Understanding the accumulation of P-glycoprotein substrates within cells: The effect of cholesterol on membrane partitioning

Subramanian, Nandhitha, Schumann-Gillett, Alexandra, Mark, Alan E. and O'Mara, Megan L. (2016) Understanding the accumulation of P-glycoprotein substrates within cells: The effect of cholesterol on membrane partitioning. Biochimica et Biophysica Acta: Biomembranes, 1858 4: 776-782. doi:10.1016/j.bbamem.2015.12.025


Author Subramanian, Nandhitha
Schumann-Gillett, Alexandra
Mark, Alan E.
O'Mara, Megan L.
Title Understanding the accumulation of P-glycoprotein substrates within cells: The effect of cholesterol on membrane partitioning
Journal name Biochimica et Biophysica Acta: Biomembranes   Check publisher's open access policy
ISSN 0005-2736
Publication date 2016-04
Year available 2015
Sub-type Article (original research)
DOI 10.1016/j.bbamem.2015.12.025
Open Access Status Not Open Access
Volume 1858
Issue 4
Start page 776
End page 782
Total pages 27
Place of publication Amsterdam, Netherlands
Publisher Elsevier
Collection year 2016
Language eng
Formatted abstract
The apparent activity of the multidrug transporter P-glycoprotein (P-gp) is enhanced by the presence of cholesterol. Whether this is due to the direct effect of cholesterol on the activity of P-gp, its effect on the local concentration of substrate in the membrane, or its effect on the rate of entry of the drug into the cell, is unknown. In this study, molecular dynamics simulation techniques coupled with potential of mean force calculations have been used to investigate the role of cholesterol in the movement of four P-gp substrates across a POPC bilayer in the presence or absence of 10% cholesterol. The simulations suggest that the presence of cholesterol lowers the free energy associated with entering the middle of the bilayer in a substrate-specific manner. These findings suggest that P-gp substrates may preferentially accumulate in cholesterol-rich regions of the membrane, which may explain its enhanced transport activity.
Keyword Cholesterol
Drug partitioning
Membrane composition
Multidrug resistance
P-glycoprotein
Potential of mean force
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
School of Chemistry and Molecular Biosciences
Institute for Molecular Bioscience - Publications
 
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Created: Fri, 15 Jan 2016, 11:51:19 EST by Mrs Louise Nimwegen on behalf of School of Chemistry & Molecular Biosciences