Swelling-induced taurine transport: relationship with chloride channels, anion-exchangers and other swelling-activated transport pathways

Cells have to regulate their volume in order to survive. Moreover, it is now evident that cell volume per se and the membrane transport processes which regulate it, comprise an important signalling unit. For example, macromolecular synthesis, apoptosis, cell growth and hormone secretion are all influenced by the cellular hydration state. Therefore, a thorough understanding of volume-activated transport processes could lead to new strategies being developed to control the function and growth of both normal and cancerous cells. Cell swelling stimulates the release of ions such as K+ and Cl- together with organic osmolytes, especially the β-amino acid taurine. Despite being the subject of intense research interest, the nature of the volume-activated taurine efflux pathway is still a matter of controversy. On the one hand it has been suggested that osmosensitive taurine efflux utilizes volume-sensitive anion channels whereas on the other it has been proposed that the band 3 anion-exchanger is a swelling-induced taurine efflux pathway. This article reviews the evidence for and against a role of anion channels and exchangers in osmosensitive taurine transport. Furthermore, the distinct possibility that neither pathway is involved in taurine transport is highlighted. The putative relationship between swelling-induced taurine transport and volume-activated anionic amino acid, α-neutral amino acid and K+ transport is also examined

Inhibition of system L (LAT1/CD98hc) reduces the growth of cultured human breast cancer cells

It has been suggested that system L (LAT1/CD98hc) is up-regulated in cancer cells, including breast tumour cells, and is therefore a promising molecular target to inhibit or limit tumour cell growth. In view of this, we have examined the effect of BCH and other inhibitors of system L on the growth of MCF-7, ZR-75-1 and MDA-MB-231 cells. Treating cells with BCH markedly inhibited the metabolism of WST-1 in a dose-dependent fashion. Similarly, melphalan and D-leucine inhibited the growth of cultured breast cancer cells whereas MeAIB, an inhibitor of system A, was without effect. The effects of BCH and melphalan on cell growth were non-additive suggesting that both compounds were acting at a single locus. The results indicate that system L is required to maintain MCF-7, ZR-75-1 and MDA-MB-231 cell growth and support the notion that LAT1/CD98hc may be a suitable target to inhibit breast cancer progression

Peptide aminonitrogen transport by the lactating rat mammary gland

AbstractRecent studies have shown that the lactating mammary gland is able to utilize plasma-derived dipeptides for milk protein synthesis. However, it was not clear whether the peptides were hydrolysed followed by uptake of the constituent amino acids or were taken up intact. In view of this, we have designed experiments to investigate (a) whether the lactating rat mammary gland is capable of transporting hydrolysis-resistant dipeptides and (b) whether or not mammary cells are able to hydrolyse peptides, including glutathione, extracellularly. The uptake of the hydrolysis-resistant dipeptides d-[3H]Phe-l-Gln and d-[3H]Phe-l-Glu by the perfused rat mammary gland was low. Concomitant addition of l-Leu-l-Ala (50 mM) had no effect on the clearance of either labelled dipeptide suggesting that the small, albeit significant, uptake of the dipeptides is not via a high affinity peptide transporter (PepT1/PepT2). All anionic dipeptides tested (l-Glu-l-Ala, l-Asp-l-Ala, l-Ala-l-Asp, l-Asp-Gly, Gly-l-Asp and Gly-l-Glu) with the exception of d-Phe-l-Glu were able to trans-accelerate the efflux of labelled d-aspartate from preloaded rat mammary tissue (explants and perfused mammary gland). It appears that these peptides were being hydrolysed extracellularly followed by the uptake of free anionic amino acids via the mammary tissue high affinity, Na+-dependent anionic amino acid carrier operating in the exchange mode. Glutathione was able to trans-accelerate d-aspartate efflux from lactating rat mammary tissue in a fashion which was sensitive to the peptidase inhibitor acivicin. This suggests that γ-glutamyltranspeptidase hydrolyses glutathione to produce l-glutamate which is subsequently transported via the high-affinity anionic amino acid carrier. Hydrolysis of peptides followed by uptake of the constituent amino acids may provide an important source of amino acids for milk protein synthesis