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J Biol Chem
2009 Nov 06;28445:31422-30. doi: 10.1074/jbc.M109.024489.
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Interaction of organic cations with organic anion transporters.
Ahn SY
,
Eraly SA
,
Tsigelny I
,
Nigam SK
.
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Studies of the organic anion transporters (Oats) have focused mainly on their interactions with organic anionic substrates. However, as suggested when Oat1 was originally identified as NKT (Lopez-Nieto, C. E., You, G., Bush, K. T., Barros, E. J., Beier, D. R., and Nigam, S. K. (1997) J. Biol. Chem. 272, 6471-6478), since the Oats share close homology with organic cation transporters (Octs), it is possible that Oats interact with cations as well. We now show that mouse Oat1 (mOat1) and mOat3 and, to a lesser degree, mOat6 bind a number of "prototypical" Oct substrates, including 1-methyl-4-phenylpyridinium. In addition to oocyte expression assays, we have tested binding of organic cations to Oat1 and Oat3 in ex vivo assays by analyzing interactions in kidney organ cultures deficient in Oat1 and Oat3. We also demonstrate that mOat3 transports organic cations such as 1-methyl-4-phenylpyridinium and cimetidine. A pharmacophore based on the binding affinities of the tested organic cations for Oat3 was generated. Using this pharmacophore, we screened a chemical library and were able to identify novel cationic compounds that bound to Oat1 and Oat3. These compounds bound Oat3 with an affinity higher than the highest affinity compounds in the original set of prototypical Oct substrates. Thus, whereas Oat1, Oat3, and Oat6 appear to function largely in organic anion transport, they also bind and transport some organic cations. These findings could be of clinical significance, since drugs and metabolites that under normal physiological conditions do not bind to the Oats may undergo changes in charge and become Oat substrates during pathologic conditions wherein significant variations in body fluid pH occur.
Ahn,
Toward a systems level understanding of organic anion and other multispecific drug transporters: a remote sensing and signaling hypothesis.
2009, Pubmed
Ahn,
Toward a systems level understanding of organic anion and other multispecific drug transporters: a remote sensing and signaling hypothesis.
2009,
Pubmed
Barnum,
Identification of common functional configurations among molecules.
1996,
Pubmed
Dantzler,
Verapamil and quinidine effects on PAH transport by isolated perfused renal tubules.
1984,
Pubmed
Eraly,
Decreased renal organic anion secretion and plasma accumulation of endogenous organic anions in OAT1 knock-out mice.
2006,
Pubmed
,
Xenbase
Jensen,
Epinephrine and norepinephrine enhance p-aminohippurate transport into basolateral membrane vesicles.
1988,
Pubmed
Kaler,
Structural variation governs substrate specificity for organic anion transporter (OAT) homologs. Potential remote sensing by OAT family members.
2007,
Pubmed
Kaler,
Olfactory mucosa-expressed organic anion transporter, Oat6, manifests high affinity interactions with odorant organic anions.
2006,
Pubmed
Karbach,
Localization of organic cation transporters OCT1 and OCT2 in rat kidney.
2000,
Pubmed
Koepsell,
Organic cation transporters.
2003,
Pubmed
Lopez-Nieto,
Molecular cloning and characterization of NKT, a gene product related to the organic cation transporter family that is almost exclusively expressed in the kidney.
1997,
Pubmed
,
Xenbase
Monte,
Identification of a novel murine organic anion transporter family member, OAT6, expressed in olfactory mucosa.
2004,
Pubmed
Motohashi,
Gene expression levels and immunolocalization of organic ion transporters in the human kidney.
2002,
Pubmed
Russell,
Relation of nicotine yield of cigarettes to blood nicotine concentrations in smokers.
1980,
Pubmed
Sokol,
Gentamicin and verapamil compete for a common transport mechanism in renal brush border membrane vesicles.
1989,
Pubmed
Sugawara-Yokoo,
Differential localization of organic cation transporters rOCT1 and rOCT2 in the basolateral membrane of rat kidney proximal tubules.
2000,
Pubmed
Sweet,
Expression cloning and characterization of ROAT1. The basolateral organic anion transporter in rat kidney.
1997,
Pubmed
,
Xenbase
Sweet,
Organic anion transporter 3 (Slc22a8) is a dicarboxylate exchanger indirectly coupled to the Na+ gradient.
2003,
Pubmed
,
Xenbase
Sweet,
Impaired organic anion transport in kidney and choroid plexus of organic anion transporter 3 (Oat3 (Slc22a8)) knockout mice.
2002,
Pubmed
,
Xenbase
Truong,
Multi-level analysis of organic anion transporters 1, 3, and 6 reveals major differences in structural determinants of antiviral discrimination.
2008,
Pubmed
,
Xenbase
Ullrich,
Bisubstrates: substances that interact with renal contraluminal organic anion and organic cation transport systems. I. Amines, piperidines, piperazines, azepines, pyridines, quinolines, imidazoles, thiazoles, guanidines and hydrazines.
1993,
Pubmed
Ullrich,
Bisubstrates: substances that interact with both, renal contraluminal organic anion and organic cation transport systems. II. Zwitterionic substrates: dipeptides, cephalosporins, quinolone-carboxylate gyrase inhibitors and phosphamide thiazine carboxylates; nonionizable substrates: steroid hormones and cyclophosphamides.
1993,
Pubmed
Vallon,
Overlapping in vitro and in vivo specificities of the organic anion transporters OAT1 and OAT3 for loop and thiazide diuretics.
2008,
Pubmed
,
Xenbase
Vallon,
Organic anion transporter 3 contributes to the regulation of blood pressure.
2008,
Pubmed
,
Xenbase
Wright,
Role of organic cation transporters in the renal handling of therapeutic agents and xenobiotics.
2005,
Pubmed
Wu,
Analysis of a large cluster of SLC22 transporter genes, including novel USTs, reveals species-specific amplification of subsets of family members.
2009,
Pubmed
