Abstract-Atrial tachycardia (AT) downregulates L-type Ca 2ϩ current (I CaL ) 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 I CaL and transient outward current (I to ), unchanged I CaT , I Kr , and I Ks , and reduced action potential duration (APD). I CaL was unchanged in P3 at 2 and 8 hours but decreased by 55Ϯ6% at 24 hours. Tachypacing caused Ca 2ϩ i accumulation in P3 cells at 2 to 8 hours, but, by 24 hours, Ca 2ϩ i returned to baseline. Ca v 1.2 mRNA expression was not altered at 2 hours but decreased significantly at 8 and 24 hours (32Ϯ4% and 48Ϯ4%, respectively) and protein expression was decreased (47Ϯ8%) at 24 hours only. Suppressing Ca 2ϩ i increases during tachypacing with the I CaL blocker nimodipine or the Ca 2ϩ chelator BAPTA-AM prevented I CaL 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 2ϩ -dependent signaling was probed with inhibitors of Ca 2ϩ /calmodulin (W-7), calcineurin , and NFAT (INCA6): each prevented I CaL downregulation. Significant APD reductions (Ϸ30%) at 24 hours in P3 cells were prevented by nimodipine, BAPTA-AM, W-7, or FK-506. Thus, rapid atrial cardiomyocyte activation causes Ca 2ϩ loading, which activates the Ca 2ϩ -dependent calmodulin-calcineurin-NFAT system to cause transcriptional downregulation of I CaL , restoring Ca 2ϩ i to normal at the cost of APD reduction. These studies elucidate for the first time the molecular feedback mechanisms underlying arrhythmogenic AT remodeling. (Circ Res. 2008;103:845-854.)Key Words: atrial fibrillation Ⅲ electrophysiological remodeling Ⅲ arrhythmia mechanisms Ⅲ antiarrhythmic therapy A trial fibrillation (AF) is the most common clinical tachyarrhythmia, with an incidence that increases with age and a significant association with cardiovascular morbidity and mortality. 1 AF causes electrophysiological changes, primarily resulting from the rapid atrial activation rates, that promote arrhythmia perpetuation. 2,3 Atrial action potential (AP) duration (APD) shortening is a major contributor to refractoriness abbreviation, which is, in turn, a primary factor in AF promotion. 4,5 Loss of APD and impaired APD rate adaptation are largely attributable to the associated I CaL reduction. 4,6 Atrial remodeling is believed to have important therapeutic implications, and there is interest in developing antiremodeling therapies, 7 but this approach is limited by an insufficient understanding of underlying mechanisms to allow for the definition of molecular targets. There is indirect evidence for a role of Ca 2ϩ overload in the remodeling caused by atrial tachycardia (AT), 8,9 and transcriptional downregulation of the Ca v 1.2 I CaL ␣-subunit...