Fine-tuning of the activity of inositol 1,4,5-trisphosphate receptors (IPR) by a diverse array of regulatory inputs results in intracellular Ca signals with distinct characteristics. These events allow the activation of specific downstream effectors. We reported previously that region-specific proteolysis represents a novel regulatory event for type 1 IPR (R1). Specifically, caspase-fragmented R1 display a marked increase in single-channel open probability. More importantly, the distinct characteristics of the Ca signals elicited via fragmented R1 can activate alternate downstream effectors. In this report, we expand these studies to investigate whether all IPR subtypes are regulated by proteolysis. We now show that type 2 and type 3 IPR (R2 and R3, respectively) are proteolytically cleaved in rodent models of acute pancreatitis. Surprisingly, fragmented IPR retained tetrameric architecture, remained embedded in endoplasmic reticulum membranes and were not functionally disabled. Proteolysis was associated with a marked attenuation of the frequency of Ca signals in pancreatic lobules. Consistent with these data, expression of DNAs encoding complementary R2 and R3 peptides mimicking fragmented receptors at particular sites, resulted in a significant decrease in the frequency of agonist-stimulated Ca oscillations. Further, proteolysis of R2 resulted in a marked decrease in single-channel open probability. Taken together, proteolytic fragmentation modulates R2 and R3 activity in a region-specific manner, and this event may contribute to the altered Ca signals in pancreatic acinar cells during acute pancreatitis.