Calcium signalling: a historical account, recent developments and future perspectives

Ca2+ is a uniquely important messenger that penetrates into cells through g ated channels to transmit signals to a large number of enzymes. The evoluti onary choice of Ca2+ was dictated by its unusual chemical properties, which permit its reversible complexation by specific proteins in the presence of much larger amounts of other potentially competing cations. The decoding o f the Ca2+ signal consists in two conformational changes of the complexing proteins, of which calmodulin is the most important. The first occurs when Ca2+ is bound, the second (a collapse of the elongated protein) when intera ction with the targeted enzymes occurs. Soluble proteins such as calmodulin contribute to the buffering of cell Ca2+, but membrane intrinsic transport ing proteins are more important. Ca2+ is transported across the plasma memb rane (channel, a pump, a Na+/Ca2+ exchanger) and across the membrane of the organelles. The endoplasmic reticulum is the most dynamic store: it accumu lates Ca2+ by a pump, and releases it via channels gated by either inositol 1,4,5-trisphosphate (IP3) and cyclic adenosine diphosphate ribose (cADPr). The mitochondrion is more sluggish, but it is closed-connected with the re ticulum, and senses microdomains of high Ca2+ close to IF, or cADPr release channels. The regulation of Ca2+ in the nucleus, where important Ca2'-sens itive processes reside, is a debated issue. Finally, if the control of cell ular Ca2+ homeostasis somehow fails (excess penetration), mitochondria "buy time" by precipitating inside Ca2+ and phosphate. If injury persists, Ca2-death eventually ensues.