TY - JOUR TI - A calcium transport mechanism for atrial fibrillation in Tbx5-mutant mice AU - Dai, Wenli AU - Laforest, Brigitte AU - Tyan, Leonid AU - Shen, Kaitlyn M AU - Nadadur, Rangarajan D AU - Alvarado, Francisco J AU - Mazurek, Stefan R AU - Lazarevic, Sonja AU - Gadek, Margaret AU - Wang, Yitang AU - Li, Ye AU - Valdivia, Hector H AU - Shen, Le AU - Broman, Michael T AU - Moskowitz, Ivan P AU - Weber, Christopher R A2 - Aldrich, Richard A2 - Lewis, Richard S A2 - Kass, Robert S A2 - Eisner, David VL - 8 PY - 2019 DA - 2019/03/21 SP - e41814 C1 - eLife 2019;8:e41814 DO - 10.7554/eLife.41814 UR - https://doi.org/10.7554/eLife.41814 AB - Risk for Atrial Fibrillation (AF), the most common human arrhythmia, has a major genetic component. The T-box transcription factor TBX5 influences human AF risk, and adult-specific Tbx5-mutant mice demonstrate spontaneous AF. We report that TBX5 is critical for cellular Ca2+ homeostasis, providing a molecular mechanism underlying the genetic implication of TBX5 in AF. We show that cardiomyocyte action potential (AP) abnormalities in Tbx5-deficient atrial cardiomyocytes are caused by a decreased sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA2)-mediated SR calcium uptake which was balanced by enhanced trans-sarcolemmal calcium fluxes (calcium current and sodium/calcium exchanger), providing mechanisms for triggered activity. The AP defects, cardiomyocyte ectopy, and AF caused by TBX5 deficiency were rescued by phospholamban removal, which normalized SERCA function. These results directly link transcriptional control of SERCA2 activity, depressed SR Ca2+ sequestration, enhanced trans-sarcolemmal calcium fluxes, and AF, establishing a mechanism underlying the genetic basis for a Ca2+-dependent pathway for AF risk. KW - atrial fibrillation KW - Tbx5 KW - SR calcium ATPase KW - calcium handling KW - sodium-calcium exchanger KW - triggered activity JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -