Membrane Potential and Ion Channel Dysfunction in Sickle Red Blood Cells

Abstract

Sickle cell disease (SCD) is a genetic blood disorder characterised by the presence of abnormal haemoglobin S (HbS) which polymerises in low oxygen conditions leading to red blood cell (RBC) sickling, dehydration, haemolysis and vaso-occlusion. Membrane potential and ion-channel activity are important in the maintenance of erythrocyte volume, hydration and membrane stability. In sickle red blood cells, ion transport abnormalities, including increased calcium influx and activation of the calcium dependent Gardos potassium channel, lead to excessive potassium (K+) efflux and subsequent water loss. Increased activity of the potassium chloride (K+ Cl-) cotransporter may further contribute to cellular dehydration. These modifications increase the intracellular HbS concentration thus improving HbS polymerisation and favouring repeated sickling. Ion-channel dysfunction also leads to reduced erythrocyte deformability, membrane damage and premature haemolysis. Knowledge of the relationship between membrane potential, ion-channel dysfunction, and erythrocyte dehydration provides important insight into the pathophysiology of sickle cell disease. Therapeutic approaches aimed at aberrant ion transport pathways, in particular the Gardos channel, may offer avenues for intervention to maintain RBC hydration and reduce sickling-related complications.