Abstract
Gastric acid secretion is regulated by a variety of stimuli, in particular histamine and acetyl choline. In addition, dietary factors such as the acute intake of a protein-rich diet and the subsequent increase in serum amino acids can stimulate gastric acid secretion only through partially characterized pathways. Recently, we described in mouse stomach parietal cells the expression of the system L heteromeric amino acid transporter comprised of the LAT2-4F2hc dimer. Here we address the potential role of the system L amino acid transporter in gastric acid secretion by parietal cells in freshly isolated rat gastric glands. RT-PCR, western blotting and immunohistochemistry confirmed the expression of 4F2-LAT2 amino acid transporters in rat parietal cells. In addition, mRNA was detected for the B0AT1, ASCT2, and ATB(0+) amino acid transporters. Intracellular pH measurements in parietal cells showed histamine-induced and omeprazole-sensitive H+-extrusion which was enhanced by about 50% in the presence of glutamine or cysteine (1 mM), two substrates of system L amino acid transporters. BCH, a non-metabolizable substrate and a competitive inhibitor of system L amino acid transport, abolished the stimulation of acid secretion by glutamine or cysteine suggesting that this stimulation required the uptake of amino acids by system L. In the absence of histamine glutamine also stimulated H+-extrusion, whereas glutamate did not. Also, phenylalanine was effective in stimulating H+/K+-ATPase activity. Glutamine did not increase intracellular Ca2+ levels indicating that it did not act via the recently described amino acid modulated Ca2+-sensing receptor. These data suggest a novel role for heterodimeric amino acid transporters and may elucidate a pathway by which protein-rich diets stimulate gastric acid secretion.
Similar content being viewed by others
References
Broer S (2002) Adaptation of plasma membrane amino acid transport mechanisms to physiological demands. Pflugers Arch 444:457–466
Busque SM, Kerstetter JE, Geibel JP, Insogna K (2005) L-type amino acids stimulate gastric acid secretion by activation of the calcium-sensing receptor in parietal cells. Am J Physiol Gastrointest Liver Physiol 289:G664–669
Campbell WA, Sah DE, Medina MM, Albina JE, Coleman WB, Thompson NL (2000) TA1/LAT-1/CD98 light chain and system L activity, but not 4F2/CD98 heavy chain, respond to arginine availability in rat hepatic cells. Loss of response in tumor cells. J Biol Chem 275:5347–5354
Cheng I, Qureshi I, Chattopadhyay N, Qureshi A, Butters RR, Hall AE, Cima RR, Rogers KV, Hebert SC, Geibel JP, Brown EM, Soybel DI (1999) Expression of an extracellular calcium-sensing receptor in rat stomach. Gastroenterology 116:118–126
Chew CS (1986) Cholecystokinin, carbachol, gastrin, histamine, and forskolin increase [Ca2+]i in gastric glands. Am J Physiol 250:G814–823
Chillaron J, Roca R, Valencia A, Zorzano A, Palacin M (2001) Heteromeric amino acid transporters: biochemistry, genetics, and physiology. Am J Physiol Renal Physiol 281:F995–1018
Conigrave AD, Franks AH, Brown EM, Quinn SJ (2002) L-amino acid sensing by the calcium-sensing receptor: a general mechanism for coupling protein and calcium metabolism? Eur J Clin Nutr 56:1072–1080
Dave MH, Schulz N, Zecevic M, Wagner CA, Verrey F (2004) Expression of heteromeric amino acid transporters along the murine intestine. J Physiol 558:597–610
Geibel JP, Wagner CA, Caroppo R, Qureshi I, Gloeckner J, Manuelidis L, Kirchhoff P, Radebold K (2001) The stomach divalent ion-sensing receptor scar is a modulator of gastric acid secretion. J Biol Chem 276:39549–39552
Hebert SC, Cheng S, Geibel J (2004) Functions and roles of the extracellular Ca2+-sensing receptor in the gastrointestinal tract. Cell Calcium 35:239–247
Isenberg JI, Maxwell V (1978) Intravenous infusion of amino acids stimulates gastric acid secretion in man. N Engl J Med 298:27–29
Kirchhoff P, Wagner CA, Gaetzschmann F, Radebold K, Geibel JP (2003) Demonstration of a functional apical sodium hydrogen exchanger in isolated rat gastric glands. Am J Physiol Gastrointest Liver Physiol 285:G1242–1248
