{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T23:56:34Z","timestamp":1776815794937,"version":"3.51.2"},"reference-count":44,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,1,9]],"date-time":"2021-01-09T00:00:00Z","timestamp":1610150400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST-108-2314-B-006-094"],"award-info":[{"award-number":["MOST-108-2314-B-006-094"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Columbianadin (CBN) is a bioactive coumarin-type compound with various biological activities. However, the action of CBN on the ionic mechanism remains largely uncertain, albeit it was reported to inhibit voltage-gated Ca2+ current or to modulate TRP-channel activity. In this study, whole-cell patch-clamp current recordings were undertaken to explore the modifications of CBN or other related compounds on ionic currents in excitable cells (e.g., pituitary GH3 cells and HL-1 atrial cardiomyocytes). GH3-cell exposure to CBN differentially decreased peak or late component of voltage-gated Na+ current (INa) with effective IC50 of 14.7 or 2.8 \u00b5M, respectively. The inactivation time course of INa activated by short depolarization became fastened in the presence of CBN with estimated KD value of 3.15 \u00b5M. The peak INa diminished by 10 \u00b5M CBN was further suppressed by subsequent addition of either sesamin (10 \u00b5M), ranolazine (10 \u00b5M), or tetrodotoxin (1 \u00b5M), but it was reversed by 10 \u00b5M tefluthrin (Tef); however, further application of 10 \u00b5M nimodipine failed to alter CBN-mediated inhibition of INa. CBN (10 \u00b5M) shifted the midpoint of inactivation curve of INa to the leftward direction. The CBN-mediated inhibition of peak INa exhibited tonic and use-dependent characteristics. Using triangular ramp pulse, the hysteresis of persistent INa enhanced by Tef was noticed, and the behavior was attenuated by subsequent addition of CBN. The delayed-rectifier or erg-mediated K+ current was mildly inhibited by 10 \u00b5M CBN, while it also slightly inhibited the amplitude of hyperpolarization-activated cation current. In HL-1 atrial cardiomyocytes, CBN inhibited peak INa and raised the inactivation rate of the current; moreover, further application of 10 \u00b5M Tef attenuated CBN-mediated decrease in INa. Collectively, this study provides an important yet unidentified finding revealing that CBN modifies INa in electrically excitable cells.<\/jats:p>","DOI":"10.3390\/ijms22020621","type":"journal-article","created":{"date-parts":[[2021,1,10]],"date-time":"2021-01-10T19:55:56Z","timestamp":1610308556000},"page":"621","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Effectiveness of Columbianadin, a Bioactive Coumarin Derivative, in Perturbing Transient and Persistent INa"],"prefix":"10.3390","volume":"22","author":[{"given":"Wei-Ting","family":"Chang","sequence":"first","affiliation":[{"name":"Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan"},{"name":"Division of Cardiovascular Medicine, Chi-Mei Medical Center, Tainan 71004, Taiwan"},{"name":"Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan 71004, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sheng-Nan","family":"Wu","sequence":"additional","affiliation":[{"name":"Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan 70101, Taiwan"},{"name":"Department of Physiology, National Cheng Kung University Medical College, Tainan 70101, Taiwan"},{"name":"Department of Medical Research, China Medical University, Taichung 40402, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1055\/s-2006-957987","article-title":"Anti-inflammatory and analgesic activities from roots of Angelica pubescens","volume":"61","author":"Chen","year":"1995","journal-title":"Planta Med."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Zhang, C., Hsu, A.C., Pan, H., Gu, Y., Zuo, X., Dong, B., Wang, Z., Zheng, J., Lu, J., and Zheng, R. (2019). Columbianadin Suppresses Lipopolysaccharide (LPS)-Induced Inflammation and Apoptosis through the NOD1 Pathway. Molecules, 24.","DOI":"10.3390\/molecules24030549"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.phytochem.2012.06.015","article-title":"Biotransformation of columbianadin by rat hepatic microsomes and inhibition of biotransformation products on NO production in RAW 264.7 cells in vitro","volume":"81","author":"Zhang","year":"2012","journal-title":"Phytochemistry"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1016\/j.jep.2014.07.033","article-title":"Inhibition of airway inflammation by the roots of Angelica decursiva and its constituent, columbianadin","volume":"155","author":"Lim","year":"2014","journal-title":"J. Ethnopharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/s12929-020-0619-5","article-title":"Modulation of human platelet activation and in vivo vascular thrombosis by columbianadin: Regulation by integrin alphaIIbbeta3 inside-out but not outside-in signals","volume":"27","author":"Hou","year":"2020","journal-title":"J. Biomed. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.jep.2018.10.040","article-title":"The ethnopharmacology, phytochemistry and pharmacology of Angelica biserrata\u2014A review","volume":"231","author":"Ma","year":"2019","journal-title":"J. Ethnopharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Yang, Y., Zhu, R., Li, J., Yang, X., He, J., Wang, H., and Chang, Y. (2019). Separation and Enrichment of Three Coumarins from Angelicae Pubescentis Radix by Macroporous Resin with Preparative HPLC and Evaluation of Their Anti-Inflammatory Activity. Molecules, 24.","DOI":"10.3390\/molecules24142664"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Lu, T.L., Lu, T.J., and Wu, S.N. (2020). Effectiveness in Block by Dexmedetomidine of Hyperpolarization-Activated Cation Current, Independent of Its Agonistic Effect on alpha2-Adrenergic Receptors. