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Recent studies have focused on its effects on neuronal channels and its possible therapeutic uses in the nervous system. We characterized how ranolazine affects the brain sodium channel, <jats:styled-content style=\"fixed-case\">N<\/jats:styled-content>a<jats:sub>V<\/jats:sub>1.2, and how its actions are modulated by low <jats:styled-content style=\"fixed-case\">pH<\/jats:styled-content>. In this way, we further explore ranolazine's potential as an anticonvulsant and its efficacy in conditions like those during an ischaemic stroke.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>We performed whole\u2010cell patch\u2010clamp experiments on the voltage\u2010gated sodium channel, <jats:styled-content style=\"fixed-case\">N<\/jats:styled-content>a<jats:sub>V<\/jats:sub>1.2. Experiments were performed with extracellular solution titrated to either <jats:styled-content style=\"fixed-case\">pH<\/jats:styled-content>\u20097.4 or <jats:styled-content style=\"fixed-case\">pH<\/jats:styled-content>\u20096.0 before and after ranolazine perfusion.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Ranolazine accelerates onset and slows recovery of fast and slow inactivation. Ranolazine increases the maximum probability of use\u2010dependent inactivation and reduces macroscopic and ramp sodium currents at <jats:styled-content style=\"fixed-case\">pH<\/jats:styled-content>\u20097.4. <jats:styled-content style=\"fixed-case\">pH<\/jats:styled-content>\u20096.0 reduced the slowing of fast inactivation recovery and inhibited use\u2010dependent block by ranolazine. In the presence of ranolazine, the time constants of slow inactivation recovery and onset were significantly increased at <jats:styled-content style=\"fixed-case\">pH<\/jats:styled-content>\u20096.0 relative to <jats:styled-content style=\"fixed-case\">pH<\/jats:styled-content>\u20097.4 with 100 \u03bcM ranolazine.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Our work provides novel insights into the modulation of brain sodium channel, <jats:styled-content style=\"fixed-case\">N<\/jats:styled-content>a<jats:sub>V<\/jats:sub>1.2, by ranolazine. We demonstrate that ranolazine binds <jats:styled-content style=\"fixed-case\">N<\/jats:styled-content>a<jats:sub>V<\/jats:sub>1.2 in a state\u2010dependent manner, and that the effects of ranolazine are slowed but not abolished by protons. Our results suggest that further research performed on channels with epilepsy\u2010causing mutations may prove ranolazine to be an efficacious therapy.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.12150","type":"journal-article","created":{"date-parts":[[2013,3,8]],"date-time":"2013-03-08T13:20:31Z","timestamp":1362748831000},"page":"704-716","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Effects of the antianginal drug, ranolazine, on the brain sodium channel <scp>N<\/scp>a<sub>V<\/sub>1.2 and its modulation by extracellular protons"],"prefix":"10.1111","volume":"169","author":[{"given":"CH","family":"Peters","sequence":"first","affiliation":[{"name":"Molecular Cardiac Physiology Group Department of Biomedical Physiology and Kinesiology Simon Fraser University  Burnaby BC 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