Cellular Ca2+signaling results from a complex interplay among a variety of Ca2+ fluxes going across the
plasma membrane and across the membranes of several organelles, together with the buffering effect of
large numbers of Ca2+-binding sites distributed along the cell architecture. Endoplasmic and sarcoplasmic
reticulum, mitochondria and even nucleus have all been involved in cellular Ca2+ signaling, and the
mechanisms for Ca2+ uptake and release from these organelles are well known. In neuroendocrine cells,
the secretory granules also constitute a very important Ca2+-storing organelle, and the possible role of
the stored Ca2+ as a trigger for secretion has attracted considerable attention. However, this possibility is
frequently overlooked, and the main reason for that is that there is still considerable uncertainty on the
main questions related with granular Ca2+ dynamics, e.g., the free granular [Ca2+], the physical state of
the stored Ca2+ or the mechanisms for Ca2+ accumulation and release from the granules. This review will
give a critical overview of the present state of knowledge and the main conflicting points on secretory
granule Ca2+ homeostasis in neuroendocrine cells.
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