Skip to main content
PMC home page
Biochemical Journal logoLink to Biochemical Journal
. 2001 Jul 1;357(Pt 1):1–10. doi: 10.1042/0264-6021:3570001

Functional role of polar amino acid residues in Na+/H+ exchangers.

C A Wiebe 1, E R Dibattista 1, L Fliegel 1
PMCID: PMC1221921  PMID: 11415429

Abstract

Na(+)/H(+) exchangers are a family of ubiquitous membrane proteins. In higher eukaryotes they regulate cytosolic pH by removing an intracellular H(+) in exchange for an extracellular Na(+). In yeast and Escherichia coli, Na(+)/H(+) exchangers function in the opposite direction to remove intracellular Na(+) in exchange for extracellular H(+). Na(+)/H(+) exchangers display an internal pH-sensitivity that varies with the different antiporter types. Only recently have investigations examined the amino acids involved in pH-sensitivity and in cation binding and transport. Histidine residues are good candidates for H(+)-sensing amino acids, since they can ionize within the physiological pH range. Histidine residues have been shown to be important in the function of the E. coli Na(+)/H(+) exchanger NhaA and in the yeast Na(+)/H(+) exchanger sod2. In E. coli, His(225) of NhaA may function to interact with, or regulate, the pH-sensory region of NhaA. In sod2, His(367) is also critical to transport and may be a functional analogue of His(225) of NhaA. Histidine residues are not critical for the function of the mammalian Na(+)/H(+) exchanger, although an unusual histidine-rich sequence of the C-terminal tail has some influence on activity. Other amino acids involved in cation binding and transport by Na(+)/H(+) exchangers are only beginning to be studied. Amino acids with polar side chains such as aspartate and glutamate have been implicated in transport activity of NhaA and sod2, but have not been studied in the mammalian Na(+)/H(+) exchanger. Further studies are needed to elucidate the mechanisms involved in pH-sensitivity and cation binding and transport by Na(+)/H(+) exchangers.

Full Text

The Full Text of this article is available as a PDF (368.5 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Andersen J. P., Vilsen B. Structure-function relationships of cation translocation by Ca(2+)- and Na+, K(+)-ATPases studied by site-directed mutagenesis. FEBS Lett. 1995 Feb 13;359(2-3):101–106. doi: 10.1016/0014-5793(95)00019-6. [DOI] [PubMed] [Google Scholar]
  2. Argüello J. M., Kaplan J. H. Glutamate 779, an intramembrane carboxyl, is essential for monovalent cation binding by the Na,K-ATPase. J Biol Chem. 1994 Mar 4;269(9):6892–6899. [PubMed] [Google Scholar]
  3. Aronson P. S., Nee J., Suhm M. A. Modifier role of internal H+ in activating the Na+-H+ exchanger in renal microvillus membrane vesicles. Nature. 1982 Sep 9;299(5879):161–163. doi: 10.1038/299161a0. [DOI] [PubMed] [Google Scholar]
  4. Bienengraeber M., Echtay K. S., Klingenberg M. H+ transport by uncoupling protein (UCP-1) is dependent on a histidine pair, absent in UCP-2 and UCP-3. Biochemistry. 1998 Jan 6;37(1):3–8. doi: 10.1021/bi972463w. [DOI] [PubMed] [Google Scholar]
  5. Borgese F., Sardet C., Cappadoro M., Pouyssegur J., Motais R. Cloning and expression of a cAMP-activated Na+/H+ exchanger: evidence that the cytoplasmic domain mediates hormonal regulation. Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):6765–6769. doi: 10.1073/pnas.89.15.6765. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Boyer P. D. Bioenergetic coupling to protonmotive force: should we be considering hydronium ion coordination and not group protonation? Trends Biochem Sci. 1988 Jan;13(1):5–7. doi: 10.1016/0968-0004(88)90005-9. [DOI] [PubMed] [Google Scholar]
