Relevance of conserved lysine and arginine residues in transmembrane helices for the transport activity of organic anion transporting polypeptide 1B3.

British Journal of Pharmacology
Hartmut GlaeserJörg König

Abstract

Organic anion transporting polypeptide 1B3 (OATP1B3) (SLCO1B3) mediates the uptake of endogenous substrates (e.g. estrone-3-sulphate) and drugs (e.g. pravastatin) from blood into hepatocytes. Structure-based modelling of OATP1B3 suggested that a pore with a positive electrostatic potential contributes to the transport mechanism. Therefore, we investigated the role of conserved positively charged amino acids for OATP1B3-mediated uptake of sulphobromophthalein (BSP) and pravastatin. Residues Lys28, Lys41 and Arg580 in OATP1B3 were substituted by alanine, arginine, glutamine, glycine or lysine. Using immunofluorescence, immunoblot analysis and cellular uptake assays, the effect of these mutations on protein expression and transport activity was investigated. Immunofluorescence revealed that all mutants were localized in the plasma membrane with partial intracellular retention of the Arg580>Ala and Arg580>Lys mutants. Lys41>Ala, Lys41>Gln, Lys41>Gly, Arg580>Gly and Arg580>Lys showed significantly reduced transport for BSP and pravastatin. Kinetic analyses of BSP transport revealed a significant reduction of V(max) normalized to cell surface protein expression for Lys41>Ala (wild type: 190 +/- 8, Lys41>Ala:16 +/- 4 pmol (mg protein)...Continue Reading

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Citations

Jan 25, 2013·Pharmacological Reviews·Patrick T Ronaldson, Thomas P Davis
Jun 21, 2014·Naunyn-Schmiedeberg's Archives of Pharmacology·Hartmut GlaeserKathrin Mandery
Mar 20, 2013·Molecular Aspects of Medicine·Bruno Hagenbuch, Bruno Stieger
Mar 8, 2012·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Kathrin ManderyHartmut Glaeser
Oct 22, 2011·British Journal of Pharmacology·Megan RothBruno Hagenbuch
Jun 1, 2017·Journal of Chemical Information and Modeling·Natalia KhuriKathleen M Giacomini
Nov 23, 2019·Endocrine Reviews·Stefan GroenewegW Edward Visser
Sep 27, 2019·Protein and Peptide Letters·Ruipu SunRen Lai
Jun 10, 2021·Journal of Chemical Information and Modeling·Alzbeta TuerkovaBarbara Zdrazil

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