{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T02:10:11Z","timestamp":1747188611539,"version":"3.40.5"},"reference-count":53,"publisher":"Wiley","issue":"16","license":[{"start":{"date-parts":[[2024,7,19]],"date-time":"2024-07-19T00:00:00Z","timestamp":1721347200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2024,8]]},"abstract":"<jats:sec><jats:title>Abstract<\/jats:title><jats:p>The function of the chloride channel ClC\u20101 is crucial for the control of muscle excitability. Thus, reduction of ClC\u20101 functions by <jats:italic>CLCN1<\/jats:italic> mutations leads to myotonia congenita. Many different animal models have contributed to understanding the myotonia pathophysiology. However, these models do not allow <jats:italic>in vivo<\/jats:italic> screening of potentially therapeutic drugs, as the zebrafish model does. In this work, we identified and characterized the two zebrafish orthologues (<jats:italic>clc\u20101a<\/jats:italic> and <jats:italic>clc\u20101b<\/jats:italic>) of the ClC\u20101 channel. Both channels are mostly expressed in the skeletal muscle as revealed by RT\u2010PCR, western blot, and electrophysiological recordings of myotubes, and clc\u20101a is predominantly expressed in adult stages. Characterization in <jats:italic>Xenopus<\/jats:italic> oocytes shows that the zebrafish channels display similar anion selectivity and voltage dependence to their human counterparts. However, they show reduced sensitivity to the inhibitor 9\u2010anthracenecarboxylic acid (9\u2010AC), and acidic pH inverts the voltage dependence of activation. Reduction of <jats:italic>clc\u20101a\/b<\/jats:italic> expression hampers spontaneous and mechanically stimulated movement, which could be reverted by expression of human ClC\u20101 but not by some ClC\u20101 containing myotonia mutations. Treatment of <jats:italic>clc\u20101<\/jats:italic>\u2010depleted zebrafish with mexiletine, a typical drug used in human myotonia, improves the motor behaviour. Our work extends the repertoire of ClC channels to evolutionary structure\u2013function studies and proposes the zebrafish <jats:italic>clcn1<\/jats:italic> crispant model as a simple tool to find novel therapies for myotonia.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp16208-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>We have identified two orthologues of ClC\u20101 in zebrafish (clc\u20101a and clc\u20101b) which are mostly expressed in skeletal muscle at different developmental stages.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Functional characterization of the activity of these channels reveals many similitudes with their mammalian counterparts, although they are less sensitive to 9\u2010AC and acidic pH inverts their voltage dependence of gating.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Reduction of clc\u20101a\/b expression hampers spontaneous and mechanically stimulated movement which could be reverted by expression of human ClC\u20101.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Myotonia\u2010like symptoms caused by clc\u20101a\/b depletion can be reverted by mexiletine, suggesting that this model could be used to find novel therapies for myotonia.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp286530","type":"journal-article","created":{"date-parts":[[2024,7,19]],"date-time":"2024-07-19T16:44:35Z","timestamp":1721407475000},"page":"3975-3994","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Characterization of ClC\u20101 chloride channels in zebrafish: a new 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