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Title: Regulation and modification of Band 3 and related erythrocyte transport pathways in health and disease
Author: Robinson, Hannah Catherine
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2006
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Abstract:
Band 3, the most abundant erythrocyte membrane protein, mediates one-for-one· exchange of cr and HC03- playing a crucial role in COl carrying capacity of blood. Mutant variants of band 3 account for several hereditary haemolytic anaemias, including hereditary spherocytosis and stomatocytosis, where a single amino acid substitution alters anion and cation transport via band 3 ('Bruce-Stewart' erythrocytes). Altered band 3 function has also been implicated in the pathogenesis of sickle cell anaemia. In this study, band 3 has been investigated in healthy and diseased erythrocytes, with particular emphasis on regulation by oxygen. Bruce-Stewart erythrocytes showed a reduced radioisotopic flux of cr and sol- and reduced DIDS binding sites. It is concluded that band 3 in Bruce-Stewart erythrocytes is converted from an anion transporter into a cation channel unable to bind DIDS. In contrast, erythrocytes from patients with sickle cell anaemia (HbS erythrocytes), showed no alteration in band 3 expression or anion transport function. Band 3 anion exchange activity is oxygen sensitive in HbA and HbS erythrocytes, being greater at high POl. This response was maintained in pink ghosts prepared from HbA erythrocytes, whilst white ghosts and HbA erythrocytes pretreated with carbon monoxide or nitrite were oxygen insensitive. This supports the hypothesis that haemoglobin regulates the response of band 3 to oxygen, probably due to a membrane interaction rather than a bulk haemoglobin effect. Psickle, a cation pathway specific to deoxygenated HbS erythrocytes, may result from altered band 3 function but has hitherto not been detected in HbA cells. Various treatments of HbA erythrocytes, including chemical oxidation and addition of a purinergic agonist, have been shown here to increase erythrocyte cation conductance which are not oxygen sensitive, implying that they are distinct from Psickle, at least in their regulation. Finally it was shown that Psickle could be induced in pink ghosts but not in cells pretreated with carbon monoxide, implying that deoxygenated HbS is crucial for activation. In conclusion, band 3 anion exchange can be modulated by oxygen. In hereditary spherocytosis and stomatocytosis it can be converted into a cation channel. Furthermore, it may playa role in Psickle in HbS erythrocytes.
Supervisor: Not available Sponsor: Not available
Qualification Name: University of Oxford, 2006 Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.492044  DOI: Not available
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