rBAT, together with its subunit b0,+ AT mediates the hetero- and homoexchange of neutral and dibasic amino acids. Since the heteroexchange of dibasic amino acids against neutral amino acids is coupled to net transport of positive charge, this transport is electrogenic. Extracellular addition of histidine could create an inward or an outward current depending on extracellular pH (pHe) and cell membrane potential. It has been concluded that histidine may be transported in both its protonated and its neutral form. In this study measurements of cytosolic pH (pHi) were performed to test this hypothesis. As a result, addition of protonated histidine at acidic pHe to Xenopus oocytes expressing rBAT creates an inward current which is paralleled by cytosolic acidification. Both can be reduced by increase of pHe. At alkaline pHe and simultaneous depolarization of the cell membrane the effect of histidine on pHi is virtually abolished. The neutral amino acid leucine does not alter cytosolic pH at neither pH 6.0 nor at pH 8.0. In conclusion, histidine can be transported in either its neutral or its protonated form. Transport of the protonated form is facilitated by extracellular acidification and hyperpolarization of the cell membrane.

1.
Bertran J, Werner A, Moore ML, Stange G, Markovich D, Biber J, Testar X, Zorzano A, Palacin M, Murer H: Expression cloning of a cDNA from rabbit kidney cortex that induces a single transport system for cystine and dibasic and neutral amino acids. Proc Natl Acad Sci USA 1992;89:5601–5605.
2.
Furriols M, Chillarón J, Mora C, Castelló A, Bertran J, Camps M, Testar X, Vilaró S, Zorzano A, Palacín M: rBAT, related to L-cysteine transport, is localized to the microvilli of proximal straight tubules, and its expression is regulated in kidney by development. J Biol Chem 1993;268:27060–27068.
3.
Kanai Y, Stelzner MG, Lee WS, Wells RG, Brown D, Hediger MA: Expression of mRNA (D2) encoding a protein involved in amino acid transport in S3 proximal tubule. Am J Physiol 1992;263:F1087–F1092.
4.
Wagner CA, Lang F, Bröer S: Function and structure of heterodimeric amino acid transporters. Am J Physiol Cell Physiol 2001;281:C1077–C1093.
5.
Mosckovitz R, Yan N, Heimer E, Felix A, Tate SS, Udenfriend S: Characterization of the rat neutral and basic amino acid transporter utilizing ant-peptide antibodies. Proc Natl Acad Sci USA 1993;90:4022–4026.
6.
Bertran J, Werner A, Chillaron J, Nunes V, Biber J, Testar X, Zorzano A, Estivill X, Murer H, Palacin M: Expression cloning of a human renal cDNA that induces high affinity transport of L-cystine shared with dibasic amino acids in Xenopus oocytes. J Biol Chem 1993;268:14842–14849.
7.
Lee WS, Wells RG, Sabbag RV, Mohandas TK, Hediger MA: Cloning and chromosomal localization of a human kidney cDNA involved in cystine, dibasic, and neutral amino acid transport. J Clin Invest 1993;91:1959–1963.
8.
Tate SS, Yan N, Udenfriend S: Expression cloning of a Na(+)-independent neutral amino acid transporter from rat kidney. Proc Natl Acad Sci USA 1992;89:1–5.
9.
Wells RG, Hediger MA: Cloning of a rat kidney cDNA that stimulates dibasic and neutral amino acid transport and has sequence similarity to glucosidases. Proc Natl Acad Sci USA 1992;89:5596–5600.
10.
Feliubadalo L, Font M, Purroy J, Rousaud F, Estivill X, Nunes V, Golomb E, Centola M, Aksentijevich I, Kreiss Y, Goldman B, Pras M, Kastner DL, Pras E, Gasparini P, Bisceglia L, Beccia E, Gallucci M, de Sanctis L, Ponzone A, Rizzoni GF, Zelante L, Bassi MT, George AL, Manzoni M, De Grandi A, Riboni M, Endsley JK, Ballabio A, Borsani G, Reig N, Fernandez E, Estavez R, Pineda M, Torrents D, Camps M, Lloberas J, Zorzano A, Palacín M: Non-type I cystinuria caused by mutations in SLC7A9, encoding a subunit (b0,+ AT) of rBAT. Nat Genet 1999;23:52–57.
11.
