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.

Keywords: calcium; calcium ATPase; calcium channel; calcium signal; calcium transport; calcium-binding protein; calmodulin; magnesium.

FIGURE 1.

Top, properties of hydrated and un-hydrated Ca²⁺ and Mg²⁺. Bottom, Ca²⁺ and Mg²⁺ coordination to an EF protein motif (hypothetical comparison). The binding differences are determined by the chemical properties of the two metals described in Table 1, which explain the ease with which Ca²⁺ accepts binding sites of irregular geometry. Adapted from Ref. .

FIGURE 2.

Top, the EF-hand-binding motif, proposed by Kretsinger et al. (10) from the crystal structure of parvalbumin, can be represented by the forefinger (helix E) and the thumb (helix F), enclosing the Ca²⁺-binding loop, represented by the bent middle finger. Adapted from Ref. . Bottom left, C2b motif of synaptotagmin I (Protein Data Bank (PDB) file 1TJX). Bottom right, full-length annexin A1 (PDB file 1MCX), with repeats 1–4 in red, yellow, purple, and green, respectively. The calcium ions are depicted as orange spheres, and the residues involved in its coordination are shown as sticks. Adapted from Ref. .

FIGURE 3.

A, cryo-EM structure of the rabbit voltage-gated skeletal muscle Ca²⁺ channel Ca_v1.1 complex. Left, overall EM density map; right, structure. The pore-forming subunit a1, and the auxiliary subunits a2dm b and g, are shown in different colors. Atomic coordinates are in the PDB (accession code 3JBR) (from Ref. 39). VWA, von Willebrand factor type A domain; CTD, C-terminal domain. B, overall cryo-EM structure and domain organization of the rabbit skeletal muscle ryanodine receptor (RyR1) in complex with the modulator immunophilin FKBP12. The nine cytosolic domains of the receptor are shown in different colors; FKBP12 is in red. Atomic coordinates in the Protein Data Bank: accession code 3J8H (from Ref. 42).

FIGURE 4.

A graphic showing a general view of the mitochondrial MCU complex. The channel-forming MCU is a tetrameric 40-KDa protein (a 33-KDA MCUb protein incorporates into the tetrameric MCU channel, reducing its activity). Accessory proteins (MICUs, MCU receptor (MCUR), and essential MCU regulator (EMRE)) variously associated with the mitochondrial inner membrane regulate the gating and the activity of the MCU channel. Adapted from Ref. .