100005357","name":"Slovak Research and Development Agency","doi-asserted-by":"publisher","award":["VEGA 2\/0018\/21","VEGA 2\/0160\/21","APVV-22-0061"],"award-info":[{"award-number":["VEGA 2\/0018\/21","VEGA 2\/0160\/21","APVV-22-0061"]}],"id":[{"id":"10.13039\/501100005357","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a highly arrhythmogenic syndrome triggered by stress, primarily linked to gain-of-function point mutations in the cardiac ryanodine receptor (RyR2). Flecainide, as an effective therapy for CPVT, is a known blocker of the surface-membrane Na+ channel, also affecting the intracellular RyR2 channel. The therapeutic relevance of the flecainide-RyR2 interaction remains controversial, as flecainide blocks only the RyR2 current flowing in the opposite direction to the physiological Ca2+ release from the sarcoplasmic reticulum (SR). However, it has been proposed that charge-compensating countercurrent from the cytosol to SR lumen plays a critical role, and its reduction may indeed suppress excessive diastolic SR Ca2+ release through RyR2 channels in CPVT. Monitoring single-channel properties, we examined whether flecainide can target intracellular pathways for charge-balancing currents carried by RyR2 and SR Cl\u2212 channels under cell-like conditions. Particularly, the Tris+ countercurrent flowed through the RyR2 channel simultaneously with a dominant reverse Ca2+\/Ba2+ current. We demonstrate that flecainide blocked the RyR2-mediated countercurrent without affecting channel activity. In contrast, the SR Cl\u2212 channel was completely resistant to flecainide. Based on these findings, it is reasonable to propose that the primary intracellular target of flecainide in vivo is the RyR2-mediated countercurrent.<\/jats:p>","DOI":"10.3390\/ijms26010203","type":"journal-article","created":{"date-parts":[[2024,12,31]],"date-time":"2024-12-31T07:51:57Z","timestamp":1735631517000},"page":"203","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Flecainide Specifically Targets the Monovalent Countercurrent Through the Cardiac Ryanodine Receptor, While a Dominant Opposing Ca2+\/Ba2+ Current Is Present"],"prefix":"10.3390","volume":"26","author":[{"given":"Jana","family":"Gaburjakova","sequence":"first","affiliation":[{"name":"Institute of Molecular Physiology and Genetics, Centre of Biosciences, Slovak Academy of Sciences, Dubravska cesta 9, 840 05 Bratislava, Slovakia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9874-6416","authenticated-orcid":false,"given":"Michaela","family":"Domsicova","sequence":"additional","affiliation":[{"name":"Institute of Molecular Physiology and Genetics, Centre of Biosciences, Slovak Academy of Sciences, Dubravska cesta 9, 840 05 Bratislava, Slovakia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandra","family":"Poturnayova","sequence":"additional","affiliation":[{"name":"Institute of Molecular Physiology and Genetics, Centre of Biosciences, Slovak Academy of Sciences, Dubravska cesta 9, 840 05 Bratislava, Slovakia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9300-0688","authenticated-orcid":false,"given":"Marta","family":"Gaburjakova","sequence":"additional","affiliation":[{"name":"Institute of Molecular Physiology and Genetics, Centre of Biosciences, Slovak Academy of Sciences, Dubravska cesta 9, 840 05 Bratislava, Slovakia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"273","DOI":"10.2165\/11599950-000000000-00000","article-title":"Safety of flecainide","volume":"35","author":"Tamargo","year":"2012","journal-title":"Drug Saf."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2741","DOI":"10.2165\/00003495-200464240-00003","article-title":"Pharmacological cardioversion of atrial fibrillation: Current management and treatment options","volume":"64","author":"Boriani","year":"2004","journal-title":"Drugs"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2244","DOI":"10.1016\/j.jacc.2011.01.026","article-title":"Flecainide therapy reduces exercise-induced ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia","volume":"57","author":"Kannankeril","year":"2011","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Baltogiannis, G.G., Lysitsas, D.N., di Giovanni, G., Ciconte, G., Sieira, J., Conte, G., Kolettis, T.M., Chierchia, G.-B., de Asmundis, C., and Brugada, P. (2019). CPVT: Arrhythmogenesis, therapeutic management, and future perspectives. A brief review of the literature. Front. Cardiovasc. Med., 6.","DOI":"10.3389\/fcvm.2019.00092"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1016\/j.hlc.2019.10.013","article-title":"50 years of catecholaminergic polymorphic ventricular tachycardia (CPVT)-Time to explore the dark side of the moon","volume":"29","author":"Pflaumer","year":"2020","journal-title":"Heart Lung Circ."