More than forty years ago, I showed that acetylcholine (ACh) evokes fast release of Ca2+ from intracellular stores in exocrine glands, delayed influx of Ca2+ from the extracellular solution and activation of Ca2+ extrusion (Nielsen & Petersen 1972). The now established basic elements of cellular Ca2+ homeostasis in electrically non-excitable cells, namely messenger-mediated opening of Ca2+ channels in intracellular stores, store-operated Ca2+ entry and Ca2+ pump – mediated extrusion of Ca2+ into the extracellular solution (Petersen & Tepikin 2008) were thus identified in the 1972 paper (Nielsen & Petersen 1972). The first measurements of the cytosolic Ca2+ concentration ([Ca2+]i) in exocrine gland cells were performed using the Ca2+-activated K+ channel as an intrinsic Ca2+ sensor. Combining results of single-channel current recordings in excised inside-out membrane patches, at different well-defined Ca2+ concentrations in solutions in contact with the membrane inside, with cell-attached single channel recordings from intact acinar cells in the resting state, as well as after stimulation, showed that resting [Ca2+]i was between 50 and 100 nM and that stimulation caused a significant rise in this level (Maruyama et al 1983). Later imaging studies, employing fluorescent Ca2+-sensitive dyes and patch clamp electrophysiology, showed that stimulation with physiologically relevant hormone concentrations did not evoke a sustained elevation of [Ca2+]i, but repetitive short-lasting spikes and that these were mostly confined to the apical granular part of the pancreatic acinar cells (see Petersen & Tepikin 2008). These local Ca2+ transients stimulated the exocytotic secretion process of digestive enzymes. Indeed every single Ca2+ transient evokes a transient exocytotic response (Petersen & Tepikin 2008). The continued generation of repetitive local Ca2+ signals, evoked by continuous stimulation with a physiological hormone level, relies on the Ca2+ tunnel function of the endoplasmic reticulum, the concentration of Ca2+ release channels in the apical granular area and the peri-granular mitochondrial belt, functioning as a Ca2+ firewall (see Petersen & Tepikin 2008). A sustained elevation of [Ca2+]i in the pancreatic acinar cells, evoked by hyperstimulation, only causes an initial transient secretory response but then, in contrast to what happens with physiological stimulation, activates intracellular proteases. This protease activation is initiated in the apical granular area and at the same time transformation of the normally electron-dense zymogen granules into empty looking vacuoles begins. Both intracellular protease activation and vacuolization can be prevented by intracellular Ca2+ chelation (Raraty et al 2000). These processes are characteristic of what happens in the human disease acute pancreatitis, which is mostly caused by alcohol abuse or gallstone complications. Surprisingly, we found that ethanol – even at extraordinarily high and unrealistic concentrations – had very little effect on Ca2+ homeostasis in intact pancreatic acinar cells, whereas fatty acid ethyl esters (FAEEs) – non-oxidative products of ethanol and long chain fatty acids – are very effective releasers of stored Ca2+ in pathophysiologically relevant concentrations (Gerasimenko et al 2009,2011). The surprisingly weak effect of ethanol itself is due to an intrinsic protective effect of calmodulin (CaM). In permeabilized acinar cells, ethanol – even at a modest concentration – did evoke significant Ca2+ release from internal stores, as well as trypsinogen activation, but these effects could be markedly suppressed by adding CaM to the external solution, which in these experiments was in direct contact with the cytosol (Gerasimenko et al 2011). Remarkably, a Ca2+-like peptide (CALP-3) completely suppressed trypsinogen activation induced even by a very high ethanol concentration (Gerasimenko et al 2011). Since the Ca2+ releasing effect of FAEEs is much stronger than that of ethanol alone, the mechanism of action has been explored in some detail. Knock-out of IP3 receptors of types 2 and 3 markedly reduced both the Ca2+ release and the trypsinogen activation induced by FAEEs to very low levels, indicating that most of the Ca2+ release occurs through the very same receptors that also serve normal stimulus-secretion coupling (Gerasimenko et al 2009). Under physiological conditions the IP3 receptor activation is moderate, whereas under pathological conditions maximal opening of these channels occurs, with the result that the stores are completely emptied. Overall, our results indicate that even a small, but sustained, rise in [Ca2+]i, while not in itself necessarily causing damage, sensitizes cells to noxious stimuli, for example oxidative stress, markedly increasing the risk for necrosis (Ferdek et al 2012).