Cardiac myocytes are subjected to fluid shear force (FSF) during each contraction and relaxation. Under pathological conditions, such as valve disease, heart failure and hypertension, FSF in cardiac chamber increases due to high blood volume and pressure. We have previously shown that FSF induces proarrhythmic longitudinal global Ca2+ waves and premature beat in rat atrial myocytes (Biophys J, 2014; 106 (2): 320a). In the present study, we further explored underlying cellular mechanisms for the FSF-induced longitudinal global Ca2+ waves and their effects on Ca2+ signaling in rat atrial myocytes. A FSF of ∼16 dyn/cm2 was applied onto entire single myocyte using pressurized fluid puffing. Confocal Ca2+ imaging was performed to measure local and global Ca2+ signals. Proarrhythmic longitudinal Ca2+ waves in atrial cells under FSF were resistant to the blockers for stretch-activated cation channel, Na+-Ca2+ exchange or Ca2+-activated cation channel (TRPM4), and to removal of external Ca2+. Interestingly, this FSF-induced atrial Ca2+ wave was eliminated by inositol 1,4,5-trisphosphate receptor (IP3R) blockers, tetracaine, or by phospholipase C inhibitor, and were absent in the type 2 IP3R (IP3R2) knockout cells. Furthermore, the FSF-induced atrial Ca2+ waves were suppressed by blockade of P2-purinergic receptors or by inhibition of gap junction that can secrete ATP. In field-stimulated cells, FSF immediately enlarged Ca2+ transients with larger increase in non-junctional Ca2+ release relative to junctional release. This FSF-induced enhancement in Ca2+ release was soon followed by significant reductions in Ca2+ transient and sarcoplasmic reticulum Ca2+ content. Our data suggest that IP3R2-mediated Ca2+ release, triggered by autocrine activation of P2-purinergic signaling, may generate proarrhythmic Ca2+ wave, thereby altering atrial Ca2+ signaling.