Tsai, Wei-ChungChan, Yi-HsinHsueh, Chia-HsiangEverett, Thomas H., IVChang, Po-ChengChoi, Eue-KeunOlaopa, Michael A.Lin, Shien-FongShen, ChangyuKudela, Maria AleksandraRubart-von der Lohe, MichaelChen, ZhenhuiJadiya, PoojaTomar, DhanendraLuvison, EmilyAnzalone, NicholasAnzalone, NicholasPatel, Vickas V.Chen, Peng-Sheng2018-04-052018-04-052016-07Tsai, W.-C., Chan, Y.-H., Hsueh, C., Everett, T. H., Chang, P.-C., Choi, E.-K., … Chen, P.-S. (2016). Small Conductance Calcium Activated Potassium Current and the Mechanism of Atrial Arrhythmia in Mice with Dysfunctional Melanocyte-like Cells. Heart Rhythm : The Official Journal of the Heart Rhythm Society, 13(7), 1527–1535. http://doi.org/10.1016/j.hrthm.2016.03.011https://hdl.handle.net/1805/15767BACKGROUND: The melanin synthesis enzyme dopachrome tautomerase (Dct) regulates intracellular Ca(2+) in melanocytes. Homozygous Dct knockout (Dct(-/-)) adult mice are vulnerable to atrial arrhythmias (AA). OBJECTIVE: The purpose of this study was to determine whether apamin-sensitive small conductance Ca(2+)-activated K(+) (SK) currents are upregulated in Dct(-/-) mice and contribute to AA. METHODS: Optical mapping was used to study the membrane potential of the right atrium in Langendorff perfused Dct(-/-) (n = 9) and Dct(+/-) (n = 9) mice. RESULTS: Apamin prolonged action potential duration (APD) by 18.8 ms (95% confidence interval [CI] 13.4-24.1 ms) in Dct(-/-) mice and by 11.5 ms (95% CI 5.4-17.6 ms) in Dct(+/-) mice at a pacing cycle length of 150 ms (P = .047). The pacing cycle length threshold to induce APD alternans was 48 ms (95% CI 34-62 ms) for Dct(-/-) mice and 21 ms (95% CI 12-29 ms) for Dct(+/-) mice (P = .002) at baseline, and it was 35 ms (95% CI 21-49 ms) for Dct(-/-) mice and 22 ms (95% CI 11-32 ms) for Dct(+/-) mice (P = .025) after apamin administration. Apamin prolonged post-burst pacing APD by 8.9 ms (95% CI 3.9-14.0 ms) in Dct(-/-) mice and by 1.5 ms (95% CI 0.7-2.3 ms) in Dct(+/-) mice (P = .005). Immunoblot and quantitative polymerase chain reaction analyses showed that protein and transcripts levels of SK1 and SK3 were increased in the right atrium of Dct(-/-) mice. AA inducibility (89% vs 11%; P = .003) and duration (281 seconds vs 66 seconds; P = .008) were greater in Dct(-/-) mice than in Dct(+/-) mice at baseline, but not different (22% vs 11%; P = 1.00) after apamin administration. Five of 8 (63%) induced atrial fibrillation episodes in Dct(-/-) mice had focal drivers. CONCLUSION: Apamin-sensitive SK current upregulation in Dct(-/-) mice plays an important role in the mechanism of AA.en-USPublisher PolicyApaminAtrial fibrillationMelanocyte-like cellsOptical mappingSK channelsArticle