Background: During atrial fibrillation (AF) the atrial activation rate is chronically increased 5-7fold. Unstable intracellular Ca2+ signaling (i.e. increased Ca2+-sparks and -waves), another characteristic of AF, is thought to contribute to AF perpetuation through cellular arrhythmogenic mechanisms like delayed afterdepolarizations. Also, failure of centripetal Ca2+ wave propagation might contribute to loss of atrial contractility and changes in Ca2+ dependent signaling in the nucleus. We therefore characterized Ca2+ signaling in atrial myocytes of patients with AF and in rabbits undergoing rapid atrial pacing. Methods and Results: In atrial myocytes of rabbits undergoing rapid atrial pacing (RAP; 10 Hz, 5 days) global and central-cellular Ca2+ transients (CaTs) were reduced, while subsarcolemmal CaTs were unaltered. No change in the low abundance of t-tubules was found. However, fast [Ca2+]i buffering capacity (CaBC) was increased by 180% which included troponin buffering, an increase in sarcoplasmic reticulum (SR) Ca2+ uptake and an increase in calmodulin protein expression (90%). However, SR Ca2+ load and Ca2+ spark and wave frequencies were unchanged as was Ca2+ spark-mediated Ca2+ leak. RAP did also lead to a decrease in ryanodine receptor (RyR2) expression (77%) but with an increase in RyR2 phosphorylation (7fold). Nuclear Ca2+ transient amplitude was also significantly decreased in RAP cells. 10 minutes perfusion with 10M L-Phenylephrine elevated both nuclear Ca2+ and perinuclear Ca2+ release in RAP but not in sham myocytes. Failure of centripetal Ca2+ wave propagation and unaltered t-tubular system (low abundance) were confirmed in atrial myocytes of patients with AF. Conclusion: During tachycardia-induced atrial remodeling Ca2+ signaling silencing in the central region of atrial myocytes occurs. This adaptive response to rapid myocyte activation counteracts intracellular Ca2+ overload in AF and hampers the development of Ca2+ dysregulation-based arrhythmogenic mechanisms. The results also suggest downregulation of nuclear Ca2+ signalling during RAP, but enhanced IP3-dependent regulation of the nuclear Ca2+ transients. This may contribute to Ca2+-mediated and IP3-dependent alterations of gene transcription in tachycardia-induced remodelling.