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Gamma-aminobutyric acid (GABA) transport across human intestinal epithelial (Caco-2) cell monolayers

Lookup NU author(s): Professor David Thwaites, Dr Laura Basterfield, Professor Nicholas Simmons

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Abstract

1. Transintestinal absorption of gamma-aminobutyric acid (GABA) via a pH-dependent mechanism is demonstrated in the model human intestinal epithelial cell line Caco-2. 2. Experiments with BCECF [2',7',-bis(2-carboxyethyl)-5(6)-carboxyfluorescein]-loaded Caco-2 cells demonstrate that GABA transport across the apical membrane is coupled to proton flow into the cell. 3. Short-circuit current (I(SC)) measurements using Caco-2 cell monolayers under voltage-clamped conditions demonstrate that pH-dependent GABA transport is a rheogenic process even in the absence of extracellular Na-, consistent with H+/GABA symport. 4. A range of GABA analogues were tested for their abilities to: (a) inhibit pH-dependent [3H]GABA uptake across the apical membrane; (b) stimulate H+ flow across the apical surface of BCECF-loaded Caco-2 cell monolayers; (c) increase inward I(SC) across voltage-clamped Caco-2 cell monolayers. 5. Nipecotic acid, isonipecotic acid, D,L-β-aminobutyric acid, and 3-amino-1-propanesulphonic acid each caused a marked acidification of intracellular pH and an increase in I(SC) when superfused at the epical surface of Caco-2 cell monolayers. In contrast L-α-amino-n-butyric acid failed to induce proton flow or I(SC). The ability of these compounds to induce proton or current flow across the epical surface of this intestinal epithelium was closely related to the relative inhibitory effects on [3H]GABA uptake. 6. These observations demonstrate H+/GABA symport and suggest that this transport mechanism may be accessible us a route for oral absorption of therapeutically-useful GABA analogues.


Publication metadata

Author(s): Thwaites DT, Basterfield L, McCleave P, Carter S, Simmons NL

Publication type: Article

Publication status: Published

Journal: British Journal of Pharmacology

Year: 2000

Volume: 129

Issue: 3

Pages: 457-464

ISSN (print): 0007-1188

ISSN (electronic): 1476-5381

Publisher: John Wiley & Sons Ltd.

URL: http://dx.doi.org/10.1038/sj.bjp.0703069

DOI: 10.1038/sj.bjp.0703069

PubMed id: 10711343


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