{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T22:10:05Z","timestamp":1768515005273,"version":"3.49.0"},"reference-count":40,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,8,16]],"date-time":"2021-08-16T00:00:00Z","timestamp":1629072000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["APP108477"],"award-info":[{"award-number":["APP108477"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Cardiac ryanodine receptor (RyR2) mutations are implicated in the potentially fatal catecholaminergic polymorphic ventricular tachycardia (CPVT) and in atrial fibrillation. CPVT has been successfully treated with flecainide monotherapy, with occasional notable exceptions. Reported actions of flecainide on cardiac sodium currents from mice carrying the pro-arrhythmic homozygotic RyR2-P2328S mutation prompted our explorations of the effects of flecainide on their RyR2 channels. Lipid bilayer electrophysiology techniques demonstrated a novel, paradoxical increase in RyR2 activity. Preceding flecainide exposure, channels were mildly activated by 1 mM luminal Ca2+ and 1 \u00b5M cytoplasmic Ca2+, with open probabilities (Po) of 0.03 \u00b1 0.01 (wild type, WT) or 0.096 \u00b1 0.024 (P2328S). Open probability (Po) increased within 0.5 to 3 min of exposure to 0.5 to 5.0 \u00b5M cytoplasmic flecainide, then declined with higher concentrations of flecainide. There were no such increases in a subset of high Po channels with Po \u2265 0.08, although Po then declined with \u22655 \u00b5M (WT) or \u226550 \u00b5M flecainide (P2328S). On average, channels with Po &lt; 0.08 were significantly activated by 0.5 to 10 \u00b5M of flecainide (WT) or 0.5 to 50 \u00b5M of flecainide (P2328S). These results suggest that flecainide can bind to separate activation and inhibition sites on RyR2, with activation dominating in lower activity channels and inhibition dominating in more active channels.<\/jats:p>","DOI":"10.3390\/cells10082101","type":"journal-article","created":{"date-parts":[[2021,8,16]],"date-time":"2021-08-16T21:27:45Z","timestamp":1629149265000},"page":"2101","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Flecainide Paradoxically Activates Cardiac Ryanodine Receptor Channels under Low Activity Conditions: A Potential Pro-Arrhythmic Action"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5793-2349","authenticated-orcid":false,"given":"Samantha C.","family":"Salvage","sequence":"first","affiliation":[{"name":"Physiological Laboratory, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK"},{"name":"Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QW, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Esther M.","family":"Gallant","sequence":"additional","affiliation":[{"name":"Eccles Institute of Neuroscience, John Curtin School of Medical Research, The Australian National University, 131 Garran Road, Acton 2601, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6505-1883","authenticated-orcid":false,"given":"James A.","family":"Fraser","sequence":"additional","affiliation":[{"name":"Physiological Laboratory, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9553-6112","authenticated-orcid":false,"given":"Christopher L.-H.","family":"Huang","sequence":"additional","affiliation":[{"name":"Physiological Laboratory, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK"},{"name":"Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QW, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angela F.","family":"Dulhunty","sequence":"additional","affiliation":[{"name":"Eccles Institute of Neuroscience, John Curtin School of Medical Research, The Australian National University, 131 Garran Road, Acton 2601, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1038\/415198a","article-title":"Cardiac excitation-contraction coupling","volume":"415","author":"Bers","year":"2002","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3208","DOI":"10.1161\/01.CIR.0000132472.98675.EC","article-title":"Sudden Death in Familial Polymorphic Ventricular Tachycardia Associated With Calcium Release Channel (Ryanodine Receptor) Leak","volume":"109","author":"Lehnart","year":"2004","journal-title":"Circulation"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e77","DOI":"10.1161\/01.RES.0000169067.51055.72","article-title":"Bidirectional Ventricular Tachycardia and Fibrillation Elicited in a Knock-In Mouse Model Carrier of a Mutation in the Cardiac Ryanodine Receptor","volume":"96","author":"Cerrone","year":"2005","journal-title":"Circ. 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