Human Nongastric H,K-ATPase: Current View On Structure And Functional Properties

  • Gail Adams
  • Manoranjani Tillekeratne
  • Nikolay B. Pestov
  • Nikolai N. Modyanov

Abstract

The P-type ATPases comprise a large number of highly diverse transport ATPases that are predominantly involved in the active transport of cations across biological membranes. All of these ion pumps share a common feature: formation of a phosphorylated intermediate during the reaction cycle (26,39). Different K+-dependent animal ATPases (X,K-ATPases) are the most closely related among various P-type ATPases. All of the known X,K-ATPases function as cation exchangers that pump K+ into the cell and Na+ or H+ out of the cell. X,K-ATPases exhibit a much higher level of sequence homology between their catalytic α-subunits than with other P-ATPases, and contain a second component, a ß-subunit which is absent in other P-ATPases (26,39,53). The catalytic α-subunits are large polytopic proteins (~110 kDa) with 10 transmembrane segments and contain most of the ATPase functional domains such as the ATP-hydrolyzing center and the binding sites for cations and specific inhibitors (8,26,53). The glycosylated ß-subunits (core protein ~ 30–35 kDa) have a relatively short cytoplasmic N-terminal domain, a single transmembrane segment, and a large ectodomain containing three conserved disulfide bridges and several carbohydrate chains (11,19). The X,K-ATPase family combines three distinct groups of ion pumps. Two groups, one consisting of the Na,K-ATPase isozymes formed by four α three ß isoforms and the second which includes the gastric H,K-ATPase, have long been known and studied extensively (26,53). The recently discovered catalytic a-subunits of nongastric H,K-ATPases encoded by the human ATP1 AL1 (alternative name ATP12A) gene and its animal homologues represent the third distinct group (23,27,36).

Keywords

Hydrolysis Carbohydrate Boron Adenosine Pyridine 

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References

  1. 1.
    Adams, G., Tillekeratne, M., Yu, C., Pestov, N. B., and. Modyanov,N. N. Catalytic functions ofnongastric H,K-ATPase expressed in SF-21 insect cells. Biochemistry 40: 5765–5776,2001.PubMedCrossRefGoogle Scholar
  2. 2.
    Asano, S., Hoshina, S., Nakaie, Y., Watanabe, T., Sato, M., Suzuki, Y., and Takeguchi, N. Functional expression of putative H,K- ATPase from guinea pig distal colon. Am. J. Physiol. 275 (CellPhysiol.44): C669–C674, 1998.PubMedGoogle Scholar
  3. 3.
    Asano, S., Matsuda, S., Hoshina, S., Sakamoto, S., and Takeguchi, N. A chimeric gastric H,K-ATPase inhibitable with both ouabain and SCH 28080 J. Biol. Chem. 21 A: 6848–6854, 1999.CrossRefGoogle Scholar
  4. 4.
    Asano, S., Matsuda, S., Tega, Y., Shimizu, K., Sakamoto, S., and Takeguchi, N. Mutational analysis of putative SCH 28080 binding sites of the gastric H,K-ATPase. J. Biol. Chem. 272: 17668–17674,1997.PubMedCrossRefGoogle Scholar
  5. 5.
    Asano, S., Tega, Y., Konishi, K., Fujioka, M., and Takeguchi, N. Functional expression of gastric H,K-ATPase and site-directed mutagenesis of the putative cation binding site and catalytic center. J. Biol. Chem. 271: 2740–2745, 1996.PubMedCrossRefGoogle Scholar
  6. 6.
    Autry, J.M. and L.R. Jones. Functional co-expression of the canine cardiac Ca2+ pump and phospholamban in Spodoptera frugiperda (Sf21) cells reveals new insights on ATPase regulation. J. Biol. Chem.272: 15872–15880, 1997.PubMedCrossRefGoogle Scholar
  7. 7.