  7. Brant S. R., Yun C. H., Donowitz M., Tse C. M. Cloning, tissue distribution, and functional analysis of the human Na+/N+ exchanger isoform, NHE3. Am J Physiol. 1995 Jul;269(1 Pt 1):C198–C206. doi: 10.1152/ajpcell.1995.269.1.C198. [DOI] [PubMed] [Google Scholar]
  8. Buckley J. T., Wilmsen H. U., Lesieur C., Schulze A., Pattus F., Parker M. W., van der Goot F. G. Protonation of histidine-132 promotes oligomerization of the channel-forming toxin aerolysin. Biochemistry. 1995 Dec 19;34(50):16450–16455. doi: 10.1021/bi00050a028. [DOI] [PubMed] [Google Scholar]
  9. Chanchevalap S., Yang Z., Cui N., Qu Z., Zhu G., Liu C., Giwa L. R., Abdulkadir L., Jiang C. Involvement of histidine residues in proton sensing of ROMK1 channel. J Biol Chem. 2000 Mar 17;275(11):7811–7817. doi: 10.1074/jbc.275.11.7811. [DOI] [PubMed] [Google Scholar]
  10. Clarke D. M., Loo T. W., MacLennan D. H. Functional consequences of alterations to polar amino acids located in the transmembrane domain of the Ca2(+)-ATPase of sarcoplasmic reticulum. J Biol Chem. 1990 Apr 15;265(11):6262–6267. [PubMed] [Google Scholar]
  11. Claros M. G., von Heijne G. TopPred II: an improved software for membrane protein structure predictions. Comput Appl Biosci. 1994 Dec;10(6):685–686. doi: 10.1093/bioinformatics/10.6.685. [DOI] [PubMed] [Google Scholar]
  12. Counillon L., Franchi A., Pouysségur J. A point mutation of the Na+/H+ exchanger gene (NHE1) and amplification of the mutated allele confer amiloride resistance upon chronic acidosis. Proc Natl Acad Sci U S A. 1993 May 15;90(10):4508–4512. doi: 10.1073/pnas.90.10.4508. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Counillon L., Pouysségur J. The expanding family of eucaryotic Na(+)/H(+) exchangers. J Biol Chem. 2000 Jan 7;275(1):1–4. doi: 10.1074/jbc.275.1.1. [DOI] [PubMed] [Google Scholar]
  14. Damiano E., Bassilana M., Leblanc G. Chemical modifications of the Na+-H+ antiport in Escherichia coli membrane vesicles. Eur J Biochem. 1985 Apr 1;148(1):183–188. doi: 10.1111/j.1432-1033.1985.tb08823.x. [DOI] [PubMed] [Google Scholar]
  15. Dibrov P., Fliegel L. Comparative molecular analysis of Na+/H+ exchangers: a unified model for Na+/H+ antiport? FEBS Lett. 1998 Mar 6;424(1-2):1–5. doi: 10.1016/s0014-5793(98)00119-7. [DOI] [PubMed] [Google Scholar]
  16. Dibrov P., Murtazina R., Kinsella J., Fliegel L. Characterization of a histidine rich cluster of amino acids in the cytoplasmic domain of the Na+/H+ exchanger. Biosci Rep. 2000 Jun;20(3):185–197. doi: 10.1023/a:1005567519792. [DOI] [PubMed] [Google Scholar]
  17. Dibrov P., Young P. G., Fliegel L. Functional analysis of amino acid residues essential for activity in the Na+/H+ exchanger of fission yeast. Biochemistry. 1998 Jun 9;37(23):8282–8288. doi: 10.1021/bi9801457. [DOI] [PubMed] [Google Scholar]
  18. Echtay K. S., Bienengraeber M., Winkler E., Klingenberg M. In the uncoupling protein (UCP-1) His-214 is involved in the regulation of purine nucleoside triphosphate but not diphosphate binding. J Biol Chem. 1998 Sep 18;273(38):24368–24374. doi: 10.1074/jbc.273.38.24368. [DOI] [PubMed] [Google Scholar]
