Ca 2+ signaling regulation plays an important role in triggering and/or maintaining atrial fibrillation (AF). Little is known about the relationship of the inositol-1, 4, 5-triphosphate receptors (InsP 3 Rs) and ryanodine receptors (RyRs) in left atrium to chronic AF. In this study, we investigated the expression and function of InsP 3 R 1, InsP 3 R 2 and RyR 2 in a chronic dog model of AF. AF was induced in 6 dogs by rapid right atrial pacing for 24 weeks, and a sham procedure was performed in 5 dogs (control group). The intact left atrial myocytes were used to examine the expression and function of InsP 3 Rs, RyRs by BODIPY O, R TR-X ryanodine, heparin-fluorescein conjugate, and were stimulated by caffeine, ATP to release Ca 2+ through RyRs, InsP 3 Rs separately. We also assessed the molecular components of left atrial tissue underlying the amount of RyR 2, InsP 3 R 1 and InsP 3 R 2 determined by RT-PCR, immunohistochemistry and Western blot analysis. In the chronic AF group, the Ca 2+ released through RyRs is not altered, but the Ca 2+ released through InsP 3 Rs increased significantly. RyR 2 distributed in cytosol of myocytes, cellular membrane; its expression significantly decreased in AF group compared to controls. InsP 3 R 1 distributed in cytosol, InsP 3 R 2 distributed not only in cytosol, cellular membrane, but also in nuclear envelope and intercalated discs. The InsP 3 R 1 and InsP 3 R 2 expression significantly increased in chronic AF group compared to controls. These results indicated that in a chronic dog model of AF, the expression and function of RyR 2 down-regulated; on the contrary, the expression and function of InsP 3 R 1, InsP 3 R 2 up-regulated, and InsP 3 R 2 may be the major InsP 3 Rs, which regulate intracellular or even intercellular Ca 2+ signal transmission.