{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T19:23:01Z","timestamp":1790623381112,"version":"4.1.0"},"reference-count":56,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2021,4]]},"abstract":"\n Background:<\/jats:title>\n \n KCNMA1<\/jats:italic>\n encodes the \u03b1-subunit of the large-conductance Ca\n 2+<\/jats:sup>\n -activated K\n +<\/jats:sup>\n channel, K\n Ca<\/jats:sub>\n 1.1, and lies within a linkage interval for atrial fibrillation (AF). Insights into the cardiac functions of K\n Ca<\/jats:sub>\n 1.1 are limited, and\n KCNMA1<\/jats:italic>\n has not been investigated as an AF candidate gene.\n <\/jats:p>\n <\/jats:sec>\n \n Methods:<\/jats:title>\n \n The\n KCNMA1<\/jats:italic>\n gene was sequenced in 118 patients with familial AF. The role of K\n Ca<\/jats:sub>\n 1.1 in normal cardiac structure and function was evaluated in humans, mice, zebrafish, and fly. A novel\n KCNMA1<\/jats:italic>\n variant was functionally characterized.\n <\/jats:p>\n <\/jats:sec>\n \n Results:<\/jats:title>\n \n A complex\n KCNMA1<\/jats:italic>\n variant was identified in 1 kindred with AF. To evaluate potential disease mechanisms, we first evaluated the distribution of K\n Ca<\/jats:sub>\n 1.1 in normal hearts using immunostaining and immunogold electron microscopy. K\n Ca<\/jats:sub>\n 1.1 was seen throughout the atria and ventricles in humans and mice, with strong expression in the sinus node. In an ex vivo murine sinoatrial node preparation, addition of the K\n Ca<\/jats:sub>\n 1.1 antagonist, paxilline, blunted the increase in beating rate induced by adrenergic receptor stimulation. Knockdown of the K\n Ca<\/jats:sub>\n 1.1 ortholog,\n kcnma1b<\/jats:italic>\n , in zebrafish embryos resulted in sinus bradycardia with dilatation and reduced contraction of the atrium and ventricle. Genetic inactivation of the\n Drosophila<\/jats:italic>\n K\n Ca<\/jats:sub>\n 1.1 ortholog,\n slo<\/jats:italic>\n , systemically or in adult stages, also slowed the heartbeat and produced fibrillatory cardiac contractions. Electrophysiological characterization of\n slo<\/jats:italic>\n -deficient flies revealed bursts of action potentials, reflecting increased events of fibrillatory arrhythmias. Flies with cardiac-specific overexpression of the human\n KCNMA1<\/jats:italic>\n mutant also showed increased heart period and bursts of action potentials, similar to the K\n Ca<\/jats:sub>\n 1.1 loss-of-function models.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions:<\/jats:title>\n \n Our data point to a highly conserved role of K\n Ca<\/jats:sub>\n 1.1 in sinus node function in humans, mice, zebrafish, and fly and suggest that K\n Ca<\/jats:sub>\n 1.1 loss of function may predispose to AF.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1161\/circgen.120.003144","type":"journal-article","created":{"date-parts":[[2021,2,25]],"date-time":"2021-02-25T12:00:52Z","timestamp":1614254452000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":28,"title":["Conserved Role of the Large Conductance Calcium-Activated Potassium Channel, K\n Ca<\/sub>\n 1.1, in Sinus Node Function and Arrhythmia Risk"],"prefix":"10.1161","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7012-1156","authenticated-orcid":true,"given":"Santiago","family":"Pineda","sequence":"first","affiliation":[{"name":"Development, Aging & Regeneration Program, Sanford-Burnham Prebys Medical Discovery Institute, La Jolla, CA (S.P., S.K., K.B., R.B., G.V., K.O.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vesna","family":"Nikolova-Krstevski","sequence":"additional","affiliation":[{"name":"Victor Chang Cardiac Research Institute, Darlinghurst (V.N.-K., C.L., A.-K.A., C.D.C., A.J., I.G.H., M.S., M.O., G.T., R.J., R.P.H., A.P.H., D.F.)."},{"name":"Faculty of Medicine, UNSW Sydney, Kensington (V.N.-K., I.G.H., R.J., R.P.H., A.P.H., D.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7094-3045","authenticated-orcid":true,"given":"Christiana","family":"Leimena","sequence":"additional","affiliation":[{"name":"Victor Chang Cardiac Research Institute, Darlinghurst (V.N.-K., C.L., A.-K.A., C.D.C., A.J., I.G.H., M.S., M.O., G.T., R.J., R.P.H., A.P.H., D.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J.","family":"Atkinson","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Sciences, University of Manchester, United Kingdom (A.J.A., H.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0593-2785","authenticated-orcid":true,"given":"Ann-Kristin","family":"Altekoester","sequence":"additional","affiliation":[{"name":"Victor Chang Cardiac Research Institute, Darlinghurst (V.N.-K., C.L., A.-K.A., C.D.C., A.J., I.G.H., M.S., M.O., G.T., R.J., R.P.H., A.P.H., D.F.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles D.","family":"Cox","sequence":"additional","affiliation":[{"name":"Victor Chang Cardiac Research Institute, Darlinghurst (V.N.-K., C.L., A.-K.A., C.D.C., A.J., I.G.H., M.S., M.O., G.T., 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