Association between morphologic distortion of sickle cells and deoxygenation-induced cation permeability increase

Abstract

We hypothesized that the deoxygenation-induced increase in cation permeability of sickle cells was related to mechanical distention of the membrane by growing HbS polymer within the cell. To test this hypothesis, we determined the effect of deoxygenation on cation fluxes in sickle cells under conditions that restricted or permitted extensive growth of polymer, producing different degrees of membrane distention. Manipulation of suspending medium osmolality for density-isolated high and low mean cell hemoglobin concentration (MCHC) cells was used to regulate the extensional growth of polymer bundles and hence membrane distortion. For initially low MCHC cells, the deoxygenation-induced increase in both Na and K fluxes was markedly suppressed when the MCHC was increased by increasing the osmolality. This suppression corresponded to the inhibition of extensive morphologic cellular distortion. For initially high MCHC, ISC-rich cells, deoxygenation had minimal effect on K permeability. However, reduction of MCHC by a decrease in osmolality produced a concomitant increase in cation permeability and cellular distortion. These observations support the idea that the sickling-associated increase in membrane permeability is related to mechanical stress imposed on the membrane by bundles of HbS polymer.

Effects of 5‐hydroxymethyl‐2‐furfural on the volume and membrane permeability of red blood cells from patients with sickle cell disease

“…The non‐specific deoxygenation‐induced conductance termed P sickle is thought to be activated upon reduction of oxygen tension, HbS polymerization and morphological sickling (Mohandas et al . ). Consistent with this postulate, 5HMF reduced P sickle activity (Fig.…”

“…As its morphological effects on sickling led us to expect, 5HMF reduced activation of P sickle , a pathway thought to be activated by HbS polymerization and the sickling shape change (Mohandas et al . ). P sickle activity elevates intracellular Ca 2+ and depletes Mg 2+ (Ortiz et al .…”

The conductance of red blood cells from sickle cell patients: ion selectivity and inhibitors

“…Subsequent intracellular acidification following KCl loss represents a positive feedback path which may have considerable importance (Lew & Bookchin, 2005). P sickle remains ill-defined but is often referred to as a non-selective cation conductance activated by deoxygenation, HbS polymerisation and red cell shape change (Mohandas et al 1986;Joiner, 1993). An obvious question that has prompted considerable discussion is its molecular identity.…”

Rheological Consequences of Erythrocyte Dehydration

“…Sickle cells are depleted of K + and water (Tosteson et ul, 1952) and the consequential increase in cytoplasmic viscosity is a major factor contributing to loss of deformability (Clark et al, 1980;Gulley et al, 1982). Putative mechanisms of K + loss include distortion of the membrane by extended spicules of polymer (Mohandas et al 1986); reorganization of membrane phospholipid (Chiu et al, 1979;Lubin et al, 1981;Kuypers et al, 1987); a transient increase in cytoplasmic Ca2+ with loss of K+ via the Gardos channel (Bookchin et ul, 1986); membrane damage by oxidant radicals (Hebbel et al, 1982;Rice-Evans et al, 1986); and activation, by a fall in pH, of the KCI cotransport pathway in young cells (Canessa et al 1986). As a consequence of dehydration, sickle cells show considerable heterogeneity in density (Kaul et al, 1983;Rodgers et al, 1985).…”