    Beil, W., Hackbarth, I., and Sewing, K. F. Mechanism of gastric antisecretory effect of SCH 28080. Br. J. Pharmac. 88:19–23, 1986.CrossRefGoogle Scholar
  8. 8.
    Blanco G. and Mercer, R. W. Isozymes of the Na-K-ATPase: heterogeneity in structure, diversity in function. Am. J. Physiol. 275: F633-F650, 1998.PubMedGoogle Scholar
  9. 9.
    Campbell, W. G., Weiner, I. D., Wingo, C. S., and Cain, B. D. H-K- ATPase in the RCCT-28A rabbit cortical collecting duct cell line. Am. J. Physiol. 276: F237–F245, 1999.Google Scholar
  10. 10.
    Chow, D. C. and Forte, J. G. Characterization of the beta-subunit of the H,K- ATPase using an inhibitory monoclonal antibody. Am. J. Physiol. 265: C1562–C1570, 1993.Google Scholar
  11. 11.
    Chow, D. C. and Forte, J. G. Functional significance of the beta-subunit for heterodimeric P-type ATPases. J. Exp. Biol. 198: 1–17, 1995.PubMedGoogle Scholar
  12. 12.
    Codina, J., Delmas-Mata, J. T., and DuBose, T. D., Jr. The alpha-subunit of the colonic H,K-ATPase assembles with beta 1-Na,K-ATPase in kidney and distal colon. J. Biol. Chem. 273: 7894–7899, 1998.PubMedCrossRefGoogle Scholar
  13. 13.
    Codina, J., Kone, B. C., Delmas-Mata, J. T., and DuBose, T. D., Jr. Functional expression of the colonic H,K-ATPase alpha-subunit. Pharmacologic properties and assembly with X,K-ATPase beta-subunits. J. Biol. Chem. 271: 29759–29763,1996.PubMedCrossRefGoogle Scholar
  14. 14.
    Crambert, G., Hasler, U., Beggah, A.T., Yu, C., Modyanov, N. N., Horisberger, J.-D., Lelievre, L., and Geering, K. Transport and pharmacological properties of nine different human Na,K-ATPase isozymes. J. Biol. Chem. 275: 1976–1986, 2000.PubMedCrossRefGoogle Scholar
  15. 15.
    Crowson, M. S. and Shull, G. E. Isolation and characterization of a cDNA encoding the putative distal colon H,K-ATPase. Similarity of deduced amino acid sequence to gastric H,K-ATPase and Na,K-ATPase and mRNA expression in distal colon, kidney, and uterus. J. Biol. Chem. 267: 13740–13748, 1992.PubMedGoogle Scholar
  16. 16.
    Croyle, M. L., Woo, A. L., and Lingrel, J. B. Extensive random mutagenesis analysis of the Na,K-ATPase alpha subunit identifies known and previously unidentified amino acid residues that alter ouabain sensitivity-implications for ouabain binding. Eur. J. Biochem. 248:488–495,1997.PubMedCrossRefGoogle Scholar
  17. 17.
    Driel, I. R. and Callaghan, J. M. Proton and potassium transport by H,K-ATPases.. Clin. Exp. Pharm. Physiol. 22: 952–960, 1995.CrossRefGoogle Scholar
  18. 18.
    Forte, J. G., Ganser, A., Beesley, R., and Forte, T. M. Unique enzymes of purified microsomes from pig fundic mucosa. K-stimulated adenosine triphosphatase and K-stimulated pNPPase. Gastroenterology 69: 175–189, 1975.PubMedGoogle Scholar
  19. 19.
    Geering, K. The functional role of the beta-subunit in the maturation and intracellular transport of Na,K-ATPase. FEBSLett. 285: 189–193,1991.CrossRefGoogle Scholar
  20. 20.
    Geering, K., Crambert, G., Yu, C., Korneenko, T. V., Pestov, N. B., and Modyanov, N. N., Intersubunit interactions in human X,K-ATPases: role of membrane domains M9 and MIO in the assembly process and association efficiency of human, nongastric H,K-ATPase alpha subunits (ATP1all) with known beta subunits. Biochemistry 39: 12688–12698,2000.PubMedCrossRefGoogle Scholar
  21. 21.
