{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T13:13:28Z","timestamp":1760706808083},"reference-count":43,"publisher":"Rockefeller University Press","issue":"2","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[1999,2,1]]},"abstract":"<jats:p>Site-3 toxins isolated from several species of scorpion and sea anemone bind to voltage-gated Na channels and prolong the time course of INa by interfering with inactivation with little or no effect on activation, effects that have similarities to those produced by genetic diseases in skeletal muscle (myotonias and periodic paralysis) and heart (long QT syndrome). Some published reports have also reported the presence of a noninactivating persistent current in site-3 toxin-treated cells. We have used the high affinity site-3 toxin Anthopleurin B to study the kinetics of this current and to evaluate kinetic differences between cardiac (in RT4-B8 cells) and neuronal (in N1E-115 cells) Na channels. By reverse transcription\u2013PCR from N1E-115 cell RNA multiple Na channel transcripts were detected; most often isolated were sequences homologous to rBrII, although at low frequency sequences homologous to rPN1 and rBrIII were also detected. Toxin treatment induced a voltage-dependent plateau current in both isoforms for which the relative amplitude (plateau current\/peak current) approached a constant value with depolarization, although the magnitude was much greater for neuronal (17%) than cardiac (5%) INa. Cell-attached patch recordings revealed distinct quantitative differences in open times and burst durations between isoforms, but for both isoforms the plateau current comprised discrete bursts separated by quiescent periods, consistent with toxin induction of an increase in the rate of recovery from inactivation rather than a modal failure of inactivation. In accord with this hypothesis, toxin increased the rate of whole-cell recovery at all tested voltages. Moreover, experimental data support a model whereby recovery at negative voltages is augmented through closed states rather than through the open state. We conclude that site-3 toxins produce qualitatively similar effects in cardiac and neuronal channels and discuss implications for channel kinetics.<\/jats:p>","DOI":"10.1085\/jgp.113.2.333","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T16:50:20Z","timestamp":1027702220000},"page":"333-346","update-policy":"http:\/\/dx.doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":42,"title":["Augmentation of Recovery from Inactivation by Site-3 Na Channel Toxins"],"prefix":"10.1085","volume":"113","author":[{"given":"G.","family":"Richard Benzinger","sequence":"first","affiliation":[{"name":"From the Committee on Neurobiology, The University of Chicago, Chicago, Illinois 60637"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gayle S.","family":"Tonkovich","sequence":"additional","affiliation":[{"name":"From the Committee on Neurobiology, The University of Chicago, Chicago, Illinois 60637"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dorothy A.","family":"Hanck","sequence":"additional","affiliation":[{"name":"From the Committee on Neurobiology, The University of Chicago, Chicago, Illinois 60637"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"291","published-online":{"date-parts":[[1999,2,1]]},"reference":[{"key":"2023072918072807600_B1","doi-asserted-by":"crossref","first-page":"250","DOI":"10.4065\/73.3.250","article-title":"The long QT syndrome: ion channel diseases of the heart","volume":"73","author":"Ackerman","year":"1998","journal-title":"Mayo Clin Proc"},{"key":"2023072918072807600_B2","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1038\/306436a0","article-title":"A reinterpretation of mammalian sodium channel gating based on single channel recording","volume":"306","author":"Aldrich","year":"1983","journal-title":"Nature"},{"key":"2023072918072807600_B3","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1523\/JNEUROSCI.13-02-00660.1993","article-title":"Modal gating of Na+ channels as a mechanism of persistent Na+current in pyramidal neurons from rat and cat sensorimotor cortex","volume":"13","author":"Alzheimer","year":"1993","journal-title":"J Neurosci"},{"key":"2023072918072807600_B4","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/0005-2736(76)90162-0","article-title":"Decreased rate of sodium conductance inactivation in the node of Ranvier induced by a polypeptide toxin from sea anemone","volume":"455","author":"Bergman","year":"1976","journal-title":"Biochim Biophys Acta"},{"key":"2023072918072807600_B5","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1113\/jphysiol.1989.sp017734","article-title":"Single sodium channels from canine ventricular myocytes: voltage dependence and 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(Lond)"},{"key":"2023072918072807600_B12","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/0014-5793(96)00273-6","article-title":"Sodium channel mRNA in the B104 neuroblastoma cell line","volume":"384","author":"Dib-Hajj","year":"1996","journal-title":"FEBS Lett"},{"key":"2023072918072807600_B13","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/0012-1606(91)90299-I","article-title":"Segregation of Na-channel gene expression during neuronal-glial branching of a rat PNS-derived stem cell line, RT4-AC","volume":"147","author":"Donahue","year":"1991","journal-title":"Dev Biol"},{"key":"2023072918072807600_B14","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1161\/01.RES.70.2.285","article-title":"Dose-dependent modulation of the cardiac sodium channel by sea anemone toxin ATXII","volume":"70","author":"El-Sherif","year":"1992","journal-title":"Circ Res"},{"key":"2023072918072807600_B15","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1152\/physrev.1996.76.3.887","article-title":"Structure and function of voltage-dependent sodium channels: comparison of brain II and cardiac isoforms","volume":"76","author":"Fozzard","year":"1996","journal-title":"Physiol Rev"},{"key":"2023072918072807600_B16","doi-asserted-by":"crossref","first-page":"2369","DOI":"10.1016\/S0006-3495(95)80106-2","article-title":"Sodium channel inactivation from closed states: evidence for an intrinsic voltage dependency","volume":"69","author":"Goldman","year":"1995","journal-title":"Biophys J"},{"key":"2023072918072807600_B17","doi-asserted-by":"crossref","first-page":"2836","DOI":"10.1523\/JNEUROSCI.04-11-02836.1984","article-title":"Voltage clamp analysis of sodium channels in normal and scorpion toxin\u2013resistant neuroblastoma cells","volume":"4","author":"Gonoi","year":"1984","journal-title":"J 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discrimination","volume":"34","author":"Khera","year":"1995","journal-title":"Biochemistry"},{"key":"2023072918072807600_B22","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1085\/jgp.93.1.67","article-title":"Modification of Na channel gating by an alpha scorpion toxin from Tityus serrulatus.","volume":"93","author":"Kirsch","year":"1989","journal-title":"J Gen Physiol"},{"key":"2023072918072807600_B23","first-page":"150","article-title":"Effect of scorpion venom on ionic currents in the node of Ranvier. 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cells","volume":"15","author":"Nagy","year":"1987","journal-title":"Eur Biophys J"},{"key":"2023072918072807600_B27","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/BF01871764","article-title":"Mechanism of inactivation of single sodium channels after modification by chloramine-T, sea anemone toxin and scorpion toxin","volume":"106","author":"Nagy","year":"1988","journal-title":"J Membr Biol"},{"key":"2023072918072807600_B28","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1126\/science.163.3868.680","article-title":"Condylactis toxin: interaction with nerve membrane ionic conductances","volume":"163","author":"Narahashi","year":"1969","journal-title":"Science"},{"key":"2023072918072807600_B29","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1085\/jgp.86.1.89","article-title":"Slow currents through single sodium channels of the adult rat heart","volume":"86","author":"Patlak","year":"1985","journal-title":"J Gen 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Pharmacol"},{"key":"2023072918072807600_B39","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1085\/jgp.86.5.739","article-title":"Kinetic analysis of the action of Leiurusalpha-toxin on ionic currents in myelinated nerve","volume":"86","author":"Wang","year":"1985","journal-title":"J Gen Physiol"},{"key":"2023072918072807600_B40","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1085\/jgp.81.3.305","article-title":"Effects of sea anemone toxins on the sodium inactivation process in crayfish axons","volume":"81","author":"Warashina","year":"1983","journal-title":"J Gen Physiol"},{"key":"2023072918072807600_B41","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/BF00375097","article-title":"Modification of cardiac Na+channels by Anthopleurin-A: effects on gating and kinetics","volume":"424","author":"Wasserstrom","year":"1993","journal-title":"Pfl\u00fcgers 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