Calcium in Signaling: Its Specificity and Vulnerabilities toward Biogenic and Abiogenic Metal Ions.

Divalent calcium ion (Ca) plays an indispensable role as a second messenger in a myriad of signal transduction processes. Of utmost importance for the faultless functioning of calcium-modulated signaling proteins is their binding selectivity of the native metal cation over rival biogenic/abiogenic metal ion contenders in the intra/extracellular fluids. In this Perspective, we summarize recent findings on the competition between the cognate Ca and other biogenic or abiogenic divalent cations for binding to Ca-signaling proteins or organic cofactors. We describe the competition between the two most abundant intracellular biogenic metal ions (Mg and Ca) for Ca-binding sites in signaling proteins, followed by the rivalry between native Ca and "therapeutic" Li as well as "toxic" Pb. We delineate the key factors governing the rivalry between the native and non-native cations in proteins and highlight key implications for the biological performance of the respective proteins/organic cofactors.