    Grishin, A. V., Bevensee, M. O., Modyanov, N. N., Rajendran, V., Boron, W. F., and Caplan, M. J. Functional expression of the cDNA encoded by the human ATP1AL1 gene. Am. J. Physiol. 271: F539–F551, 1996.Google Scholar
  22. 22.
    Grishin, A. V. and Caplan, M. J. ATP1AL1, a member of the non-gastric H,K-ATPase family, functions as a sodium pump. J. Biol. Chem. 273: 27772–27778, 1998.PubMedCrossRefGoogle Scholar
  23. 23.
    Grishin, A. V., Reinhard, J., Dunbar, L. A., Courtois-Coutry, N., Wang, T., Giebisch, G., and Caplan, M. J. Nongastric H,K-ATPase: cell biologic and functional properties Semin. Nephrol. 19:421–430, 1999.PubMedGoogle Scholar
  24. 24.
    Grishin, A.V., Sverdlov, V.E., Kostina, M.B., and Modyanov, N. N. Cloning and characterization of the entire cDNA encoded by ATP1AL1--a member of the human Na,K/H,K-ATPase gene family. FEBS Lett. Jul 25: 349: 144–150, 1994.PubMedCrossRefGoogle Scholar
  25. 25.
    Hansen, O. Interaction of cardiac glycosides with Na,K-activated ATPase. A biochemical link to digitalis-induced inotropy. Pharmacol. Rev. 36: 143–163,1984.PubMedGoogle Scholar
  26. 26.
    Horisberger, J. D. The Na.K-ATPase: Structure-Function Relationship, Austin, TX: R.G. Landes Company, 1994, pp.1–107.Google Scholar
  27. 27.
    Jaisser, F. and Beggah, A. T. The nongastric H,K-ATPases: molecular and functional properties. Am. J. Physiol. 276: F812-F824, 1999.Google Scholar
  28. 28.
    Korneenko, T. V., Pestov, N. B., Egorov, M. V., Ivanova, M.V., Kostina, M. B., and Shakhparonov, M. I. Monoclonal antibodies to the alpha-subunit of the putative human H,K-ATPase encoded by the ATP1AL1 gene. Russian J. Bioorgan. Chem. 23: 800–804, 1997.Google Scholar
  29. 29.
    Keeling, D. J., Taylor, A. G., and Schudt, C. The binding of a K+ competitive ligand, 2-methyl,8-(phenylmethoxy)imidazo(l,2-a)pyridine 3-acetonitrile, to the gastric H,K-ATPase. J. Biol. Chem. 264: 5545–5551, 1989.PubMedGoogle Scholar
  30. 30.
    King, L. A. and Possee, R. D. The Baculovirus Expression System: A Laboratory Guide, London: Chapman & Hall, 1992, pp. 1–222.CrossRefGoogle Scholar
  31. 31.
    Kraut, J. A., Hiura, J., Shin, J. M., Smolka, A., Sachs, G. and Scott, D. The Na,K-ATPase beta 1 subunit is associated with the HK alpha 2 protein in the rat kidney. Kidney Int. 53: 958–962, 1998.PubMedCrossRefGoogle Scholar
  32. 32.
    Lambrecht, N., Munson, K., Vagin, O., and Sachs, G. Comparison of covalent with reversible inhibitor binding sites of the gastric H,K-ATPase by site-directed mutagenesis. J. Biol. Chem. 275: 4041–4048, 2000.PubMedCrossRefGoogle Scholar
  33. 33.
    Ljungstrom, M. and Mardh, S. Kinetics of the acid pump in the stomach. Proton transport and hydrolysis of ATP and p-nitrophenyl phosphate by the gastric H,K-ATPase. J. Biol. Chem. 260: 5440–5444,1985.PubMedGoogle Scholar
  34. 34.