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1001\/jamacardio.2022.0219","article-title":"Outcomes of patients with catecholaminergic polymorphic ventricular tachycardia treated with \u03b2-blockers","volume":"7","author":"Mazzanti","year":"2022","journal-title":"JAMA Cardiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1161\/01.CIR.103.2.196","article-title":"Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia","volume":"103","author":"Priori","year":"2001","journal-title":"Circulation"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.yjmcc.2008.10.012","article-title":"Ryanodine receptor and calsequestrin in arrhythmogenesis: What we have learnt from genetic diseases and transgenic mice","volume":"46","author":"Liu","year":"2009","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/j.pharmthera.2009.03.006","article-title":"Ryanodine receptor-mediated arrhythmias and sudden cardiac death","volume":"123","author":"Blayney","year":"2009","journal-title":"Pharmacol. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1161\/CIRCRESAHA.110.226845","article-title":"Inherited dysfunction of sarcoplasmic reticulum Ca2+ handling and arrhythmogenesis","volume":"108","author":"Priori","year":"2011","journal-title":"Circ. Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1093\/europace\/euad156","article-title":"RYR2-ryanodinopathies: From calcium overload to calcium deficiency","volume":"25","author":"Steinberg","year":"2023","journal-title":"Europace"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1152\/physrev.00013.2002","article-title":"Ryanodine receptor calcium release channels","volume":"82","author":"Fill","year":"2002","journal-title":"Physiol. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1038\/415198a","article-title":"Cardiac excitation-contraction coupling","volume":"415","author":"Bers","year":"2002","journal-title":"Nature"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1146\/annurev.physiol.70.113006.100455","article-title":"Calcium cycling and signaling in cardiac myocytes","volume":"70","author":"Bers","year":"2008","journal-title":"Annu. Rev. Physiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1146\/annurev-physiol-020911-153308","article-title":"Cardiac sarcoplasmic reticulum calcium leak: Basis and roles in cardiac dysfunction","volume":"76","author":"Bers","year":"2014","journal-title":"Annu. Rev. Physiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.biocel.2018.05.004","article-title":"Ryanodine receptor Ca(2+) release channel post-translational modification: Central player in cardiac and skeletal muscle disease","volume":"101","author":"Denniss","year":"2018","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1085\/jgp.20028558","article-title":"Channel openings are necessary but not sufficient for use-dependent block of cardiac Na+ channels by flecainide: Evidence from the analysis of disease-linked mutations","volume":"120","author":"Liu","year":"2002","journal-title":"J. Gen. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1085\/jgp.20028723","article-title":"Common molecular determinants of flecainide and lidocaine block of heart Na+ channels: Evidence from experiments with neutral and quaternary flecainide analogues","volume":"121","author":"Liu","year":"2003","journal-title":"J. Gen. Physiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1113\/jphysiol.2004.065003","article-title":"State-dependent trapping of flecainide in the cardiac sodium channel","volume":"560","author":"Ramos","year":"2004","journal-title":"J. Physiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2558","DOI":"10.1111\/bph.15718","article-title":"Moving in the right direction: Elucidating the mechanisms of interaction between flecainide and the cardiac ryanodine receptor","volume":"179","author":"Bannister","year":"2022","journal-title":"Br. J. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1038\/nm.1942","article-title":"Flecainide prevents catecholaminergic polymorphic ventricular tachycardia in mice and humans","volume":"15","author":"Watanabe","year":"2009","journal-title":"Nat. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.yjmcc.2009.10.005","article-title":"Flecainide inhibits arrhythmogenic Ca2+ waves by open state block of ryanodine receptor Ca2+ release channels and reduction of Ca2+ spark mass","volume":"48","author":"Hilliard","year":"2010","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1161\/CIRCRESAHA.120.316819","article-title":"RYR2 channel inhibition is the principal mechanism of flecainide action in CPVT","volume":"128","author":"Kryshtal","year":"2021","journal-title":"Circ. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1111\/bph.13807","article-title":"Multiple targets for flecainide action: Implications for cardiac arrhythmogenesis","volume":"175","author":"Salvage","year":"2018","journal-title":"Br. J. