Role of reticulocyte transport heterogeneity in the generation of mature sickle cells with different volumes.

Introduction and background The question we shall be addressing concerns the origin of dense sickle cell anaemia red cells (SS cells), a fraction of circulating cells rich in irreversibly sickled cells (ISCs), which are thought to play an important role in the pathophysiology of sickle cell disease. The question of their origin was traditionally formulated in terms of their presumed progressive dehydration, and research focused largely on the mechanisms by which sickling might cause the gradual dehydration of SS cells. Three mechanisms were considered: two triggered by sickling-induced membrane permeabilization and one by acidification of the cells. Those triggered by membrane permeabilization and by the consequent increases in cell [Ca2+], and in the [Na+],/[K+], ratio were the Ca2+-sensitive K+ channels and the Na+ pump respectively. Acid-triggered dehydration was via a K + :C1co-transporter [ l , 21; in all probability the same transporter originally characterized in rabbit and sheep reticulocytes [3-61. These mechanisms differ fundamentally in their ion transport capacity and consequently in the rate at which they may dehydrate cells. The Ca2+sensitive K' channels can dehydrate young and mature cells alike very rapidly if fully activated. There is sound but indirect evidence of activation of this pathway in vivo. Normal and SS red cells have endocytic vesicles capable of Ca' + accumulation if permeabilized to Ca2+ in vitro [7, 81, but only SS cells accumulate Ca2+ in vivo [9, 101. Ca2+ accumulation therefore documents episodes of Ca2+ permeabilization with transient [Ca2 + 1, elevations in vivo [7]. [Caz+], levels high enough to cause endocytic Ca2+ accumulation were also shown to activate K + channels and dehydrate normal cells [ l l ] , but the full extent to which these channels contribute to dehydration of SS cells in vivo remains unknown. The K+ :Clco-transporter is highly