{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T07:12:27Z","timestamp":1791616347843,"version":"4.3.4"},"reference-count":48,"publisher":"Wiley","issue":"18","license":[{"start":{"date-parts":[[2017,8,20]],"date-time":"2017-08-20T00:00:00Z","timestamp":1503187200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100011391","name":"Canadian Geriatrics Society","doi-asserted-by":"publisher","award":["CGSD3\u2010489113\u20102016"],"award-info":[{"award-number":["CGSD3\u2010489113\u20102016"]}],"id":[{"id":"10.13039\/100011391","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004326","name":"Simon Fraser University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004326","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2017,9,15]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>SCN5a mutations may express gain\u2010of\u2010function (Long QT Syndrome\u20103), loss\u2010of\u2010function (Brugada Syndrome 1) or both (mixed syndromes), depending on the mutation and environmental triggers. One such trigger may be an increase in cytosolic calcium, accompanying exercise.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Many mixed syndromes mutants, including \u2206KPQ, E1784K, 1795insD and Q1909R, are found in calcium\u2010sensitive regions.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Elevated cytosolic calcium attenuates gain\u2010of\u2010function properties in \u2206KPQ, 1795insD and Q1909R, but not in E1784K. By contrast, elevated cytosolic calcium further exacerbates gain\u2010of\u2010function in E1784K by destabilizing slow inactivation.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Action potential modelling, using a modified O'Hara Rudy model, suggests that elevated heart rate rescues action potential duration in \u2206KPQ, 1795insD and Q1909R, but not in E1784K.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Action potential simulations suggest that E1784K carriers have an increased intracellular sodium\u2010to\u2010calcium ratio under bradycardia and tachycardia conditions.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Elevated cytosolic calcium, which is common during high heart rates, ameliorates or exacerbates the mixed syndrome phenotype depending on the genetic signature.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Inherited arrhythmias may arise from mutations in the gene for SCN5a, which encodes the cardiac voltage\u2010gated sodium channel, Na<jats:sub>V<\/jats:sub>1.5. Mutants in Na<jats:sub>V<\/jats:sub>1.5 result in Brugada Syndrome (BrS1), Long\u2010QT Syndrome (LQT3) or mixed syndromes (an overlap of BrS1\/LQT3). Exercise is a potential arrhythmogenic trigger in mixed syndromes. We aimed to determine the effects of elevated cytosolic calcium, which is common during exercise, in mixed syndrome Na<jats:sub>V<\/jats:sub>1.5 mutants. We used whole\u2010cell patch clamp to assess the biophysical properties of Na<jats:sub>V<\/jats:sub>1.5 wild\u2010type (WT), \u2206KPQ, E1784K, 1795insD and Q1909R mutants in human embryonic kidney 293 cells transiently transfected with the Na<jats:sub>V<\/jats:sub>1.5 \u03b1 subunit (WT or mutants), \u03b21 subunit and enhanced green fluorescent protein. Voltage\u2010dependence and kinetics were measured at cytosolic calcium levels of approximately 0, 500\u00a0and 2500\u00a0n<jats:sc>m<\/jats:sc>. <jats:italic>In silico<\/jats:italic>, action potential (AP) model simulations were performed using a modified O'Hara Rudy model. Elevated cytosolic calcium attenuates the late sodium current in \u2206KPQ, 1795insD and Q1909R, but not in E1784K. Elevated cytosolic calcium restores steady\u2010state slow inactivation (SSSI) to the WT\u2010form in Q1909R, but depolarized SSSI in E1784K. Our AP simulations showed a frequency\u2010dependent reduction of AP duration in \u2206KPQ, 1795insD and Q1909R carriers. In E1784K, AP duration is relatively prolonged at both low and high heart rates, resulting in a sodium overload. Cellular perturbations during exercise may affect BrS1\/LQT3 patients differently depending on their individual genetic signature. Thus, exercise may be therapeutic or may be an arrhythmogenic trigger in some SCN5a patients.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp274536","type":"journal-article","created":{"date-parts":[[2017,7,22]],"date-time":"2017-07-22T10:22:37Z","timestamp":1500718957000},"page":"6165-6186","source":"Crossref","is-referenced-by-count":18,"title":["Differential calcium sensitivity in Na<sub>V<\/sub>1.5 mixed syndrome mutants"],"prefix":"10.1113","volume":"595","author":[{"given":"Mena","family":"Abdelsayed","sequence":"first","affiliation":[{"name":"Department of Biomedical Physiology and Kinesiology Simon Fraser University  Burnaby Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alban\u2010Elouen","family":"Baruteau","sequence":"additional","affiliation":[{"name":"LIRYC Institute, Division of Pediatric Cardiology, Haut\u2010L\u00e9v\u00e8que Hospital Bordeaux University  Bordeaux 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