    Ljungstrom, M., Vega, F.V., and Mardh, S. Effects of pH on the interaction of ligands with the H,K-ATPase purified from pig gastric mucosa. Biochim. Biophys. Acta 769: 220–230, 1984.PubMedCrossRefGoogle Scholar
  35. 35.
    Mendlein, J. and Sachs, G. Interaction of a K+-competitive inhibitor, a substituted imidazo[l,2a] pyridine, with the phospho- and dephosphoenzyme forms of H,K-ATPase J. Biol. Chem. 265: 5030–5036, 1990.PubMedGoogle Scholar
  36. 36.
    Modyanov, N. N., Adams, G., Pestov, N. B., Yu, C., Tillekeratne, M., Korneenko, T. V., Shakhparonov, M.I., Crambert, G., Horisberger, J. D., and Geering, K. Structural and functional properties of human ouabain-sensitive H,K-ATPase. in Na/K-ATPase and Related ATPases, Elsevier, Amsterdam (K. Taniguchi and S. Kanya, eds.) pp. 139–146,2000.Google Scholar
  37. 37.
    Modyanov, N., Mathews, P., Grishin, A., Beguin, P., Beggah, A., Rossier, B., Horisberger, J.-D., and Geering, K. Human ATP1AL1 gene encodes a ouabain-sensitive H-K-ATPase. V(1995)Am. J. Physiol. 269: C992–C997, 1995.Google Scholar
  38. 38.
    Modyanov, N. N., Petrukhin, K. E., Sverdlov, V. E., Grishin, A.V., Orlova, M. Y., Kostina, M. B., Makarevich, O. I., Broude, N. E., Monastyrskaya, G. S., and Sverdlov, E. D. The family of human Na,K-ATPase genes. ATP1AL1 gene is transcriptionally competent and probably encodes the related ion transport ATPase. FEBS Lett. 278: 91–94, 1991.PubMedCrossRefGoogle Scholar
  39. 39.
    Moller, J.V., Juui, B., and le Maire, M. Structural organization, ion transport, and energy transduction of P-type ATPases. Biochim. Biophys. Acta 1286: 1–51,1996.PubMedCrossRefGoogle Scholar
  40. 40.
    Palvani, C., Sachs, G., and Biostein, R. Sodium ions as substitutes for protons in the gastric H.K-ATPase. J. Biol. Chem. 264: 17854–17859, 1989.Google Scholar
  41. 41.
    Pestov, N. B., Adams, G., Shakhparonov, M. I., and Modyanov, N. N. Identification of a novel gene of the X,K-ATPase beta-subunit family that is predominantly expressed in skeletal and heart muscles. FEBSLett. 456: 243–248, 1999.CrossRefGoogle Scholar
  42. 42.
    Pestov, N., Romanova, L., Korneenko, T., Egorov, M., Kostina, M., Sverdlov, V., Askari, A., Shakhparonov, M., and Modyanov, N. Ouabain-sensitive H,K-ATPase: tissue-specific expression of the mammalian genes encoding the catalytic alpha subunit. FEBS Lett. 440: 320–324, 1998.PubMedCrossRefGoogle Scholar
  43. 43.
    Reenstra, W. W., Bettencourt, J. D., and Forte, J. G. Kinetic studies of the gastric H,K-ATPase. Evidence for simultaneous binding of ATP and inorganic phosphate. J. Biol. Chem. 263: 19618–19625, 1988.PubMedGoogle Scholar
  44. 44.
    Sangan, P., Kolla, S. S., Rajendran, V. M., Kashgarian, M., and Binder, H. J. Colonic H-K-ATPase beta-subunit: identification in apical membranes and regulation by dietary K depletion. Am. J. Physiol. 276: C350–360, 1999.PubMedGoogle Scholar
  45. 45.
    Shull, M. M. and Lingrel, J.B. Multiple genes encode the human Na,K-ATPase catalytic subunit. Proc. Natl. Acad. Sei. USA 84: 4039–4043, 1987.CrossRefGoogle Scholar
  46. 46.
