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Originally published In Press as doi:10.1194/jlr.M400220-JLR200 on July 16, 2004

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Journal of Lipid Research, Vol. 45, 1910-1918, October 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

P-glycoprotein retains function when reconstituted into a sphingolipid- and cholesterol-rich environment

Szabolcs Modok, Catherine Heyward and Richard Callaghan1

Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, United Kingdom

1 To whom correspondence should be addressed. e-mail: richard.callaghan{at}ndcls.ox.ac.uk

P-glycoprotein (P-gp) appears to be associated within specialized raftlike membrane microdomains. The activity of P-gp is sensitive to its lipid environment, and a functional association in raft microdomains will require that P-gp retains activity in the microenvironment. Purified hamster P-gp was reconstituted in liposomes comprising sphingomyelin and cholesterol, both highly enriched in membrane microdomains and known to impart a liquid-ordered phase to bilayers. The activity of P-gp was compared with that of proteoliposomes composed of crude egg phosphatidylcholine (unsaturated) or dipalmitoyl phosphatidylcholine (saturated) in the presence or absence of cholesterol. The maximal rate of ATP hydrolysis was not significantly altered by the nature of the lipid species. However, the potencies of nicardipine and XR9576 to modulate the ATPase activity of P-gp were increased in the sphingolipid-based proteoliposomes. The drug-P-gp interaction was investigated by measurement of the rates of [3H]XR9576 association and dissociation from the transporter. The lipid environment of P-gp did not affect these kinetic parameters of drug binding.

In summary, P-gp retains function in liquid-ordered cholesterol and sphingolipid model membranes in which the communication between the transmembrane and the nucleotide binding domains after drug binding to the protein is more efficient.

Supplementary key words membrane microdomain • lipid raft • liquid-ordered phase • ATP binding cassette transporter • drug binding


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