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e202213089","DOI":"10.1085\/jgp.202213089","article-title":"How does flecainide impact RyR2 channel function?","volume":"154","author":"Salvage","year":"2022","journal-title":"J. Gen. Physiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1161\/CIRCEP.110.959916","article-title":"Inhibition of cardiac Ca2+ release channels (RyR2) determines efficacy of class I antiarrhythmic drugs in catecholaminergic polymorphic ventricular tachycardia","volume":"4","author":"Hwang","year":"2011","journal-title":"Circ. Arrhythm. Electrophysiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1124\/mol.114.094623","article-title":"Multiple modes of ryanodine receptor 2 inhibition by flecainide","volume":"86","author":"Mehra","year":"2014","journal-title":"Mol. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1161\/CIRCRESAHA.116.305347","article-title":"The mechanism of flecainide action in CPVT does not involve a direct effect on RyR2","volume":"116","author":"Bannister","year":"2015","journal-title":"Circ. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2446","DOI":"10.1111\/bph.13521","article-title":"Effect of flecainide derivatives on sarcoplasmic reticulum calcium release suggests a lack of direct action on the cardiac ryanodine receptor","volume":"173","author":"Bannister","year":"2016","journal-title":"Br. J. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3706","DOI":"10.1529\/biophysj.108.131987","article-title":"Intracellular calcium release channels mediate their own countercurrent: The ryanodine receptor case study","volume":"95","author":"Gillespie","year":"2008","journal-title":"Biophys. J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1085\/jgp.76.4.425","article-title":"Ionic selectivity, saturation, and block in a K+-selective channel from sarcoplasmic reticulum","volume":"76","author":"Coronado","year":"1980","journal-title":"J. Gen. Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1006\/jmcc.2002.2041","article-title":"Sarcoplasmic reticulum K+ channels from human and sheep atrial cells display a specific electro-pharmacological profile","volume":"34","author":"Picard","year":"2002","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1242\/jcs.090126","article-title":"Endoplasmic reticulum potassium-hydrogen exchanger and small conductance calcium-activated potassium channel activities are essential for ER calcium uptake in neurons and cardiomyocytes","volume":"125","author":"Kuum","year":"2012","journal-title":"J. Cell Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1161\/CIRCRESAHA.121.318706","article-title":"Is the debate on the flecainide action on the RYR2 in CPVT closed?","volume":"128","author":"Benitah","year":"2021","journal-title":"Circ. Res."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Steer, E.J., Yang, Z., Al-Owais, M.M., Kirton, H.M., White, E.W., and Steele, D.S. (2023). Flecainide induces a sustained countercurrent dependent effect on RyR2 in permeabilized WT ventricular myocytes but not in intact cells. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1155601"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"13111","DOI":"10.1073\/pnas.1814928115","article-title":"Fenestrations control resting-state block of a voltage gated sodium channel","volume":"115","author":"Lenaeus","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1085\/jgp.69.4.497","article-title":"Local anesthetics: Hydrophilic and hydrophobic pathways for the drug-receptor reaction","volume":"69","author":"Hille","year":"1977","journal-title":"J. Gen. Physiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1126\/science.249.4972.1000","article-title":"In situ interfacial mass detection with piezoelectric transducers","volume":"249","author":"Ward","year":"1990","journal-title":"Science"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-1-62703-275-9_1","article-title":"Quartz crystal microbalances as tools for probing protein-membrane interactions","volume":"974","author":"Nielsen","year":"2013","journal-title":"Methods Mol. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Johannsmann, D., Langhoff, A., and Leppin, C. (2021). Studying soft interfaces with shear waves: Principles and applications of the quartz crystal microbalance (QCM). Sensors, 21.","DOI":"10.3390\/s21103490"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1007\/s11220-023-00413-w","article-title":"A review of quartz crystal microbalance for chemical and biological sensing applications","volume":"24","author":"Alanazi","year":"2023","journal-title":"Sens. Imaging"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1113\/jphysiol.1991.sp018676","article-title":"Monovalent cation conductance in the ryanodine receptor-channel of sheep cardiac muscle sarcoplasmic reticulum","volume":"439","author":"Lindsay","year":"1991","journal-title":"J. Physiol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Salvage, S.C., Gallant, E.M., Fraser, J.A., Huang, C.L.