Interplay of Ca²⁺ and Mg²⁺ in Sodium-Calcium Exchanger and in Other Ca²⁺-Binding Proteins: Magnesium, Watchdog That Blocks Each Turn if Able

Abstract

Sodium-calcium exchange across plasma membrane is regulated by intracellular calcium ions. The sodium-calcium exchanger (NCX1) is activated by successive saturation of numerous Ca²⁺-binding sites located in the intracellular loop of the protein. The progressive saturation of the binding domain CBD12 by Ca²⁺ results in a series of conformational changes of CBD12 as well as of entire NCX1 molecule. Like other soluble and membrane Ca²⁺-binding proteins, NCX1 can also be regulated by Mg²⁺ that antagonises Ca²⁺ at the level of divalent cation-binding sites. This chapter summarises data on Mg²⁺ impacts in the cells. Regulatory action of Mg²⁺ on intracellular Ca²⁺-dependent processes can be achieved due to changes of its cytoplasmic level, which take place in the range of [Mg²⁺]_i from 0.5 to 3 mM. Under normal conditions, these changes are ensured by activation of plasmalemmal Mg²⁺ transport systems and by variations in ATP level in cytoplasm. In heart and in brain, some pathological conditions, such as hypoxia, ischemia and ischemia followed by reperfusion, are associated with an important increase in intracellular Ca²⁺. The tissue damage due to Ca²⁺ overload may be prevented by Mg²⁺. The protective actions of Mg²⁺ can be achieved due to its ability to compete with Ca²⁺ for the binding sites in a number of proteins responsible for the rise in intracellular free Ca²⁺, including NCX1, in case when the reverse mode of Na⁺/Ca²⁺ exchange becomes predominant. Saturation of CBD12 by Mg²⁺ results in important changes of NCX1 conformation. Modulating actions of Mg²⁺ on the conformation of NCX1 were detected at a narrow range of Mg²⁺ concentration, from 0.5 to 1 mM. These data support an idea that variations of intracellular Mg²⁺ could modify transmembrane Ca²⁺ movements ensured by NCX1.