Chairoungdua A, Segawa H, Kim JY, Miyamoto K, Haga H, Fukui Y, Mizoguchi K, Ito H, Takeda E, Endou H, Kanai Y: Identification of an amino acid transporter associated with the cystinuria-related type II membrane glycoprotein. J Biol Chem 1999;274:28845–28848.
12.
Pfeiffer R, Loffing J, Rossier G, Bauch C, Meier C, Eggermann T, Loffing-Cueni D, Kuhn LC, Verrey F: Luminal heterodimeric amino acid transporter defective in cystinuria. Mol Biol Cell 1999;10:4135–4137.
13.
Busch AE, Herzer T, Waldegger S, Palacín M, Biber J, Markovich D, Murer H, Lang F: Opposite directed currents induced by the transport of dibasic and neutral amino acids in Xenopus oocytes expressing the protein rBAT. J Biol Chem 1994;269:25581–25586.
14.
Chillaron J, Estevez R, Mora C, Wagner CA, Suessbrich H, Lang F, Gelpi JL, Testar X, Busch AE, Zorzano A, Palacin M: Obligatory amino acid exchange via systems b0,+-like and y+L-like: A tertiary active transport mechanism for renal reabsorption of cystine and dibasic amino acids. J Biol Chem 1996;271:17761–17770.
15.
Calonge MJ, Gasparini P, Chillarón J, Chillón M, Gallucci M, Rousaud F, Zelante L, Testar X, Dallapiccola B, Di Silverio F, Barceló P, Estivill X, Zorzano A, Nunes V, Palacín M: Cystinuria caused by mutations in rBAT, a gene involved in the transport of cystine. Nat Genet 1994;6:420–425.
16.
Saadi I, Chen XZ, Hediger MA, Ong P, Pereira P, Goodyer P, Rozen R: Molecular genetics of cystinuria: Mutation analysis of SLC3A1 and evidence for another gene in type I (silent) phenotype. Kidney Int 1998;54:48–55.
17.
Albers A, Lahme S, Wagner CA, Kaiser P, Zerres K, Capasso G, Pica A, Palacin M, Lang F, Bichler K-H, Eggermann T: Mutations in the SLC3A1 gene in cystinuric patients: Frequencies and identification of a novel mutation. Genet Test 1999;3:227–231.
18.
Egoshi K-I, Akakura K, Kodama T, Ito H: Identification of five novel SLC3A1 (rBAT) gene mutations in Japanese cystinuria. Kidney Int 1999;57:25–32.
19.
Gasparini P, Calonge MJ, Biscelgia L, Purroy J, Dianzani I, Notarangelo A, Rousaud F, Gallucci M, Testar X, Ponzone A, Estivill X, Zorzano A, Palacin M, Nunes V, Zelante L: Molecular genetics of cystinuria: identification of four new mutations and seven new polymorphisms, and evidence for genetic heterogeneity. Am J Hum Genet 1995;57:781–788.
20.
Ahmed A, Yao PC, Brant AM, Peter GJ, Harper AA: Electrogenic L-histidine transport in neutral and basic amino acid transporter (NBAT)-expressing Xenopus laevis oocytes: Evidence for two functionally distinct transport mechanisms induced by NBAT expression. J Biol Chem 1997;272:125–130.
21.
Burckhardt BC, Kroll B, Frömter E: Proton transport mechanism in the cell membrane of Xenopus laevis oocytes. Pflügers Arch 1992;402:78–82.
22.
Bröer S, Schneider HP, Bröer A, Rahman B, Hamprecht B, Deitmer JW: Characterization of the monocarboxylate transporter 1 expressed in Xenopus laevis oocytes by changes in cytosolic pH. Biochem J 1998;333:167–174.
23.
Wagner CA, Friedrich B, Setiawan I, Lang F, Bröer S: The use of Xenopus laevis oocytes for the functional characterization of heterologously expressed membrane proteins. Cell Physiol Biochem 2000;10:1–12.
24.
Dascal N, Landau EM, Lass Y: Xenopus oocytes resting potential, muscarinic responses and the role of calcium and cyclic GMP. J Physiol 1984;352:551.
25.
Moschèn I, Setiawan I, Bröer S, Murer H, Lang F: Effect of NaPi-mediated phosphate transport on intracellular pH. Pflügers Arch 2001;441:802–806.
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