Impaired Ca2+ homeostasis is associated with atrial fibrillation in the α1D L-type Ca2+ channel KO mouse

Salvatore Mancarella, Yuankun Yue, Eddy Karnabi, Yongxia Qu, Nabil El-Sherif, Mohamed Boutjdir

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

The novel α1D Ca2+ channel together with α1C Ca2+ channel contribute to the L-type Ca 2+ current (ICa-L) in the mouse supraventricular tissue. However, its functional role in the heart is just emerging. We used the α1D gene knockout (KO) mouse to investigate the electrophysiological features, the relative contribution of the α1D Ca2+ channel to the global ICa-L, the intracellular Ca2+ transient, the Ca2+ handling by the sarcoplasmic reticulum (SR), and the inducibility of atrial fibrillation (AF). In vivo and ex vivo ECG recordings from α1D KO mice demonstrated significant sinus bradycardia, atrioventricular block, and vulnerability to AF. The wild-type mice showed no ECG abnormalities and no AF. Patch-clamp recordings from isolated α1D KO atrial myocytes revealed a significant reduction of ICa-L (24.5%; P < 0.05). However, there were no changes in other currents such as INa, I Ca-T, IK, If, and Ito and no changes in α1C mRNA levels of α1D KO atria. Fura 2-loaded atrial myocytes showed reduced intracellular Ca2+ transient (∼40%; P < 0.05) and rapid caffeine application caused a 17% reduction of the SR Ca2+ content (P < 0.05) and a 28% reduction (P < 0.05) of fractional SR Ca2+ release in α1D KO atria. In conclusion, genetic deletion of α1D Ca2+ channel in mice results in atrial electrocardiographic abnormalities and AF vulnerability. The electrical abnormalities in the α1D KO mice were associated with a decrease in the total ICa-L density, a reduction in intracellular Ca2+ transient, and impaired intracellular Ca 2+ handling. These findings provide new insights into the mechanism leading to atrial electrical dysfunction in the α1D KO mice.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume295
Issue number5
DOIs
StatePublished - Nov 1 2008

Fingerprint

Knockout Mice
Atrial Fibrillation
Sarcoplasmic Reticulum
Homeostasis
Muscle Cells
Electrocardiography
Gene Knockout Techniques
Atrioventricular Block
Fura-2
Bradycardia
Caffeine
Messenger RNA

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Impaired Ca2+ homeostasis is associated with atrial fibrillation in the α1D L-type Ca2+ channel KO mouse. / Mancarella, Salvatore; Yue, Yuankun; Karnabi, Eddy; Qu, Yongxia; El-Sherif, Nabil; Boutjdir, Mohamed.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 295, No. 5, 01.11.2008.

Research output: Contribution to journalArticle

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abstract = "The novel α1D Ca2+ channel together with α1C Ca2+ channel contribute to the L-type Ca 2+ current (ICa-L) in the mouse supraventricular tissue. However, its functional role in the heart is just emerging. We used the α1D gene knockout (KO) mouse to investigate the electrophysiological features, the relative contribution of the α1D Ca2+ channel to the global ICa-L, the intracellular Ca2+ transient, the Ca2+ handling by the sarcoplasmic reticulum (SR), and the inducibility of atrial fibrillation (AF). In vivo and ex vivo ECG recordings from α1D KO mice demonstrated significant sinus bradycardia, atrioventricular block, and vulnerability to AF. The wild-type mice showed no ECG abnormalities and no AF. Patch-clamp recordings from isolated α1D KO atrial myocytes revealed a significant reduction of ICa-L (24.5{\%}; P < 0.05). However, there were no changes in other currents such as INa, I Ca-T, IK, If, and Ito and no changes in α1C mRNA levels of α1D KO atria. Fura 2-loaded atrial myocytes showed reduced intracellular Ca2+ transient (∼40{\%}; P < 0.05) and rapid caffeine application caused a 17{\%} reduction of the SR Ca2+ content (P < 0.05) and a 28{\%} reduction (P < 0.05) of fractional SR Ca2+ release in α1D KO atria. In conclusion, genetic deletion of α1D Ca2+ channel in mice results in atrial electrocardiographic abnormalities and AF vulnerability. The electrical abnormalities in the α1D KO mice were associated with a decrease in the total ICa-L density, a reduction in intracellular Ca2+ transient, and impaired intracellular Ca 2+ handling. These findings provide new insights into the mechanism leading to atrial electrical dysfunction in the α1D KO mice.",
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