-H., and Dulhunty, A.F. (2021). Flecainide paradoxically activates cardiac ryanodine receptor channels under low activity conditions: A potential pro-arrhythmic action. Cells, 10.","DOI":"10.3390\/cells10082101"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1484","DOI":"10.1016\/S0006-3495(94)80622-8","article-title":"Gating of the native and purified cardiac SR Ca2+-release channel with monovalent cations as permeant species","volume":"67","author":"Sitsapesan","year":"1994","journal-title":"Biophys. J."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/S0008-6363(02)00846-5","article-title":"Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: Evidence for a provisional safety margin in drug development","volume":"58","author":"Redfern","year":"2003","journal-title":"Cardiovasc. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1016\/j.bpj.2017.11.3775","article-title":"Sarcoplasmic reticulum Ca(2+) release uses a cascading network of intra-SR and channel countercurrents","volume":"114","author":"Zsolnay","year":"2018","journal-title":"Biophys. J."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1113\/JP271282","article-title":"In silico prediction of drug therapy in catecholaminergic polymorphic ventricular tachycardia","volume":"594","author":"Yang","year":"2016","journal-title":"J. Physiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.colsurfb.2011.04.012","article-title":"An impedance QCM study on the partitioning of bioactive compounds in supported phospholipid bilayers","volume":"86","author":"Kannistoa","year":"2011","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.colsurfb.2018.04.016","article-title":"A QCM-D study of the concentration- and time-dependent interactions of human LL37 with model mammalian lipid bilayers","volume":"167","author":"Lozeau","year":"2018","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Li, X., Song, S., Shuai, Q., Pei, Y., Aastrup, T., Pei, Y., and Pei, Z. (2015). Real-time and label-free analysis of binding thermodynamics of carbohydrate-protein interactions on unfixed cancer cell surfaces using a QCM biosensor. Sci. Rep., 5.","DOI":"10.1038\/srep14066"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/0011-2240(86)90014-3","article-title":"Pharmacology of DMSO","volume":"23","author":"Jacob","year":"1986","journal-title":"Cryobiology"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"13982","DOI":"10.1021\/ja063363t","article-title":"Molecular basis for dimethylsulfoxide (DMSO) action on lipid membranes","volume":"128","author":"Notman","year":"2006","journal-title":"J. Am. Chem. Soc."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.bpj.2020.05.037","article-title":"Effect of DMSO on the mechanical and structural properties of model and biological membranes","volume":"119","author":"Gironi","year":"2020","journal-title":"Biophys. J."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/S0301-4622(01)00206-X","article-title":"Insights into the dynamics of DMSO in phosphatidylcholine bilayers","volume":"94","author":"Chang","year":"2001","journal-title":"Biophys. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1016\/j.bpj.2015.06.011","article-title":"DMSO induces dehydration near lipid membrane surfaces","volume":"109","author":"Cheng","year":"2015","journal-title":"Biophys. J."},{"key":"ref_56","first-page":"1218","article-title":"Distribution of caffeine between selected water-organic solvent media","volume":"13","author":"Edwards","year":"2015","journal-title":"Int. J. Chem. Sci."},{"key":"ref_57","first-page":"789","article-title":"Interactions of flecainide with guinea pig cardiac sodium channels","volume":"66","author":"Anno","year":"1990","journal-title":"Importance of activation unblocking to the voltage dependence of recovery Circ. Res."},{"key":"ref_58","first-page":"101","article-title":"Preferential block of late sodium current in the LQT3 \u0394KPQ mutant by the class I(C) antiarrhythmic flecainide","volume":"57","author":"Nagatomo","year":"2000","journal-title":"Mol. Pharmacol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/j.ceca.2012.02.001","article-title":"Is ryanodine receptor a calcium or magnesium channel? Roles of K+ and Mg2+ during Ca2+ release","volume":"51","author":"Gillespie","year":"2012","journal-title":"Cell Calcium"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"6801","DOI":"10.1016\/S0021-9258(18)88850-0","article-title":"Electron probe x-ray microanalysis of post-tetanic Ca2+ and Mg2+ movements across the sarcoplasmic reticulum in situ","volume":"260","author":"Somlyo","year":"1985","journal-title":"J. Biol. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1038\/nature05928","article-title":"TRIC channels are essential for Ca2+ handling in intracellular stores","volume":"448","author":"Yazawa","year":"2007","journal-title":"Nature"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.bpj.2010.04.051","article-title":"Charade of the SR K+ channel: Two ion-channels, TRIC-A and TRIC-B, masquerade as a single K+ channel","volume":"99","author":"Pitt","year":"2010","journal-title":"Biophys. J."