  19. Ek J. F., Delmar M., Perzova R., Taffet S. M. Role of histidine 95 on pH gating of the cardiac gap junction protein connexin43. Circ Res. 1994 Jun;74(6):1058–1064. doi: 10.1161/01.res.74.6.1058. [DOI] [PubMed] [Google Scholar]
  20. Enslen H., Brancho D. M., Davis R. J. Molecular determinants that mediate selective activation of p38 MAP kinase isoforms. EMBO J. 2000 Mar 15;19(6):1301–1311. doi: 10.1093/emboj/19.6.1301. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Fafournoux P., Ghysdael J., Sardet C., Pouysségur J. Functional expression of the human growth factor activatable Na+/H+ antiporter (NHE-1) in baculovirus-infected cells. Biochemistry. 1991 Oct 1;30(39):9510–9515. doi: 10.1021/bi00103a018. [DOI] [PubMed] [Google Scholar]
  22. Feng J., Lingrel J. B. Functional consequences of substitutions of the carboxyl residue glutamate 779 of the Na,K-ATPase. Cell Mol Biol Res. 1995;41(1):29–37. [PubMed] [Google Scholar]
  23. Fulkerson J. F., Jr, Garner R. M., Mobley H. L. Conserved residues and motifs in the NixA protein of Helicobacter pylori are critical for the high affinity transport of nickel ions. J Biol Chem. 1998 Jan 2;273(1):235–241. doi: 10.1074/jbc.273.1.235. [DOI] [PubMed] [Google Scholar]
  24. Gerchman Y., Olami Y., Rimon A., Taglicht D., Schuldiner S., Padan E. Histidine-226 is part of the pH sensor of NhaA, a Na+/H+ antiporter in Escherichia coli. Proc Natl Acad Sci U S A. 1993 Feb 15;90(4):1212–1216. doi: 10.1073/pnas.90.4.1212. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Gerchman Y., Rimon A., Padan E. A pH-dependent conformational change of NhaA Na(+)/H(+) antiporter of Escherichia coli involves loop VIII-IX, plays a role in the pH response of the protein, and is maintained by the pure protein in dodecyl maltoside. J Biol Chem. 1999 Aug 27;274(35):24617–24624. doi: 10.1074/jbc.274.35.24617. [DOI] [PubMed] [Google Scholar]
  26. Grillo F. G., Aronson P. S. Inactivation of the renal microvillus membrane Na+-H+ exchanger by histidine-specific reagents. J Biol Chem. 1986 Jan 25;261(3):1120–1125. [PubMed] [Google Scholar]
  27. Grinstein S., Cohen S., Rothstein A. Chemical modification of the Na+/H+ exchanger of thymic lymphocytes. Inhibition by N-ethylmaleimide. Biochim Biophys Acta. 1985 Jan 10;812(1):213–222. doi: 10.1016/0005-2736(85)90541-3. [DOI] [PubMed] [Google Scholar]
  28. Grinstein S., Rotin D., Mason M. J. Na+/H+ exchange and growth factor-induced cytosolic pH changes. Role in cellular proliferation. Biochim Biophys Acta. 1989 Jan 18;988(1):73–97. doi: 10.1016/0304-4157(89)90004-x. [DOI] [PubMed] [Google Scholar]
  29. Gross R., Simon J., Lancaster C. R., Kröger A. Identification of histidine residues in Wolinella succinogenes hydrogenase that are essential for menaquinone reduction by H2. Mol Microbiol. 1998 Nov;30(3):639–646. doi: 10.1046/j.1365-2958.1998.01100.x. [DOI] [PubMed] [Google Scholar]
  30. Harris C., Fliegel L. Amiloride and the Na(+)/H(+) exchanger protein: mechanism and significance of inhibition of the Na(+)/H(+) exchanger (review). Int J Mol Med. 1999 Mar;3(3):315–321. doi: 10.3892/ijmm.3.3.315. [DOI] [PubMed] [Google Scholar]
  31. He M. M., Kaback H. R. Interaction between residues Glu269 (helix VIII) and His322 (helix X) of the lactose permease of Escherichia coli is essential for substrate binding. Biochemistry. 1997 Nov 4;36(44):13688–13692. doi: 10.1021/bi9715324. [DOI] [PubMed] [Google Scholar]
