Alkali metals easily lose one electron at the outer s-shell to form singly charged cations. Among these, the Na⁺ and K⁺ ions play the most important biological roles. Because of the weak and nonspecific nature of the interaction with other ligands, the biological significance is determined primarily by the magnitude of the concentrations. Similar chemical principles are applicable in a series of alkaline earth metal cations, except these are doubly positively charged. Moreover, the sizes become smaller, because the biologically important Mg^{2 +} (0.60 ) and Ca^{2 +} (1 ) ions correspond to Li⁺ (0.6 ) and Na⁺ (0.95 ) ions, respectively. These concentrations of the alkali and alkaline earth metal ions reflect those of seawater, and this coincidence evidences that the first life was born in archeological seawater. Therefore, the “physiological salt solution” employs concentrations in which Na⁺ > K⁺ > Mg^{2 +} > Ca^{2 +}. This order, however, shows a discrepancy from the one found in the earth's crust, where Ca, Na, K, and Mg occupy the fifth to the eighth elements in this order. The reason for this difference is that the Ca^{2 +} ion is selectively eliminated from solution by the tendency to form insoluble precipitates such as CaCO₃ or Ca₄(PO₄)₃. According to this tendency, CaCO₃ is accumulated in rocks, and Ca₄ (PO₄)₃ is an important component of bone and tooth in the biological systems.

Dominant alkali metal ions, Na⁺ and K⁺, are highly soluble in aqueous solution and are the most important components in maintaining the salt concentrations inside and outside the cell, necessary to keep homeostasis of biological cells. At the same time, their single charge is associated with relatively small solvation energies, 98.5 and 80.5 kcal mol^{- 1} for Na⁺ and K⁺ ions, respectively, reflecting the size difference on delocalizing the positive charges. These ions are most appropriately employed as messengers of biological signal transduction by mass (i.e., charge) transport across the membrane.1 Compared to these ions, Mg^{2 +} with two positive charges is constrained in a small atomic volume and must compensate by strong ion pairing with anionic counterparts of high charge densities. Phosphate anions are the most satisfactory as a pair component, and Mg - phosphates behave like molecules in many chemical events. The high solvation energy of the Mg^{2 +} ion (454 kcal mol^{- 1}) makes it difficult to use as the charge messenger of signal transduction.

The Ca^{2 +} ion possesses properties that are intermediate, and it is associated with various biologically important roles. It does not favor any specific coordination structure but still interacts strongly with ligands, especially with an oxygen anion, to alter the charged state and geometrical structure of the ligands, just as transition metal ions do. At the same time, the Ca^{2 +} ion can be transferred into the cell across the biological membrane, in spite of its high hydration energy (379 kcal mol^{- 1}), and plays a role as a second messenger in the cell. For example, acetylcholine is ejected into a synaptic crevasse triggered by the entry of a Ca^{2 +} ion. However, the presence of the Ca^{2 +} ion in the cell is hazardous because of its wide spectrum of actions and is eliminated from the inside cell and stored in endocellular cavities immediately after the completion of the specific role. When the Ca^{2 +} concentration is monitored by, e.g., Ca^{2 +}-specific sensors, a Ca^{2 +} wave can actually be observed. When this control system is destroyed, cells suffer fatal damage. For example, Alzheimer's and other related diseases are believed to induce such an uncontrolled entry of Ca^{2 +} ion and to cause fatal damage to nerve cells. The entry of the Ca^{2 +} ion was demonstrated by single channel measurements, and its close relationship with diseases was invoked.2