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

Abstract.

Ca²⁺ is a uniquely important messenger that penetrates into cells through gated channels to transmit signals to a large number of enzymes. The evolutionary 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 of 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 interaction with the targeted enzymes occurs. Soluble proteins such as calmodulin contribute to the buffering of cell Ca²⁺, but membrane intrinsic transporting proteins are more important. Ca²⁺ is transported across the plasma membrane (channel, a pump, a Na⁺/Ca²⁺ exchanger) and across the membrane of the organelles. The endoplasmic reticulum is the most dynamic store: it accumulates 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 reticulum, and senses microdomains of high Ca²⁺ close to IP₃ or cADPr release channels. The regulation of Ca²⁺ in the nucleus, where important Ca²⁺-sensitive processes reside, is a debated issue. Finally, if the control of cellular Ca²⁺ homeostasis somehow fails (excess penetration), mitochondria ‘buy time’ by precipitating inside Ca²⁺ and phosphate. If injury persists, Ca²⁺-death eventually ensues.