  32. Hesketh T. R., Moore J. P., Morris J. D., Taylor M. V., Rogers J., Smith G. A., Metcalfe J. C. A common sequence of calcium and pH signals in the mitogenic stimulation of eukaryotic cells. Nature. 1985 Feb 7;313(6002):481–484. doi: 10.1038/313481a0. [DOI] [PubMed] [Google Scholar]
  33. Hoth S., Dreyer I., Dietrich P., Becker D., Müller-Röber B., Hedrich R. Molecular basis of plant-specific acid activation of K+ uptake channels. Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4806–4810. doi: 10.1073/pnas.94.9.4806. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Hoth S., Hedrich R. Distinct molecular bases for pH sensitivity of the guard cell K+ channels KST1 and KAT1. J Biol Chem. 1999 Apr 23;274(17):11599–11603. doi: 10.1074/jbc.274.17.11599. [DOI] [PubMed] [Google Scholar]
  35. Inoue H., Noumi T., Tsuchiya T., Kanazawa H. Essential aspartic acid residues, Asp-133, Asp-163 and Asp-164, in the transmembrane helices of a Na+/H+ antiporter (NhaA) from Escherichia coli. FEBS Lett. 1995 Apr 24;363(3):264–268. doi: 10.1016/0014-5793(95)00331-3. [DOI] [PubMed] [Google Scholar]
  36. Jia Z. P., McCullough N., Martel R., Hemmingsen S., Young P. G. Gene amplification at a locus encoding a putative Na+/H+ antiporter confers sodium and lithium tolerance in fission yeast. EMBO J. 1992 Apr;11(4):1631–1640. doi: 10.1002/j.1460-2075.1992.tb05209.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Johnson C. L., Kuntzweiler T. A., Lingrel J. B., Johnson C. G., Wallick E. T. Glutamic acid 327 in the sheep alpha 1 isoform of Na+,K(+)-ATPase is a pivotal residue for cation-induced conformational changes. Biochem J. 1995 Jul 1;309(Pt 1):187–194. doi: 10.1042/bj3090187. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Karmazyn M., Gan X. T., Humphreys R. A., Yoshida H., Kusumoto K. The myocardial Na(+)-H(+) exchange: structure, regulation, and its role in heart disease. Circ Res. 1999 Oct 29;85(9):777–786. doi: 10.1161/01.res.85.9.777. [DOI] [PubMed] [Google Scholar]
  39. Kim Y., Bang H., Kim D. TASK-3, a new member of the tandem pore K(+) channel family. J Biol Chem. 2000 Mar 31;275(13):9340–9347. doi: 10.1074/jbc.275.13.9340. [DOI] [PubMed] [Google Scholar]
  40. Kuroda T., Shimamoto T., Mizushima T., Tsuchiya T. Mutational analysis of amiloride sensitivity of the NhaA Na+/H+ antiporter from Vibrio parahaemolyticus. J Bacteriol. 1997 Dec;179(23):7600–7602. doi: 10.1128/jb.179.23.7600-7602.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Ladoux A., Miglierina R., Krawice I., Cragoe E. J., Jr, Abita J. P., Frelin C. Single-cell analysis of the intracellular pH and its regulation during the monocytic differentiation of U937 human leukemic cells. Eur J Biochem. 1988 Aug 15;175(3):455–460. doi: 10.1111/j.1432-1033.1988.tb14216.x. [DOI] [PubMed] [Google Scholar]
  42. Malakooti J., Dahdal R. Y., Schmidt L., Layden T. J., Dudeja P. K., Ramaswamy K. Molecular cloning, tissue distribution, and functional expression of the human Na(+)/H(+) exchanger NHE2. Am J Physiol. 1999 Aug;277(2 Pt 1):G383–G390. doi: 10.1152/ajpgi.1999.277.2.G383. [DOI] [PubMed] [Google Scholar]
  43. Mamedov F., Sayre R. T., Styring S. Involvement of histidine 190 on the D1 protein in electron/proton transfer reactions on the donor side of photosystem II. Biochemistry. 1998 Oct 6;37(40):14245–14256. doi: 10.1021/bi980194j. [DOI] [PubMed] [Google Scholar]
