Subtype-specific affinity for corticosterone of rat organic cation transporters rOCT1 and rOCT2 depends on three amino acids within the substrate binding region - PubMed (original) (raw)
Comparative Study
doi: 10.1124/mol.104.008821. Epub 2005 Jan 20.
Affiliations
- PMID: 15662045
- DOI: 10.1124/mol.104.008821
Comparative Study
Subtype-specific affinity for corticosterone of rat organic cation transporters rOCT1 and rOCT2 depends on three amino acids within the substrate binding region
Valentin Gorboulev et al. Mol Pharmacol. 2005 May.
Abstract
The affinity of corticosterone to organic cation transporters (OCTs) is subtype- and species-dependent. For example, the IC50 values for corticosterone inhibition of cation uptake by transporters rOCT1 and rOCT2 are approximately 150 and approximately 4 microM, respectively. By introducing domains and amino acids from rOCT2 into rOCT1, we found that the exchange of three amino acids in the presumed 10th transmembrane alpha helix is sufficient to increase the affinity of rOCT1 for corticosterone to that of rOCT2. Replacement of these amino acids in rOCT2 decreased the affinity for corticosterone. These amino acids (Ala443, Leu447, and Gln448 in rOCT1 and Ile443, Tyr447, and Glu448 in rOCT2) are probably located within the substrate binding region because in rOCT1 mutants, the K(m) values for uptake of tetraethylammonium (TEA) and 1-methyl-4-phenylpyridinium (MPP) were decreased in parallel with a decrease of the IC50 values for the inhibition of cation uptake by corticosterone. In mutant rOCT1(L447Y/Q448E), the IC50 value for the inhibition of [3H]MPP (0.1 microM) uptake by corticosterone (24 +/- 4 microM) was significantly higher compared with the IC50 value for inhibition of [14C]TEA (10 microM) uptake (5.3 +/- 1.7 microM). This finding suggests an allosteric interaction between transported cation and corticosterone. Because this substrate-specific effect cannot be explained by differential replacement of corticosterone by MPP versus TEA and was observed after point mutations within the presumed substrate region, the data suggest that MPP or TEA bind to the substrate binding region simultaneously with corticosterone and cause a short-range allosteric effect on the corticosterone binding site.
Comment in
- Polyspecific organic cation transport: insights into the substrate binding site.
Burckhardt G. Burckhardt G. Mol Pharmacol. 2005 May;67(5):1391-2. doi: 10.1124/mol.105.012161. Epub 2005 Feb 25. Mol Pharmacol. 2005. PMID: 15737954 Review.
Similar articles
- Five amino acids in the innermost cavity of the substrate binding cleft of organic cation transporter 1 interact with extracellular and intracellular corticosterone.
Volk C, Gorboulev V, Kotzsch A, Müller TD, Koepsell H. Volk C, et al. Mol Pharmacol. 2009 Aug;76(2):275-89. doi: 10.1124/mol.109.054783. Epub 2009 May 12. Mol Pharmacol. 2009. PMID: 19435783 - Amino acids critical for substrate affinity of rat organic cation transporter 1 line the substrate binding region in a model derived from the tertiary structure of lactose permease.
Popp C, Gorboulev V, Müller TD, Gorbunov D, Shatskaya N, Koepsell H. Popp C, et al. Mol Pharmacol. 2005 May;67(5):1600-11. doi: 10.1124/mol.104.008839. Epub 2005 Jan 20. Mol Pharmacol. 2005. PMID: 15662044 - Identification of cysteines in rat organic cation transporters rOCT1 (C322, C451) and rOCT2 (C451) critical for transport activity and substrate affinity.
Sturm A, Gorboulev V, Gorbunov D, Keller T, Volk C, Schmitt BM, Schlachtbauer P, Ciarimboli G, Koepsell H. Sturm A, et al. Am J Physiol Renal Physiol. 2007 Sep;293(3):F767-79. doi: 10.1152/ajprenal.00106.2007. Epub 2007 Jun 13. Am J Physiol Renal Physiol. 2007. PMID: 17567940 - Polyspecific organic cation transport: insights into the substrate binding site.
Burckhardt G. Burckhardt G. Mol Pharmacol. 2005 May;67(5):1391-2. doi: 10.1124/mol.105.012161. Epub 2005 Feb 25. Mol Pharmacol. 2005. PMID: 15737954 Review. - [Molecular diversity of organic cation transporter (OCT) mediating renal excretion of drugs].
Urakami Y. Urakami Y. Yakugaku Zasshi. 2002 Nov;122(11):957-65. doi: 10.1248/yakushi.122.957. Yakugaku Zasshi. 2002. PMID: 12440152 Review. Japanese.
Cited by
- Effect of pregnane X receptor ligands on transport mediated by human OATP1B1 and OATP1B3.
Gui C, Miao Y, Thompson L, Wahlgren B, Mock M, Stieger B, Hagenbuch B. Gui C, et al. Eur J Pharmacol. 2008 Apr 14;584(1):57-65. doi: 10.1016/j.ejphar.2008.01.042. Epub 2008 Feb 8. Eur J Pharmacol. 2008. PMID: 18321482 Free PMC article. - Substrate-dependent inhibition of human MATE1 by cationic ionic liquids.
Martínez-Guerrero LJ, Wright SH. Martínez-Guerrero LJ, et al. J Pharmacol Exp Ther. 2013 Sep;346(3):495-503. doi: 10.1124/jpet.113.204206. Epub 2013 Jun 19. J Pharmacol Exp Ther. 2013. PMID: 23785176 Free PMC article. - Neurobiological mechanisms that contribute to stress-related cocaine use.
Mantsch JR, Vranjkovic O, Twining RC, Gasser PJ, McReynolds JR, Blacktop JM. Mantsch JR, et al. Neuropharmacology. 2014 Jan;76 Pt B(0 0):383-94. doi: 10.1016/j.neuropharm.2013.07.021. Epub 2013 Aug 2. Neuropharmacology. 2014. PMID: 23916481 Free PMC article. Review. - A three-dimensional model of human organic anion transporter 1: aromatic amino acids required for substrate transport.
Perry JL, Dembla-Rajpal N, Hall LA, Pritchard JB. Perry JL, et al. J Biol Chem. 2006 Dec 8;281(49):38071-9. doi: 10.1074/jbc.M608834200. Epub 2006 Oct 11. J Biol Chem. 2006. PMID: 17038320 Free PMC article. - Organic cation transporter 3: A cellular mechanism underlying rapid, non-genomic glucocorticoid regulation of monoaminergic neurotransmission, physiology, and behavior.
Gasser PJ, Lowry CA. Gasser PJ, et al. Horm Behav. 2018 Aug;104:173-182. doi: 10.1016/j.yhbeh.2018.05.003. Epub 2018 May 10. Horm Behav. 2018. PMID: 29738736 Free PMC article. Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources