Acute pancreatitis (AP) is a human disease characterised by inflammation and necrosis of pancreatic tissue. The most common causes of AP are excessive alcohol intake, gallstones and a fatty diet. The hallmark of AP is premature intracellular activation of digestive, resulting in the digestion of pancreatic tissues1,2. The premature activation of enzymes has been shown to be the result of elevated cytosolic Ca2+ concentration1,2. Pathophysiological Ca2+ signals are typically global, sustained increases in cytosolic Ca2+ and deplete Ca2+ stores. This sustained elevation of cytosolic results in intracellular activation of enzymes1,2. Pathological stimulation depletes the ER of Ca2+, this depletion is determined by a Ca2+ sensor located in the ER membrane, STIM12. STIM1 is activated by the depletion of ER Ca2+, it is coupled to Orai-1 located in the plasma membrane (PM). Orai-1 is a store-operated Ca2+ (SOC) channel activated via depletion of the ER, resulting in Ca2+ influx2. Store-operated Ca2+ entry (SOCE) serves to refill the depleted ER with Ca2+ in non-excitable cells. However, during pathological stimulation additional Ca2+ entering the cell will serve to further exacerbate already elevated cytosolic Ca2+ concentrations. SOCE, as such, is ideal to target in order to reduce cytosolic Ca2+. C57BL/6 mice were killed humanely in accordance with the UK Schedule 1 of the Animals (Scientific Procedures) Act, 1986. Pancreatic acinar cells were isolated as described previously3. Cytosolic Ca2+ measurements were made using intact cells loaded with the Ca2+-sensitive dye Fura-2 in AM form. Preliminary data, using inhibitory compounds of SOC channels, indicate a significant reduction in Ca2+ overload and therefore partial protection of necrosis in acinar cells treated with reported pancreatitis-inducing agents3,4. In addition to focusing on SOCE, there are other mechanisms that could serve to decrease Ca2+ overload, such as potentiation of the plasma membrane Ca2+-ATPase (PMCA) driving Ca2+ extrusion from the cell4 as well as reducing calcium release through the calmodulin regulation5. We have measured the rates of Ca2+ entry and extrusion under control and pathological conditions, and compared the potential benefits of interfering with different calcium signalling pathways. Targeting SOC channels and PMCA in order to reduce cytosolic Ca2+ overload could be an attractive strategy to reduce necrosis of pancreatic tissue.