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

Divalent calcium ion (Ca²⁺) 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 Ca²⁺ and other biogenic or abiogenic divalent cations for binding to Ca²⁺-signaling proteins or organic cofactors. We describe the competition between the two most abundant intracellular biogenic metal ions (Mg²⁺ and Ca²⁺) for Ca²⁺-binding sites in signaling proteins, followed by the rivalry between native Ca²⁺ and "therapeutic" Li⁺ as well as "toxic" Pb²⁺. 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.