Calcium in Red Blood Cells—A Perilous Balance

Ca(2+) is a universal signalling molecule involved in regulating cell cycle and fate, metabolism and structural integrity, motility and volume. Like other cells, red blood cells (RBCs) rely on Ca(2+) dependent signalling during differentiation from precursor cells. Intracellular Ca(2+) levels in the circulating human RBCs take part not only in controlling biophysical properties such as membrane composition, volume and rheological properties, but also physiological parameters such as metabolic activity, redox state and cell clearance. Extremely low basal permeability of the human RBC membrane to Ca(2+) and a powerful Ca(2+) pump maintains intracellular free Ca(2+) levels between 30 and 60 nM, whereas blood plasma Ca(2+) is approximately 1.8 mM. Thus, activation of Ca(2+) uptake has an impressive impact on multiple processes in the cells rendering Ca(2+) a master regulator in RBCs. Malfunction of Ca(2+) transporters in human RBCs leads to excessive accumulation of Ca(2+) within the cells. This is associated with a number of pathological states including sickle cell disease, thalassemia, phosphofructokinase deficiency and other forms of hereditary anaemia. Continuous progress in unravelling the molecular nature of Ca(2+) transport pathways allows harnessing Ca(2+) uptake, avoiding premature RBC clearance and thrombotic complications. This review summarizes our current knowledge of Ca(2+) signalling in RBCs emphasizing the importance of this inorganic cation in RBC function and survival.