The role of Membrane potential and calcium homeostasis in sickle erythrocyte sickling

Abstract

Sickle cell anaemia (SCA) is a genetic haemoglobin disorder characterised by the production of haemoglobin S (HbS) which polymerises on deoxygenation and causes sickling, dehydration, haemolysis and vaso-occlusion of erythrocytes. Polymerisation of HbS is the key event in sickling, but alterations in membrane potential and calcium homeostasis are important in regulating erythrocyte hydration and sickling evolution. Changes of ion transport occur in sickle erythrocytes with increased calcium permeability and activation of calcium sensitive potassium channels, especially the Gardos channel. Intracellular calcium increases lead to activation of potassium efflux, loss of chloride and water, hyperpolarisation of the membrane, and dehydration of the erythrocyte. This results in an increased intracellular concentration of HbS which favours polymer formation and speeds the transition from the normal biconcave erythrocyte to the sickled form. Mechanosensitive pathways like Piezo1 might be involved in calcium influx and activation of Gardos-mediated potassium loss during membrane deformation. These ionic abnormalities reduce the deformability of the erythrocytes, increase the fragility of the membrane and contribute to haemolysis and microvascular obstruction. Membrane potential, calcium homeostasis, ion-channel activity and cellular hydration interplay is thus important for insight into the pathophysiology of sickle cell anaemia. Therapeutic interventions aimed at ion transport pathways, particularly calcium-activated potassium channels and associated mechanisms, may reduce erythrocyte dehydration and the propensity for sickle cell polymerisation and sickling. This review addresses the relationship between membrane potential and calcium homeostasis in sickle erythrocyte sickling and discusses their potential importance in developing targeted treatments.