  44. Mogi T., Stern L. J., Marti T., Chao B. H., Khorana H. G. Aspartic acid substitutions affect proton translocation by bacteriorhodopsin. Proc Natl Acad Sci U S A. 1988 Jun;85(12):4148–4152. doi: 10.1073/pnas.85.12.4148. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Nakamura T., Komano Y., Itaya E., Tsukamoto K., Tsuchiya T., Unemoto T. Cloning and sequencing of an Na+/H+ antiporter gene from the marine bacterium Vibrio alginolyticus. Biochim Biophys Acta. 1994 Mar 23;1190(2):465–468. doi: 10.1016/0005-2736(94)90109-0. [DOI] [PubMed] [Google Scholar]
  46. Nakamura T., Komano Y., Unemoto T. Three aspartic residues in membrane-spanning regions of Na+/H+ antiporter from Vibrio alginolyticus play a role in the activity of the carrier. Biochim Biophys Acta. 1995 Jun 30;1230(3):170–176. doi: 10.1016/0005-2728(95)00053-l. [DOI] [PubMed] [Google Scholar]
  47. Nicoll D. A., Hryshko L. V., Matsuoka S., Frank J. S., Philipson K. D. Mutation of amino acid residues in the putative transmembrane segments of the cardiac sarcolemmal Na+-Ca2+ exchanger. J Biol Chem. 1996 Jun 7;271(23):13385–13391. doi: 10.1074/jbc.271.23.13385. [DOI] [PubMed] [Google Scholar]
  48. Noumi T., Inoue H., Sakurai T., Tsuchiya T., Kanazawa H. Identification and characterization of functional residues in a Na+/H+ antiporter (NhaA) from Escherichia coli by random mutagenesis. J Biochem. 1997 Apr;121(4):661–670. doi: 10.1093/oxfordjournals.jbchem.a021637. [DOI] [PubMed] [Google Scholar]
  49. Németh-Cahalan K. L., Hall J. E. pH and calcium regulate the water permeability of aquaporin 0. J Biol Chem. 2000 Mar 10;275(10):6777–6782. doi: 10.1074/jbc.275.10.6777. [DOI] [PubMed] [Google Scholar]
  50. Olami Y., Rimon A., Gerchman Y., Rothman A., Padan E. Histidine 225, a residue of the NhaA-Na+/H+ antiporter of Escherichia coli is exposed and faces the cell exterior. J Biol Chem. 1997 Jan 17;272(3):1761–1768. doi: 10.1074/jbc.272.3.1761. [DOI] [PubMed] [Google Scholar]
  51. Orlowski J., Grinstein S. Na+/H+ exchangers of mammalian cells. J Biol Chem. 1997 Sep 5;272(36):22373–22376. doi: 10.1074/jbc.272.36.22373. [DOI] [PubMed] [Google Scholar]
  52. Orlowski J., Kandasamy R. A. Delineation of transmembrane domains of the Na+/H+ exchanger that confer sensitivity to pharmacological antagonists. J Biol Chem. 1996 Aug 16;271(33):19922–19927. doi: 10.1074/jbc.271.33.19922. [DOI] [PubMed] [Google Scholar]
  53. Orlowski J., Kandasamy R. A., Shull G. E. Molecular cloning of putative members of the Na/H exchanger gene family. cDNA cloning, deduced amino acid sequence, and mRNA tissue expression of the rat Na/H exchanger NHE-1 and two structurally related proteins. J Biol Chem. 1992 May 5;267(13):9331–9339. [PubMed] [Google Scholar]
  54. Otto H., Marti T., Holz M., Mogi T., Lindau M., Khorana H. G., Heyn M. P. Aspartic acid-96 is the internal proton donor in the reprotonation of the Schiff base of bacteriorhodopsin. Proc Natl Acad Sci U S A. 1989 Dec;86(23):9228–9232. doi: 10.1073/pnas.86.23.9228. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Pinner E., Carmel O., Bercovier H., Sela S., Padan E., Schuldiner S. Cloning, sequencing and expression of the nhaA and nhaR genes from Salmonella enteritidis. Arch Microbiol. 1992;157(4):323–328. doi: 10.1007/BF00248676. [DOI] [PubMed] [Google Scholar]
  56. Pinner E., Padan E., Schuldiner S. Kinetic properties of NhaB, a Na+/H+ antiporter from Escherichia coli. J Biol Chem. 1994 Oct 21;269(42):26274–26279. [PubMed] [Google Scholar]
