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

Atrial tachycardia (AT) downregulates L-type Ca2+ 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 55 +/- 6% at 24 hours. Tachypacing caused Ca-i(2+) accumulation in P3 cells at 2 to 8 hours, but, by 24 hours, Ca-i(2+) returned to baseline. Ca(v)1.2 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 Ca-i(2+) increases during tachypacing with the I-CaL blocker nimodipine or the Ca2+ 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. Ca2+-dependent signaling was probed with inhibitors of Ca2+/calmodulin (W-7), calcineurin (FK-506), and NFAT (INCA6): each prevented I-CaL downregulation. Significant APD reductions (approximate to 30%) at 24 hours in P3 cells were prevented by nimodipine, BAPTA-AM, W-7, or FK-506. Thus, rapid atrial cardiomyocyte activation causes Ca2+ loading, which activates the Ca2+-dependent calmodulin -calcineurin -NFAT system to cause transcriptional downregulation of I-CaL, restoring Ca-i(2+) to normal at the cost of APD reduction. These studies elucidate for the first time the molecular feedback mechanisms underlying arrhythmogenic AT remodeling.