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21239110"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.jep.2016.11.046","article-title":"Analgesic effect of coumarins from Radix angelicae pubescentis is mediated by inflammatory factors and TRPV1 in a spared nerve injury model of neuropathic pain","volume":"195","author":"Li","year":"2017","journal-title":"J. Ethnopharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1522","DOI":"10.3389\/fphar.2019.01522","article-title":"Inhibitory Effects of Columbianadin on Nociceptive Behaviors in a Neuropathic Pain Model, and on Voltage-Gated Calcium Currents in Dorsal Root Ganglion Neurons in Mice","volume":"10","author":"Su","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"113445","DOI":"10.1016\/j.jpba.2020.113445","article-title":"Systematic analysis of the metabolites of Angelicae Pubescentis Radix by UPLC-Q-TOF-MS combined with metabonomics approaches after oral administration to rats","volume":"188","author":"Wan","year":"2020","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"107593","DOI":"10.1016\/j.pharmthera.2020.107593","article-title":"Induction of programmed necrosis: A novel anti-cancer strategy for natural compounds","volume":"214","author":"Yu","year":"2020","journal-title":"Pharmacol. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1797","DOI":"10.2174\/1871520620666200310094646","article-title":"Nanoformulations of Coumarins and the Hybrid Molecules of Coumarins with Potential Anticancer Effects","volume":"20","author":"Yerer","year":"2020","journal-title":"Anticancer Agents Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"320","DOI":"10.4062\/biomolther.2015.145","article-title":"Columbianadin Inhibits Cell Proliferation by Inducing Apoptosis and Necroptosis in HCT116 Colon Cancer Cells","volume":"24","author":"Kang","year":"2016","journal-title":"Biomol. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"335","DOI":"10.3389\/fphar.2020.00335","article-title":"Traditional Chinese Medicine of Angelicae Pubescentis Radix: A Review of Phytochemistry, Pharmacology and Pharmacokinetics","volume":"11","author":"Lu","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/S0944-7113(97)80064-5","article-title":"Calcium channel blocking activity: Screening methods for plant derived compounds","volume":"4","author":"Vuorela","year":"1997","journal-title":"Phytomedicine"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1055\/s-2006-960907","article-title":"The furanocoumarin columbianadin inhibits depolarization induced Ca2+ uptake in rat pituitary GH3 cells","volume":"56","author":"Tornquist","year":"1990","journal-title":"Planta Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1186\/gb-2003-4-3-207","article-title":"Overview of the voltage-gated sodium channel family","volume":"4","author":"Yu","year":"2003","journal-title":"Genome Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1124\/pr.57.4.4","article-title":"International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels","volume":"57","author":"Catterall","year":"2005","journal-title":"Pharmacol. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1210\/er.2010-0005","article-title":"Ion channels and signaling in the pituitary gland","volume":"31","author":"Stojilkovic","year":"2010","journal-title":"Endocr. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1254\/jphs.09018FP","article-title":"Effects of ranolazine, a novel anti-anginal drug, on ion currents and membrane potential in pituitary tumor GH(3) cells and NG108-15 neuronal cells","volume":"110","author":"Chen","year":"2009","journal-title":"J. Pharmacol. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5110","DOI":"10.1111\/bph.13276","article-title":"Actions of KMUP-1, a xanthine and piperazine derivative, on voltage-gated Na(+) and Ca(2+) -activated K(+) currents in GH3 pituitary tumour cells","volume":"172","author":"Lo","year":"2015","journal-title":"Br. J. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"C709","DOI":"10.1152\/ajpcell.1994.266.3.C709","article-title":"A background sodium conductance is necessary for spontaneous depolarizations in rat pituitary cell line GH3","volume":"266","author":"Simasko","year":"1994","journal-title":"Am. J. Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/S0005-2736(01)00301-7","article-title":"Nonlinear temperature modulation of sodium channel kinetics in GH(3) cells","volume":"1511","author":"Rosen","year":"2001","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Kuo, P.C., Kao, Z.H., Lee, S.W., and Wu, S.N. (2020). Effects of Sesamin, the Major Furofuran Lignan of Sesame Oil, on the Amplitude and Gating of Voltage-Gated Na(+) and K(+) Currents. Molecules, 25.","DOI":"10.3390\/molecules25133062"},{"key":"ref_26","first-page":"161","article-title":"Functional coupling of voltage-dependent L-type Ca2+ current to Ca2+-activated K+ current in pituitary GH3 cells","volume":"44","author":"Wu","year":"2001","journal-title":"Chin. J. Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.tox.2009.01.009","article-title":"Underlying mechanism of actions of tefluthrin, a pyrethroid insecticide, on voltage-gated ion currents and on action currents in pituitary tumor (GH3) cells and GnRH-secreting (GT1-7) neurons","volume":"258","author":"Wu","year":"2009","journal-title":"Toxicology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.toxlet.2018.01.002","article-title":"Differential regulation of tefluthrin and telmisartan on the gating charges of INa activation and inactivation as well as on resurgent and persistent INa in a pituitary cell line (GH3)","volume":"285","author":"So","year":"2018","journal-title":"Toxicol. Lett."},{"key":"ref_29","first-page":"E405","article-title":"Characterization of a hyperpolarization-activated cation current in rat pituitary cells","volume":"272","author":"Simasko","year":"1997","journal-title":"Am. J. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1021\/acschemneuro.9b00475","article-title":"Photodynamic Modification of Native HCN Channels Expressed in Thalamocortical Neurons","volume":"11","author":"Wei","year":"2020","journal-title":"ACS Chem. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.brainresbull.2019.03.016","article-title":"Concerted suppression of Ih and activation of IK(M) by ivabradine, an HCN-channel inhibitor, in pituitary cells and hippocampal neurons","volume":"149","author":"Hsiao","year":"2019","journal-title":"Brain Res. Bull."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1038\/242459a0","article-title":"Currents related to movement of the gating particles of the sodium channels","volume":"242","author":"Armstrong","year":"1973","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1080\/19336950.2016.1243190","article-title":"Hysteresis in voltage-gated channels","volume":"11","year":"2017","journal-title":"Channels"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"392","DOI":"10.3736\/jcim20080413","article-title":"[Absorption and transport of 6 coumarins isolated from the roots of Angelica pubescens f. biserrata in human Caco-2 cell monolayer model]","volume":"6","author":"Yang","year":"2008","journal-title":"Zhong Xi Yi Jie He Xue Bao"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1002\/bmc.3543","article-title":"Tissue distribution study of columbianadin and its active metabolite columbianetin in rats","volume":"30","author":"Zhang","year":"2016","journal-title":"Biomed. Chromatogr."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2365697","DOI":"10.1155\/2019\/2365697","article-title":"The Tissue Distribution of Four Major Coumarins after Oral Administration of Angelicae Pubescentis Radix Extract to Rats Using Ultra-High-Performance Liquid Chromatography","volume":"2019","author":"Ge","year":"2019","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"8568303","DOI":"10.1155\/2018\/8568303","article-title":"Simultaneous Determination of Columbianadin and Its Metabolite Columbianetin in Rat Plasma by LC-MS\/MS: Application to Pharmacokinetics of Columbianadin after Oral Administration","volume":"2018","author":"Li","year":"2018","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1186\/s13065-014-0064-1","article-title":"LC-MS\/MS determination and pharmacokinetic study of columbianadin in rat plasma after intravenous administration of pure columbianadin","volume":"8","author":"Chang","year":"2014","journal-title":"Chem. Cent. J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1007\/BF02518890","article-title":"Applications of reconstructed skin models in pharmaco-toxicological trials","volume":"36","author":"Damour","year":"1998","journal-title":"Med. Biol. Eng. Comput."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/S1386-1425(02)00148-8","article-title":"Vibrational spectroscopic studies on the natural product, columbianadin","volume":"59","author":"Abraham","year":"2003","journal-title":"Spectrochim. Acta A Mol. Biomol. Spectrosc."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3409","DOI":"10.1002\/jcp.25788","article-title":"Stimulatory actions of a novel thiourea derivative on large-conductance, calcium-activated potassium channels","volume":"232","author":"Wu","year":"2017","journal-title":"J. Cell Physiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2979","DOI":"10.1073\/pnas.95.6.2979","article-title":"HL-1 cells: A cardiac muscle cell line that contracts and retains phenotypic characteristics of the adult cardiomyocyte","volume":"95","author":"Claycomb","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1007\/BF00370626","article-title":"How do patch clamp seals form? A lipid bleb model","volume":"416","author":"Milton","year":"1990","journal-title":"Pfl\u00fcgers Archiv"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/nprot.2009.182","article-title":"Nonlinear least-squares data fitting in Excel spreadsheets","volume":"5","author":"Kemmer","year":"2010","journal-title":"Nat. Protoc."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/2\/621\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:09:17Z","timestamp":1760159357000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/2\/621"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,9]]},"references-count":44,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2021,1]]}},"alternative-id":["ijms22020621"],"URL":"https:\/\/doi.org\/10.3390\/ijms22020621","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,9]]}}}