Introduction: Store-operated calcium entry (SOCE) is implicated in many pathologies including acute pancreatitis (AP)1. Calcium-release activated calcium (CRAC) channels, composed of the endoplasmic reticulum (ER) Ca2+ sensor STIM-1 and the pore forming subunit Orai1 in the plasma membrane, are expressed in pancreatic acinar cells (PAC)2. During pathological stimulation by necrotising agents, such as fatty acid ethyl esters (FAEE) or bile acids, CRAC channels are activated by the depletion of ER Ca2+. Subsequent SOCE maintains sustained increase in [Ca2+]i3 – thought to be the trigger for premature, intracellular activation of digestive enzymes and the autodigestion of the pancreas, hallmarks of AP. Methods: C57BL/6 mice were killed humanely in accordance with the UK Schedule 1 of the Animals (Scientific Procedures) Act, 1986. [Ca2+]i measurements were made in PAC loaded with the Ca2+-sensitive dye, Fura-2. Results: In order to activate CRAC channels it was necessary to deplete ER store. Stores were depleted by the application of SERCA inhibitors thapsigargin or CPA in nominally Ca2+ free extracellular solution. Extracellular application of CRAC channel antagonists such as GSK7975-A (10µM)1, dramatically reduced [Ca2+]i when applied before the re-admission of Cao2+. When applied on top of a sustained increase in [Ca2+]i, due to the re-admission of Cao2+, acute application of GSK7975-A also reduces [Ca2+]i. Concurrently a reduction in cellular necrosis was also seen. Increases in [Ca2+]i usually induced by FAEE were markedly reduced too. 2-APB is known for its biphasic actions on SOCE4 – potently inhibitory at 100µM, whilst potentiating SOCE at 1-5µM. Analogues of 2-APB were generated: DPB162 and DPB163, and are more potent than 2-APB at inhibiting SOCE. Both analogues markedly inhibited SOCE in PAC (3µM), when applied before the re-admission of Cao2+ and when applied acutely on top of a sustained increase in [Ca2+]i. In addition to CRAC channels, PAC express TRPC3 – a Ca2+-permeable cation channel. Pyr10, a selective TRPC3 inhibitor, blocked SOCE when applied to PAC (10µM), however, GSK7975-A was more effective. Orai1 is reported to have a calmodulin (CaM) binding domain, thought to regulate its channel function5. CaM agonist, calcium-like peptide-3 (CALP-3), markedly inhibited SOCE when applied to PAC and reduced [Ca2+]i. Furthermore, when CaM itself was applied to cells there was a significant reduction in SOCE. Conclusion: Inhibition of SOCE, via entry channels such as CRAC and TRPC3 is an important target for reducing [Ca2+]i. Using a direct pharmacological approach or a more indirect method by modulating CaM has been effective in reducing SOCE and as such reducing [Ca2+]i. A combination of both methods could prove an efficient mechanism in acutely targeting cytosolic Ca2+ overload, reducing the intracellular activation of digestive enzyme and ameliorating AP.