  57. Poolman B., Knol J., van der Does C., Henderson P. J., Liang W. J., Leblanc G., Pourcher T., Mus-Veteau I. Cation and sugar selectivity determinants in a novel family of transport proteins. Mol Microbiol. 1996 Mar;19(5):911–922. doi: 10.1046/j.1365-2958.1996.397949.x. [DOI] [PubMed] [Google Scholar]
  58. Pouysségur J., Sardet C., Franchi A., L'Allemain G., Paris S. A specific mutation abolishing Na+/H+ antiport activity in hamster fibroblasts precludes growth at neutral and acidic pH. Proc Natl Acad Sci U S A. 1984 Aug;81(15):4833–4837. doi: 10.1073/pnas.81.15.4833. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Prior C., Potier S., Souciet J. L., Sychrova H. Characterization of the NHA1 gene encoding a Na+/H+-antiporter of the yeast Saccharomyces cerevisiae. FEBS Lett. 1996 May 27;387(1):89–93. doi: 10.1016/0014-5793(96)00470-x. [DOI] [PubMed] [Google Scholar]
  60. Prior C., Potier S., Souciet J. L., Sychrova H. Characterization of the NHA1 gene encoding a Na+/H+-antiporter of the yeast Saccharomyces cerevisiae. FEBS Lett. 1996 May 27;387(1):89–93. doi: 10.1016/0014-5793(96)00470-x. [DOI] [PubMed] [Google Scholar]
  61. Püttner I. B., Sarkar H. K., Padan E., Lolkema J. S., Kaback H. R. Characterization of site-directed mutants in the lac permease of Escherichia coli. 1. Replacement of histidine residues. Biochemistry. 1989 Mar 21;28(6):2525–2533. doi: 10.1021/bi00432a027. [DOI] [PubMed] [Google Scholar]
  62. Rajan S., Wischmeyer E., Xin Liu G., Preisig-Müller R., Daut J., Karschin A., Derst C. TASK-3, a novel tandem pore domain acid-sensitive K+ channel. An extracellular histiding as pH sensor. J Biol Chem. 2000 Jun 2;275(22):16650–16657. doi: 10.1074/jbc.M000030200. [DOI] [PubMed] [Google Scholar]
  63. Rimon A., Gerchman Y., Olami Y., Schuldiner S., Padan E. Replacements of histidine 226 of NhaA-Na+/H+ antiporter of Escherichia coli. Cysteine (H226C) or serine (H226S) retain both normal activity and pH sensitivity, aspartate (H226D) shifts the pH profile toward basic pH, and alanine (H226A) inactivates the carrier at all pH values. J Biol Chem. 1995 Nov 10;270(45):26813–26817. doi: 10.1074/jbc.270.45.26813. [DOI] [PubMed] [Google Scholar]
  64. Rothman A., Padan E., Schuldiner S. Topological analysis of NhaA, a Na+/H+ antiporter from Escherichia coli. J Biol Chem. 1996 Dec 13;271(50):32288–32292. doi: 10.1074/jbc.271.50.32288. [DOI] [PubMed] [Google Scholar]
  65. Sardet C., Franchi A., Pouysségur J. Molecular cloning, primary structure, and expression of the human growth factor-activatable Na+/H+ antiporter. Cell. 1989 Jan 27;56(2):271–280. doi: 10.1016/0092-8674(89)90901-x. [DOI] [PubMed] [Google Scholar]
  66. Shirvan A., Laskar O., Steiner-Mordoch S., Schuldiner S. Histidine-419 plays a role in energy coupling in the vesicular monoamine transporter from rat. FEBS Lett. 1994 Dec 12;356(1):145–150. doi: 10.1016/0014-5793(94)01252-0. [DOI] [PubMed] [Google Scholar]
  67. Steidl J. V., Yool A. J. Differential sensitivity of voltage-gated potassium channels Kv1.5 and Kv1.2 to acidic pH and molecular identification of pH sensor. Mol Pharmacol. 1999 May;55(5):812–820. [PubMed] [Google Scholar]
  68. Taglicht D., Padan E., Schuldiner S. Overproduction and purification of a functional Na+/H+ antiporter coded by nhaA (ant) from Escherichia coli. J Biol Chem. 1991 Jun 15;266(17):11289–11294. [PubMed] [Google Scholar]
