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Walsh Prostate Cancer Research Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100016737","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2022,2]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>Voltage\u2010gated sodium (Na<jats:sub>V<\/jats:sub>) channels are expressed de novo in carcinomas where their activity promotes invasiveness. Breast and colon cancer cells express the neonatal splice variant of Na<jats:sub>V<\/jats:sub>1.5 (nNa<jats:sub>V<\/jats:sub>1.5), which has several amino acid substitutions in the domain I voltage\u2010sensor compared with its adult counterpart (aNa<jats:sub>V<\/jats:sub>1.5). This study aimed to determine whether nNa<jats:sub>V<\/jats:sub>1.5 channels could be distinguished pharmacologically from aNa<jats:sub>V<\/jats:sub>1.5 channels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Cells expressing either nNa<jats:sub>V<\/jats:sub>1.5 or aNa<jats:sub>V<\/jats:sub>1.5 channels were exposed to low MW inhibitors, an antibody or natural toxins, and changes in electrophysiological parameters were measured. Stable expression in EBNA cells and transient expression in <jats:styled-content style=\"fixed-case\"><jats:italic>Xenopus laevis<\/jats:italic><\/jats:styled-content> oocytes were used. Currents were recorded by whole\u2010cell patch clamp and two\u2010electrode voltage\u2010clamp, respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Several clinically used blockers of Na<jats:sub>V<\/jats:sub> channels (lidocaine, procaine, phenytoin, mexiletine, ranolazine, and riluzole) could not distinguish between nNa<jats:sub>V<\/jats:sub>1.5 or aNa<jats:sub>V<\/jats:sub>1.5 channels. However, two tarantula toxins (HaTx and ProTx\u2010II) and a polyclonal antibody (NESOpAb) preferentially inhibited currents elicited by either nNa<jats:sub>V<\/jats:sub>1.5 or aNa<jats:sub>V<\/jats:sub>1.5 channels by binding to the spliced region of the channel. Furthermore, the amino acid residue at position 211 (aspartate in aNa<jats:sub>V<\/jats:sub>1.5\/lysine in nNa<jats:sub>V<\/jats:sub>1.5), that is, the charge reversal in the spliced region of the channel, played a key role in the selectivity, especially in antibody binding.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>We conclude that the cancer\u2010related nNa<jats:sub>V<\/jats:sub>1.5 channel can be distinguished pharmacologically from its nearest neighbour, aNa<jats:sub>V<\/jats:sub>1.5 channels. Thus, it may be possible to design low MW compounds as antimetastatic drugs for non\u2010toxic therapy of nNa<jats:sub>V<\/jats:sub>1.5\u2010expressing carcinomas.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15668","type":"journal-article","created":{"date-parts":[[2021,8,19]],"date-time":"2021-08-19T20:05:27Z","timestamp":1629403527000},"page":"473-486","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Neonatal Na<sub>V<\/sub>1.5 channels: pharmacological distinctiveness of a cancer\u2010related voltage\u2010gated sodium channel splice variant"],"prefix":"10.1111","volume":"179","author":[{"given":"Scott P.","family":"Fraser","sequence":"first","affiliation":[{"name":"Department of Life Sciences, Neuroscience Solutions to Cancer Research Group Imperial College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rustem","family":"Onkal","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, Neuroscience Solutions to Cancer Research Group Imperial College London  London UK"},{"name":"Biotechnology Research Centre Cyprus International University  Mersin 10 Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaux","family":"Theys","sequence":"additional","affiliation":[{"name":"Department of Basic and Applied Medical Sciences University of Ghent  Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Bosmans","sequence":"additional","affiliation":[{"name":"Department of Basic and Applied Medical Sciences University of Ghent  Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mustafa B. A.","family":"Djamgoz","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, Neuroscience Solutions to Cancer Research Group Imperial College London  London UK"},{"name":"Biotechnology Research Centre Cyprus International University  Mersin 10 Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,12,2]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201511492"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14752"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14749"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1080\/19336950.2019.1666455"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2009.12.046"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3940(02)01288-0"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/bja\/aeu104"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.81.5.613"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2013.09.012"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-021119-034627"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature07473"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10549-006-9281-1"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41391-019-0128-3"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.200809995"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201310998"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M801892200"},{"issue":"1","key":"e_1_2_12_18_1","first-page":"95","article-title":"Antitumor effects of lidocaine on human breast cancer cells: An in vitro and in vivo experimental trial","volume":"38","author":"Chamaraux\u2010Tran T. 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