Membrane Transport in Sickle Cell Disease

The Use of Radioisotopes to Characterise the Abnormal Permeability of Red Blood Cells from Sickle Cell Patients

“…To analyse red blood cell shape, aliquots of cells were placed in saline containing 0.3% glutaraldehyde before examination under light microscopy. Tonometry: Several of the transport systems found in red blood cells are O 2 -sensitive (Gibson et al, 2000;Gibson & Ellory, 2002). It is therefore important to regulate O 2 tension during incubation.…”

“…The deleterious effect on red blood cell rheology (Hebbel et al, 1980;Eaton & Hofrichter, 1987), together with altered nitric oxide scavenging by haemoglobin following intravascular haemolysis (Hebbel, 1991;Reiter et al, 2002;Gladwin et al, 2004;Kato et al, 2006) and also release of inflammatory cytokines , are thought to contribute to SCD complications. Our interest lies in the involvement in pathogenesis of the abnormal permeability of the red blood cell membrane in SCD patients (Joiner, 1993;Ellory et al, 1998;Gibson & Ellory, 2002;Lew & Bookchin, 2005).…”

“…Over the subsequent 50 years, the pathways responsible have been well investigated. We now know that three systems are particularly implicated (Joiner, 1993;Gibson & Ellory, 2002;Lew & Bookchin, 2005): the KCl cotransporter (KCC, likely a mix of isoforms KCC1 and KCC3; Crable et al, 2005), the Gardos channel (KCNN4, IK1; Ishii et al, 1997;Hoffman et al, 2003) and a deoxygenation-induced "cation" conductance (sometimes termed P sickle ; Joiner et al, 1988;Joiner et al, 1993;Lew et al, 1997 Lauf, 1984;3 Garay et al, 1988;4 Alvarez et al, 1992;5 Brugnara et al, 1993;6 Stocker et al, 2003;7 Wolff et al, 1988;8 Kaji, 1990;9 Reichstein & Rothstein, 1981;10 Ellory et al, 1992;11 Joiner, 1990;12 Ellory et al, 2007;13 Clark & Rossi, 1990;14 Joiner et al, 2001;15 Tiffert & Lew, 2001;16 Zhang et al, 2010;17 Sachs, 1980;18 Cantley et al, 1978;19 Russell, 2000;20 Bernhardt et al, 1987;21 Pedersen et al, 2007;22 Counillon et al, 1993;23 Masereel et al, 2003;24 Weiss et al, 2004;25 Halperin et al, 1989;26 Bennekou et al, 2004;27 Lang et al, 2003;28 Duranton et al, 2002;29 Feray & Garay, 1986;30 Feray & Garay, 1988;31 Gunther & Vormann, 1990. Table 1.…”

Leaky Cl − –HCO 3 − exchangers: cation fluxes via modified AE1

“…These include the effects of oxidation, peroxynitrite, the mercurial p-chloromercuriphenylsulphonic acid ( pCMBS), phenazinemethosulphate and radiation (Browning et al 2006). There are two other biological situations where a similar pathway occurs, namely malaria infection of red cells (Kirk 2001), and the channel called P sickle seen on deoxygenation of homozygous sickle red blood cells (Gibson & Ellory 2002). It is tempting to speculate that changes in AE1 in the membrane may be involved in the activation of these fluxes, and that this protein represents a common link in all these phenomena.…”

Effect of Phenazine Methosulphate on K⁺ Transport in Human red Cells

“…Furthermore, HbS-containing red cells contain lower levels of the major anti-oxidant reduced glutathione (GSH) [4]. An important feature of HbS-containing red cells is their raised cation permeability compared to HbA cells, especially when deoxygenated, which leads to solute loss 330 and cell shrinkage, elevating the concentration of HbS and thereby promoting HbS polymerisation and sickling [5,6]. It has been proposed that oxidant damage of HbScontaining red cells accounts partly for their unusual permeability [5,7].…”