Small conductance calcium-activated potassium current and the mechanism of atrial arrhythmia in mice with dysfunctional melanocyte-like cells

Wei Chung Tsai, Yi Hsin Chan, Chia Hsiang Hsueh, Thomas H. Everett, Po Cheng Chang, Eue Keun Choi, Michael A. Olaopa, Shien Fong Lin, Changyu Shen, Maria Aleksandra Kudela, Michael Rubart-Von Der Lohe, Zhenhui Chen, Pooja Jadiya, Dhanendra Tomar, Emily Luvison, Nicholas Anzalone, Vickas V. Patel, Peng Sheng Chen

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6 Scopus citations

Abstract

Background The melanin synthesis enzyme dopachrome tautomerase (Dct) regulates intracellular Ca2+ 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 Ca2+-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.

Original languageEnglish (US)
Pages (from-to)1527-1535
Number of pages9
JournalHeart Rhythm
Volume13
Issue number7
DOIs
StatePublished - Jul 1 2016

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Keywords

  • Apamin
  • Atrial fibrillation
  • Melanocyte-like cells
  • Optical mapping
  • SK channels

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Tsai, W. C., Chan, Y. H., Hsueh, C. H., Everett, T. H., Chang, P. C., Choi, E. K., Olaopa, M. A., Lin, S. F., Shen, C., Kudela, M. A., Rubart-Von Der Lohe, M., Chen, Z., Jadiya, P., Tomar, D., Luvison, E., Anzalone, N., Patel, V. V., & 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, 13(7), 1527-1535. https://doi.org/10.1016/j.hrthm.2016.03.011