Konturek SJ, Tasler J, Cieszkowski M, Jaworek J (1978) Comparison of intravenous amino acids in the stimulation of gastric secretion. Gastroenterology 75:817–824
Mastroberardino L, Spindler B, Pfeiffer R, Skelly PJ, Loffing J, Shoemaker CB, Verrey F (1998) Amino-acid transport by heterodimers of 4F2hc/CD98 and members of a permease family. Nature 395:288–291
McArthur KE, Isenberg JI, Hogan DL, Dreier SJ (1983) Intravenous infusion of L-isomers of phenylalanine and tryptophan stimulate gastric acid secretion at physiologic plasma concentrations in normal subjects and after parietal cell vagotomy. J Clin Invest 71:1254–1262
McLean IW, Nakane PK (1974) Periodate-lysine-paraformaldehyde fixative. A new fixation for immunoelectron microscopy. J Histochem Cytochem 22:1077–1083
Meier C, Ristic Z, Klauser S, Verrey F (2002) Activation of system L heterodimeric amino acid exchangers by intracellular substrates. EMBO J 21:580–589
Palacin M, Estevez R, Bertran J, Zorzano A (1998) Molecular biology of mammalian plasma membrane amino acid transporters. Physiol Rev 78:969–1054
Richardson CT, Walsh JH, Hicks MI, Fordtran JS (1976) Studies on the mechanisms of food-stimulated gastric acid secretion in normal human subjects. J Clin Invest 58:623–631
Rossier G, Meier C, Bauch C, Summa V, Sordat B, Verrey F, Kühn LC (1999) LAT2, a new basolateral 4F2hc/CD98-associated amino acid transporter of kidney and intestine. J Biol Chem 274:34948–34954
Schubert ML, Makhlouf GM (1992) Neural, hormonal, and paracrine regulation of gastrin and acid secretion. Yale J Biol Med 65:553–560
Shaw GP, Anderson NG, Hanson PJ (1985) Metabolism and gastric acid secretion. Substrate-dependency of aminopyrine accumulation in isolated rat parietal cells. Biochem J 227:223–229
Sloan JL, Mager S (1999) Cloning and functional expression of a human Na(+) and Cl(−)-dependent neutral and cationic amino acid transporter B(0+). J Biol Chem 274:23740–23745
Sobrevia L, Medina V, Reinicke K, Bravo I (1992) Uptake of L-leucine and L-phenylalanine across the basolateral cell surface in isolated oxyntic glands. Biochim Biophys Acta 1106:257–263
Thomas JA, Buchsbaum RN, Zimniak A, Racker E (1979) Intracellular pH measurements in Ehrlich ascites tumor cells utilizing spectroscopic probes generated in situ. Biochemistry 18:2210–2218
Thompson JC (1978) Hormonal influences on gastric secretion. Adv Surg 12:53–83
Thorens B (2001) GLUT2 in pancreatic and extra-pancreatic gluco-detection (review). Mol Membr Biol 18:265–273
Verrey F, Closs EI, Wagner CA, Palacin M, Endou H, Kanai Y (2004) CATs and HATs: the SLC7 family of amino acid transporters. Pflugers Arch 447:532–542
Verrey F, Meier C, Rossier G, Kühn LC (2000) Glycoprotein-associated amino acid exchangers: broadening the range of transport specificity. Pflugers Arch 440:503–512
Wagner CA, Lang F, Broer S (2001) Function and structure of heterodimeric amino acid transporters. Am J Physiol Cell Physiol 281:C1077–1093
Wagner CA, Lukewille U, Valles P, Breton S, Brown D, Giebisch GH, Geibel JP (2003) A rapid enzymatic method for the isolation of defined kidney tubule fragments from mouse. Pflugers Arch 446:623–632
Yao X, Forte JG (2003) Cell biology of acid secretion by the parietal cell. Annu Rev Physiol 65:103–131
Acknowledgements
This study was supported by grants from the Theodor and Ida Herzog-Egli foundation to F.V. and C.A.W., by the Hartmann Müller foundation to P.K. and C.A.W., by the EUGINDAT project of the sixth Framework of the EU to F.V. and C.A.W., and by the NIH to J.P.G. (DK-50230, DK-14669, DK-17433, DK-60069). We thank N. Thompson, Brown University, RI, USA for providing us with the anti-LAT1 antibody.
Author information
Authors and Affiliations
Corresponding author
Additional information
P. Kirchhoff and M.H. Dave contributed equally to this study and therefore share first authorship
Rights and permissions
About this article
Cite this article
Kirchhoff, P., Dave, M.H., Remy, C. et al. An amino acid transporter involved in gastric acid secretion. Pflugers Arch - Eur J Physiol 451, 738–748 (2006). https://doi.org/10.1007/s00424-005-1507-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00424-005-1507-2