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Blood, 1 April 2002, Vol. 99, No. 7, pp. 2578-2585
RED CELLS
Dehydration response of sickle cells to sickling-induced
Ca++ permeabilization
Virgilio L. Lew,
Zipora Etzion, and
Robert M. Bookchin
From the Physiological Laboratory, University of
Cambridge, United Kingdom; and Department of Medicine, Albert Einstein
College of Medicine, Bronx, NY.
Interaction of hemoglobin S polymers with the red blood cell (RBC)
membrane induces a reversible increase in permeability ("Psickle") to (at least) Na+,
K+, Ca2+, and Mg2+. Resulting
changes in [Ca2+] and [H+] in susceptible
cells activate 2 transporters involved in sickle cell dehydration, the
Ca2+-sensitive K+ ("Gardos") channel
(KCa) and the acid- and volume-sensitive K:Cl cotransport.
We investigated the distribution of Psickle expression among deoxygenated sickle cell anemia (SS) RBCs using new experimental designs in which the RBC Ca2+ pumps were partially
inhibited by vanadate, and the cells' dehydration rates were detected
as progressive changes in the profiles of osmotic fragility curves and
correlated with flow cytometric measurements. The results exposed
marked variations in (sickling plus Ca2+)-induced
dehydration rates within populations of deoxygenated SS cells, with
complex distributions, reflecting a broad heterogeneity of their
Psickle values. Psickle-mediated dehydration
was inhibited by clotrimazole, verifying the role of KCa,
and also by elevated [Ca2+]o, above 2 mM.
Very high Psickle values occurred with some SS discocytes,
which had a wide initial density (osmotic resistance) distribution.
Together with its previously shown stochastic nature, the irregular
distribution of Psickle documented here in discocytes is
consistent with a mechanism involving low-probability, reversible interactions between sickle polymers and membrane or cytoskeletal components, affecting only a fraction of the RBCs during each deoxygenation event and a small number of activated pathways per RBC. A
higher participation of SS reticulocytes in
Psickle-triggered dehydration suggests that they form these
pathways more efficiently than discocytes despite their lower cell
hemoglobin concentrations.
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