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

Research output: Contribution to journalArticle

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Abstract

Background 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.

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

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Melanocytes
Cardiac Arrhythmias
Potassium
Calcium
Apamin
Confidence Intervals
dopachrome isomerase
Action Potentials
Heart Atria
Melanins

Keywords

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

Cite this

Tsai, Wei Chung ; Chan, Yi Hsin ; Hsueh, Chia Hsiang ; Everett, Thomas H. ; Chang, Po Cheng ; Choi, Eue Keun ; Olaopa, Michael A. ; Lin, Shien Fong ; Shen, Changyu ; Kudela, Maria Aleksandra ; Rubart-Von Der Lohe, Michael ; Chen, Zhenhui ; Jadiya, Pooja ; Tomar, Dhanendra ; Luvison, Emily ; Anzalone, Nicholas ; Patel, Vickas V. ; Chen, Peng Sheng. / Small conductance calcium-activated potassium current and the mechanism of atrial arrhythmia in mice with dysfunctional melanocyte-like cells. In: Heart Rhythm. 2016 ; Vol. 13, No. 7. pp. 1527-1535.
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title = "Small conductance calcium-activated potassium current and the mechanism of atrial arrhythmia in mice with dysfunctional melanocyte-like cells",
abstract = "Background 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.",
keywords = "Apamin, Atrial fibrillation, Melanocyte-like cells, Optical mapping, SK channels",
author = "Tsai, {Wei Chung} and Chan, {Yi Hsin} and Hsueh, {Chia Hsiang} and Everett, {Thomas H.} and Chang, {Po Cheng} and Choi, {Eue Keun} and Olaopa, {Michael A.} and Lin, {Shien Fong} and Changyu Shen and Kudela, {Maria Aleksandra} and {Rubart-Von Der Lohe}, Michael and Zhenhui Chen and Pooja Jadiya and Dhanendra Tomar and Emily Luvison and Nicholas Anzalone and Patel, {Vickas V.} and Chen, {Peng Sheng}",
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Tsai, WC, Chan, YH, Hsueh, CH, Everett, TH, Chang, PC, Choi, EK, Olaopa, MA, Lin, SF, Shen, C, Kudela, MA, Rubart-Von Der Lohe, M, Chen, Z, Jadiya, P, Tomar, D, Luvison, E, Anzalone, N, Patel, VV & Chen, PS 2016, 'Small conductance calcium-activated potassium current and the mechanism of atrial arrhythmia in mice with dysfunctional melanocyte-like cells', Heart Rhythm, vol. 13, no. 7, pp. 1527-1535. https://doi.org/10.1016/j.hrthm.2016.03.011

Small conductance calcium-activated potassium current and the mechanism of atrial arrhythmia in mice with dysfunctional melanocyte-like cells. / Tsai, Wei Chung; Chan, Yi Hsin; Hsueh, Chia Hsiang; Everett, Thomas H.; Chang, Po Cheng; Choi, Eue Keun; Olaopa, Michael A.; Lin, Shien Fong; Shen, Changyu; Kudela, Maria Aleksandra; Rubart-Von Der Lohe, Michael; Chen, Zhenhui; Jadiya, Pooja; Tomar, Dhanendra; Luvison, Emily; Anzalone, Nicholas; Patel, Vickas V.; Chen, Peng Sheng.

In: Heart Rhythm, Vol. 13, No. 7, 01.07.2016, p. 1527-1535.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Small conductance calcium-activated potassium current and the mechanism of atrial arrhythmia in mice with dysfunctional melanocyte-like cells

AU - Tsai, Wei Chung

AU - Chan, Yi Hsin

AU - Hsueh, Chia Hsiang

AU - Everett, Thomas H.

AU - Chang, Po Cheng

AU - Choi, Eue Keun

AU - Olaopa, Michael A.

AU - Lin, Shien Fong

AU - Shen, Changyu

AU - Kudela, Maria Aleksandra

AU - Rubart-Von Der Lohe, Michael

AU - Chen, Zhenhui

AU - Jadiya, Pooja

AU - Tomar, Dhanendra

AU - Luvison, Emily

AU - Anzalone, Nicholas

AU - Patel, Vickas V.

AU - Chen, Peng Sheng

PY - 2016/7/1

Y1 - 2016/7/1

N2 - Background 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.

AB - Background 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.

KW - Apamin

KW - Atrial fibrillation

KW - Melanocyte-like cells

KW - Optical mapping

KW - SK channels

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DO - 10.1016/j.hrthm.2016.03.011

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