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Lookup NU author(s): Dr Catriona AndersonORCiD, Professor David Thwaites
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A H+-coupled amino acid transporter has been characterised functionally at the brush border membrane of the human intestinal cell line Caco-2. This carrier, hPAT1 (human Proton-coupled Amino acid Transporter 1)or SLC36A1, has been identified recently at the molecular level and hPAT1 protein is localised to the brush border membrane of human small intestine. hPAT1 transports both amino acids (e.g., β-alanine) and therapeutic agents (e.g., o-cycloserine). In human Caco-2 cells, hPAT1 function (H+/amino acid symport) is associated with a decrease in intracellular pH (pHi), which selectively activates the Na+AH+ exchanger NHE3, and thus maintains pHi and the driving force for hPAT1 function (the H+ electrochemical gradient). This study provides the first evidence for regulation of hPAT1 function. Activation of the cAMP/protein kinase A pathway in Caco-2 cell monolayers either using pharmacological tools (forskolin, 8-br-cAMP, [11,22,28Ala]VIP) or physiological activators (the neuropeptides VIP and PACAP) inhibited hPAT1 function (β-alanine uptake) at the apical membrane. Under conditions where NHE3 is inactive (the absence of Na+, apical pH 5.5, the presence of the NHE3 inhibitor S1611) no regulation of β-alanine uptake is observed. Forskolin and VIP inhibit pH, recovery (NHE3 function) from β-alanine-induced intracellular acidification. Immunocytochemistry localises NHERF1 (NHE3 regulatory factor 1) to the apical portion of Caco-2 cells where it will interact with NHE3 and allow PKA-mediated phosphorylation of NHE3. In conclusion, we have shown that amino acid uptake via hPAT1 is inhibited by activators of the cAMP pathway indirectly through inhibition of NHE3 activity. © 2005 Wiley-Liss, Inc.
Author(s): Anderson CMH, Thwaites DT
Publication type: Article
Publication status: Published
Journal: Journal of Cellular Physiology
Year: 2005
Volume: 204
Issue: 2
Pages: 604-613
Print publication date: 01/08/2005
ISSN (print): 0021-9541
ISSN (electronic): 1097-4652
Publisher: John Wiley & Sons, Inc.
URL: http://dx.doi.org/10.1002/jcp.20337
DOI: 10.1002/jcp.20337
PubMed id: 15754324
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