    Silver, R.B. and Soleimani, M. H,K-ATPases: regulation and role in pathophysiological states Am. J. Physiol. 276, F799–F811, 1999PubMedGoogle Scholar
  47. 47.
    Skou, J.C. and Esmann, M. The Na,K-ATPase. J. Bioenerg. Biomembr. 24: 249–261, 1992.PubMedGoogle Scholar
  48. 48.
    Stewart, B., Wallmark, B., and Sachs, G. The interaction of H+ and K+ with the partial reactions of gastric H,K-ATPase. J. Biol. Chem. 256: 2628–2690. 1981Google Scholar
  49. 49.
    Sverdlov, E. D., Monastyrskaya, G. S., Broude, N. E., Ushkaryov, Yu. A., Allikmets, R. L., Melkov, A. M., Smirnov, Yu. V., Malyshev, I.V., Dulobova, I.E., Petrukhin, K.E., Grishin, A.V., Kijatkin, N. I., Kostina, M. B., Sverdlov, V., Modyanov, N., and Ovchinnikov, Yu.A. The family of human Na,K-ATPase genes. No less than five genes and/or pseudogenes related to the alpha-subunit. FEBS Lett. 217: 275–278,1987.PubMedCrossRefGoogle Scholar
  50. 50.
    Sverdlov V., Kostina, M., and Modyanov, N. Genomic organization of the human ATP1AL1 gene encoding a ouabain-sensitive H,K-ATPase., Genomics 32: 317–327, 1996.PubMedCrossRefGoogle Scholar
  51. 51.
    Therien, A, and Blostein R. Mechanisms of sodium pump regulation Am. J. Physiol. Cell. Physiol. 279: C541–C566, 2000.Google Scholar
  52. 52.
    Vagin, O., Munson, K., Lambrecht, N., Karlish, S.J., and Sachs G. Mutational analysis of the K-competitive inhibitor site of gastric H,K- ATPase; Biochemistry 40: 7480–7490, 2001PubMedCrossRefGoogle Scholar
  53. 53.
    Van Uem, T. J. F., and De Pont, J. J. H. H. M. Structure and function of gastric H,K-ATPase, in Molecular Aspects of Transport Proteins (De Pont, J. J. H. H. M., Ed.) Elsevier: N.Y. 1992, pp 27–55,1992.Google Scholar
  54. 54.
    Wallmark, B., Stewart, H. B., Rabon, E., Saccomani, G., and Sachs, G. The catalytic cycle of gastric H,K-ATPase. J. Biol. Chem. 255: 5313–5319, 1980.PubMedGoogle Scholar
  55. 55.
    Wingo, C. S. and Smolka, A. J. Function and structure of H-K-ATPase in the kidney. Am. J.Physiol. 269: F1–F16, 1995.Google Scholar
  56. 56.
    Woo, A. L., James, P. F., and Lingrel, J. B. Characterization of the fourth alpha isoform of the Na, K-ATPase. J. Membr. Biol. 169:39–44, 1999.PubMedCrossRefGoogle Scholar
  57. 57.
    Xie, Z. J., Wang Y., Liu G., Zolotarjova, N., Periyasamy, S. M., and Askari, A. Similarities and differences between the properties of native and recombinant Na,K-ATPase. Arch. Biochem. Biophys. 330: 153–162, 1996.PubMedCrossRefGoogle Scholar
  58. 58.
    Yu, C., Xie, Z., Askari, A., and Modyanov, N.N. Enzymatic properties of human Na,K-ATPase alphalbeta3 isozyme. Arch. Biochem. Biophys. 345: 143–149, 1997.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • Gail Adams
    • 1
  • Manoranjani Tillekeratne
    • 1
  • Nikolay B. Pestov
    • 1
  • Nikolai N. Modyanov
    • 1
  1. 1.Department of PharmacologyMedical College of OhioToledoUSA

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