These include the K+–Cl− cotransporter (or KCC) and the Ca2+-activated K+ channel (or Gardos channel), transport systemswhose molecular identities are established. A third pathway, sometimes termed Psickle, is activated by HbS polymerisation
and RBC shape change. Psickle is thought to function predominantly as a deoxygenation-induced cation pathway. Although it remains enigmatic at a molecular level, Psickle will allow entry of Ca2+ , and loss of Mg2+, with subsequent activation of the Gardos channel and perhaps KCC. The three pathways interact to mediate solute loss, thereby concentrating HbS, which greatly reduces the lag time for polymerisation upon deoxygenation—hence increasing the likelihood of sickling and ischaemia in the microvasculature.