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The Human Organic Cation Transporter (hOCT2) Recognizes the Degree of Substrate Ionization

The Human Organic Cation Transporter (hOCT2) Recognizes the Degree of Substrate Ionization

Authors :
Wendy M. Barendt
Stephen H. Wright
Source :
Journal of Biological Chemistry. 277:22491-22496
Publication Year :
2002
Publisher :
Elsevier BV, 2002.

Abstract

The organic cation transporter, OCT2, plays a role in renal secretion of a broad array of weak bases. To determine whether the degree of ionization of these compounds plays a role in their interaction with OCT2, we examined the influence of external pH values on the activity of the human ortholog of OCT2, as expressed in Chinese hamster ovary-K1 cells. Importantly, changing the pH value from 7.0 to 8.0 had no effect on the rate of transport of the fixed cations, tetraethylammonium and 1-methyl-4-phenylpyridinium, i.e. the pH value did not have an effect upon the transporter itself. Cimetidine (pK(a) 6.92), a competitive inhibitor of hOCT2, displayed a 3.5-fold increase in IC(50) as pH values increased from 7 to 8. hOCT2-mediated cimetidine transport decreased over this pH range, the consequence of an increase in K(t) and decrease in J(max) at the higher pH value. The weak bases trimethoprim and 4-phenylpyridine showed a similar pattern of pH-sensitive interaction with hOCT2. The non-ionizable sterol, corticosterone, also inhibited hOCT2 activity, although it was neither competitive in nature nor was it sensitive to pH in the manner observed with weak bases. We conclude that the degree of ionization plays a critical role in binding of substrate to organic cation transporters.

Details

ISSN :
00219258
Volume :
277
Database :
OpenAIRE
Journal :
Journal of Biological Chemistry
Accession number :
edsair.doi.dedup.....3c4737168abc3211d2aae20518f90d57
Full Text :
https://doi.org/10.1074/jbc.m203114200