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The inhibition by NS\u20107 occurred in the presence of ouabain, an inhibitor of Na<jats:sup>+<\/jats:sup>,K<jats:sup>+<\/jats:sup> ATPase, but disappeared at higher concentration of veratridine, and upon the washout of NS\u20107.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>NS\u20107 attenuated veratridine\u2010induced <jats:sup>45<\/jats:sup>Ca<jats:sup>2+<\/jats:sup> influx <jats:italic>via<\/jats:italic> voltage\u2010dependent Ca<jats:sup>2+<\/jats:sup> channels (IC<jats:sub>50<\/jats:sub>=20.0\u2003\u03bc<jats:sc>M<\/jats:sc>) and catecholamine secretion (IC<jats:sub>50<\/jats:sub>=25.8\u2003\u03bc<jats:sc>M<\/jats:sc>).<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Chronic (12\u2003h) treatment of cells with NS\u20107 increased cell surface [<jats:sup>3<\/jats:sup>H]\u2010STX binding by 86% (EC<jats:sub>50<\/jats:sub>=10.5\u2003\u03bc<jats:sc>M<\/jats:sc>; <jats:italic>t<\/jats:italic><jats:sub>1\/2<\/jats:sub>=27\u2003h), but did not alter the <jats:italic>K<\/jats:italic><jats:sub><jats:italic>D<\/jats:italic><\/jats:sub> value; it was prevented by cycloheximide, an inhibitor of protein synthesis, or brefeldin A, an inhibitor of vesicular transport from the <jats:italic>trans<\/jats:italic>\u2010Golgi network, but was not associated with increased levels of Na<jats:sup>+<\/jats:sup> channel \u03b1\u2010 and \u03b2<jats:sub>1<\/jats:sub>\u2010subunit mRNAs.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>In cells subjected to chronic NS\u20107 treatment, <jats:sup>22<\/jats:sup>Na<jats:sup>+<\/jats:sup> influx caused by veratridine (site 2 toxin), \u03b1\u2010scorpion venom (site 3 toxin) or \u03b2\u2010scorpion venom (site 4 toxin) was suppressed even after the extensive washout of NS\u20107, and veratridine\u2010induced <jats:sup>22<\/jats:sup>Na<jats:sup>+<\/jats:sup> influx remained depressed even at higher concentration of veratridine; however, either \u03b1\u2010 or \u03b2\u2010scorpion venom, or Ptychodiscus brevis toxin\u20103 (site 5 toxin) enhanced veratridine\u2010induced <jats:sup>22<\/jats:sup>Na<jats:sup>+<\/jats:sup> influx as in nontreated cells.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>These results suggest that in the acute treatment, NS\u20107 binds to the site 2 and reversibly inhibits Na<jats:sup>+<\/jats:sup> channels, thereby reducing Ca<jats:sup>2+<\/jats:sup> channel gating and catecholamine secretion. Chronic treatment with NS\u20107 up\u2010regulates cell surface Na<jats:sup>+<\/jats:sup> channels <jats:italic>via<\/jats:italic> translational and externalization events, but persistently inhibits Na<jats:sup>+<\/jats:sup> channel gating without impairing the cooperative interaction between the functional domains of Na<jats:sup>+<\/jats:sup> channels.<\/jats:p><\/jats:list-item>\n<\/jats:list>\n<\/jats:p><jats:p><jats:italic>British Journal of Pharmacology<\/jats:italic> (2000) <jats:bold>131<\/jats:bold>, 779\u2013787; doi:<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1038\/sj.bjp.0703622\">10.1038\/sj.bjp.0703622<\/jats:ext-link><\/jats:p>","DOI":"10.1038\/sj.bjp.0703622","type":"journal-article","created":{"date-parts":[[2005,1,28]],"date-time":"2005-01-28T20:58:37Z","timestamp":1106945917000},"page":"779-787","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Short\u2010 and long\u2010term differential effects of neuroprotective drug NS\u20107 on voltage\u2010dependent sodium channels in adrenal chromaffin cells"],"prefix":"10.1111","volume":"131","author":[{"given":"Hiroki","family":"Yokoo","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seiji","family":"Shiraishi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hideyuki","family":"Kobayashi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshihiko","family":"Yanagita","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shin\u2010ichi","family":"Minami","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryuichi","family":"Yamamoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akihiko","family":"Wada","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2009,1,29]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.3.7.2565840"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1975.sp010810"},{"key":"e_1_2_7_4_1","doi-asserted-by":"crossref","first-page":"5528","DOI":"10.1016\/S0021-9258(17)33092-2","article-title":"Purification of a toxic protein from scorpion venom which activates the action potential Na+ ionophore","volume":"251","author":"CATTERALL W.A.","year":"1976","journal-title":"J. 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