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1016\/j.bpj.2013.07.042","article-title":"Sarcoplasmic reticulum K+ (TRIC) channel does not carry essential countercurrent during Ca2+ release","volume":"105","author":"Guo","year":"2013","journal-title":"Biophys. J."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1007\/s00424-012-1197-5","article-title":"TRIC channels supporting efficient Ca2+ release from intracellular stores","volume":"465","author":"Venturi","year":"2013","journal-title":"Pflugers Arch."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1038\/s41422-023-00798-z","article-title":"Disruption of ER ion homeostasis maintained by an ER anion channel CLCC1 contributes to ALS-like pathologies","volume":"33","author":"Guo","year":"2023","journal-title":"Cell Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/0014-2999(92)90118-N","article-title":"States and sites of actions of flecainide on guinea-pig cardiac sodium channels","volume":"214","author":"Nitta","year":"1992","journal-title":"Eur. J. Pharmacol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1085\/jgp.200308857","article-title":"State-dependent block of wild-type and inactivation-deficient Na+ channels by flecainide","volume":"122","author":"Wang","year":"2003","journal-title":"J. Gen. Physiol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1038\/nature10238","article-title":"The crystal structure of a voltage-gated sodium channel","volume":"475","author":"Payandeh","year":"2011","journal-title":"Nature"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1126\/science.1213274","article-title":"Crystal structure of the human two-pore domain potassium channel K2P1","volume":"335","author":"Miller","year":"2012","journal-title":"Science"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"5365","DOI":"10.1021\/bi500525s","article-title":"Structures of KcsA in complex with symmetrical quaternary ammonium compounds reveal a hydrophobic binding site","volume":"53","author":"Lenaeus","year":"2014","journal-title":"Biochemistry"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1126\/science.1261512","article-title":"K2P channel gating mechanisms revealed by structures of TREK-2 and a complex with Prozac","volume":"347","author":"Dong","year":"2015","journal-title":"Science"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2945","DOI":"10.1073\/pnas.1817446116","article-title":"Structural basis for antiarrhythmic drug interactions with the human cardiac sodium channel","volume":"116","author":"Nguyen","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"3010","DOI":"10.1016\/j.bbamem.2012.07.014","article-title":"Interaction of local anesthetics with lipid bilayers investigated by 1H MAS NMR spectroscopy","volume":"1818","author":"Weizenmann","year":"2012","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1724","DOI":"10.1126\/science.8085162","article-title":"Molecular determinants of state-dependent block of Na+ channels by local anesthetics","volume":"265","author":"Ragsdale","year":"1994","journal-title":"Science"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1074\/jbc.M006992200","article-title":"Molecular determinants of voltage-dependent gating and binding of pore-blocking drugs in transmembrane segment IIIS6 of the Na+ channel alpha subunit","volume":"276","author":"Brown","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1038\/ncomms1351","article-title":"Molecular basis for class Ib antiarrhythmic inhibition of cardiac sodium channels","volume":"2","author":"Pless","year":"2011","journal-title":"Nat. Commun."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s00232-006-7018-z","article-title":"Comparison of the effects exerted by luminal Ca2+ on the sensitivity of the cardiac ryanodine receptor to caffeine and cytosolic Ca2+","volume":"212","author":"Gaburjakova","year":"2006","journal-title":"J. Membr. Biol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"e171058","DOI":"10.1172\/JCI171058","article-title":"Guidelines for repeated measures statistical analysis approaches with basic science research considerations","volume":"133","author":"Muhammad","year":"2023","journal-title":"J. Clin. Investig."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/1\/203\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:56:05Z","timestamp":1760115365000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/1\/203"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,29]]},"references-count":78,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,1]]}},"alternative-id":["ijms26010203"],"URL":"https:\/\/doi.org\/10.3390\/ijms26010203","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2024,12,29]]}}}