Why Calcium? How Calcium Became the Best Communicator

Abstract

Calcium carries messages to virtually all important functions of cells. Although it was already active in unicellular organisms, its role became universally important after the transition to multicellular life. In this Minireview, we explore how calcium ended up in this privileged position. Most likely its unique coordination chemistry was a decisive factor as it makes its binding by complex molecules particularly easy even in the presence of large excesses of other cations, e.g. magnesium. Its free concentration within cells can thus be maintained at the very low levels demanded by the signaling function. A large cadre of proteins has evolved to bind or transport calcium. They all contribute to buffer it within cells, but a number of them also decode its message for the benefit of the target. The most important of these "calcium sensors" are the EF-hand proteins. Calcium is an ambivalent messenger. Although essential to the correct functioning of cell processes, if not carefully controlled spatially and temporally within cells, it generates variously severe cell dysfunctions, and even cell death.At the beginning, life on earth consisted of single cells that were capable of carrying out all vital functions. The interplay with other cells was largely limited to the competition for nutrients. Unicellularity was clearly successful, as shown by the fact that unicellular organisms are actually still predominant today. Nevertheless, at a time which was generally estimated to be at 600 -700 million years ago, but which is now being pushed back to more than 2 billion years ago (1, 2), competition was replaced by cooperation, and multicellular life evolved. It had somehow become advantageous for cells to work together rather than to live alone. Cells became gradually organized into structures in which they learned to perform different tasks and to cooperate in the division of labor. Cooperation naturally demanded the communication of cells with each other, i.e. it demanded the development of agents that could exchange messages between cells. As the complexity of the multicellular organization increased, so did the number of cells with distinct functional tasks. The number of intercellular signaling molecules and the degree of their complexity increased in parallel. A basic tenet of life is regulation. Thus, all vital functions within the cells are regulated. Indeed, they are also regulated in unicellular organisms. However, the transition to multicellular life brought with it the intercellular exchange of messages as an additional, and essential, regulation category.Calcium, the third most abundant metal in nature, was amply available to cells from the beginning, and was adopted as a regulator at an early evolutionary stage. The basic principles of calcium regulation were already present in prokaryotes and protists (3, 4), but calcium regulation gradually grew to cover nearly all aspects of cell function after the transition to multicellularity. Naturally, agents that carry messages to intracellular targets must be maint...

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