  69. Todt J. C., McGroarty E. J. Involvement of histidine-21 in the pH-induced switch in porin channel size. Biochemistry. 1992 Nov 3;31(43):10479–10482. doi: 10.1021/bi00158a010. [DOI] [PubMed] [Google Scholar]
  70. Van Huysse J. W., Jewell E. A., Lingrel J. B. Site-directed mutagenesis of a predicted cation binding site of Na, K-ATPase. Biochemistry. 1993 Jan 26;32(3):819–826. doi: 10.1021/bi00054a012. [DOI] [PubMed] [Google Scholar]
  71. Wakabayashi S., Fafournoux P., Sardet C., Pouysségur J. The Na+/H+ antiporter cytoplasmic domain mediates growth factor signals and controls "H(+)-sensing". Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2424–2428. doi: 10.1073/pnas.89.6.2424. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Wakabayashi S., Pang T., Su X., Shigekawa M. A novel topology model of the human Na(+)/H(+) exchanger isoform 1. J Biol Chem. 2000 Mar 17;275(11):7942–7949. doi: 10.1074/jbc.275.11.7942. [DOI] [PubMed] [Google Scholar]
  73. Wang D., Balkovetz D. F., Warnock D. G. Mutational analysis of transmembrane histidines in the amiloride-sensitive Na+/H+ exchanger. Am J Physiol. 1995 Aug;269(2 Pt 1):C392–C402. doi: 10.1152/ajpcell.1995.269.2.C392. [DOI] [PubMed] [Google Scholar]
  74. Wang T. L., Hackam A., Guggino W. B., Cutting G. R. A single histidine residue is essential for zinc inhibition of GABA rho 1 receptors. J Neurosci. 1995 Nov;15(11):7684–7691. doi: 10.1523/JNEUROSCI.15-11-07684.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Watanabe Y., Miwa S., Tamai Y. Characterization of Na+/H(+)-antiporter gene closely related to the salt-tolerance of yeast Zygosaccharomyces rouxii. Yeast. 1995 Jul;11(9):829–838. doi: 10.1002/yea.320110905. [DOI] [PubMed] [Google Scholar]
  76. Watanabe Y., Miwa S., Tamai Y. Characterization of Na+/H(+)-antiporter gene closely related to the salt-tolerance of yeast Zygosaccharomyces rouxii. Yeast. 1995 Jul;11(9):829–838. doi: 10.1002/yea.320110905. [DOI] [PubMed] [Google Scholar]
  77. Williams K. A. Three-dimensional structure of the ion-coupled transport protein NhaA. Nature. 2000 Jan 6;403(6765):112–115. doi: 10.1038/47534. [DOI] [PubMed] [Google Scholar]
  78. Yamaguchi A., Adachi K., Akasaka T., Ono N., Sawai T. Metal-tetracycline/H+ antiporter of Escherichia coli encoded by a transposon Tn10. Histidine 257 plays an essential role in H+ translocation. J Biol Chem. 1991 Apr 5;266(10):6045–6051. [PubMed] [Google Scholar]
  79. Yamaguchi A., Samejima T., Kimura T., Sawai T. His257 is a uniquely important histidine residue for tetracycline/H+ antiport function but not mandatory for full activity of the transposon Tn10-encoded metal-tetracycline/H+ antiporter. Biochemistry. 1996 Apr 9;35(14):4359–4364. doi: 10.1021/bi952116r. [DOI] [PubMed] [Google Scholar]
  80. Yun C. H., Little P. J., Nath S. K., Levine S. A., Pouyssegur J., Tse C. M., Donowitz M. Leu143 in the putative fourth membrane spanning domain is critical for amiloride inhibition of an epithelial Na+/H+ exchanger isoform (NHE-2). Biochem Biophys Res Commun. 1993 Jun 15;193(2):532–539. doi: 10.1006/bbrc.1993.1656. [DOI] [PubMed] [Google Scholar]
  81. Zong X., Stieber J., Ludwig A., Hofmann F., Biel M. A single histidine residue determines the pH sensitivity of the pacemaker channel HCN2. J Biol Chem. 2000 Nov 28;276(9):6313–6319. doi: 10.1074/jbc.M010326200. [DOI] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES