Fig. 1.

A schematic diagram summarising the main cation pathways involved in solute loss from red cells in patients with sickle cell disease (SCD). In deoxygenated red cells (right), HbS polymerises causing morphological sickling and activation of (i) P_sickle, a deoxygenation-induced cation conductance. Its main effect is to allow entry of Ca^2 + which activates a second transport pathway, (ii) the Ca^2 +-activated K⁺ channel or Gardos channel, which mediates conductive K⁺ loss at high rates. In oxygenated red cells (left), P_sickle and the Gardos channel are inactive. A third transport pathway, (iii) the KCl cotransporter (KCC) mediates obligatorily coupled efflux of K⁺ and Cl⁻. It is present at higher activities in HbS-containing red cells, compared to those from normal (HbAA) individuals. Activity is further enhanced by low pH, swelling and urea. KCC may remain active in deoxygenated sickle cells, with Mg^2 + loss via P_sickle, further increasing its activity. The relative importance of these pathways in red cells from HbSC and HbSS patients appears to differ which may be important in pathogenesis.