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