Cellular signaling underlying atrial tachycardia remodeling of L-type calcium current

Atrial tachycardia (AT) downregulates L-type Ca current (ICaL) and causes atrial fibrillation-promoting electric remodeling. This study assessed potential underlying signal transduction. Cultured adult canine atrial cardiomyocytes were paced at 0, 1, or 3 Hz (P0, P1, P3) for up to 24 hours. Cellular tachypacing (P3) mimicked effects of in vivo AT: decreased ICaL and transient outward current (Ito), unchanged ICaT, IKr, and IKs, and reduced action potential duration (APD). ICaL was unchanged in P3 at 2 and 8 hours but decreased by 55±6% at 24 hours. Tachypacing caused Cai accumulation in P3 cells at 2 to 8 hours, but, by 24 hours, Cai returned to baseline. Cav1.2 mRNA expression was not altered at 2 hours but decreased significantly at 8 and 24 hours (32±4% and 48±4%, respectively) and protein expression was decreased (47±8%) at 24 hours only. Suppressing Cai increases during tachypacing with the ICaL blocker nimodipine or the Ca chelator BAPTA-AM prevented ICaL downregulation. Calcineurin activity increased in P3 at 2 and 8 hours, respectively, returning to baseline at 24 hours. Nuclear factor of activated T cells (NFAT) nuclear translocation was enhanced in P3 cells. Ca-dependent signaling was probed with inhibitors of Ca/calmodulin (W-7), calcineurin (FK-506), and NFAT (INCA6): each prevented ICaL downregulation. Significant APD reductions (30%) at 24 hours in P3 cells were prevented by nimodipine, BAPTA-AM, W-7, or FK-506. Thus, rapid atrial cardiomyocyte activation causes Ca loading, which activates the Ca-dependent calmodulin-calcineurin-NFAT system to cause transcriptional downregulation of ICaL, restoring Cai to normal at the cost of APD reduction. These studies elucidate for the first time the molecular feedback mechanisms underlying arrhythmogenic AT remodeling.