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Mechanisms and Consequences of Proton Transport pp 19–31Cite as

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

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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).

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References

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  7. Beil, W., Hackbarth, I., and Sewing, K. F. Mechanism of gastric antisecretory effect of SCH 28080. Br. J. Pharmac. 88:19–23, 1986.

    Article  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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. 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. 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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  17. Driel, I. R. and Callaghan, J. M. Proton and potassium transport by H,K-ATPases.. Clin. Exp. Pharm. Physiol. 22: 952–960, 1995.

    Article  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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. 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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  26. Horisberger, J. D. The Na.K-ATPase: Structure-Function Relationship, Austin, TX: R.G. Landes Company, 1994, pp.1–107.

    Google Scholar 

  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. 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.

    CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  30. King, L. A. and Possee, R. D. The Baculovirus Expression System: A Laboratory Guide, London: Chapman & Hall, 1992, pp. 1–222.

    Book  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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. 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. 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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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. 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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  46. Silver, R.B. and Soleimani, M. H,K-ATPases: regulation and role in pathophysiological states Am. J. Physiol. 276, F799–F811, 1999

    PubMed  CAS  Google Scholar 

  47. Skou, J.C. and Esmann, M. The Na,K-ATPase. J. Bioenerg. Biomembr. 24: 249–261, 1992.

    PubMed  CAS  Google Scholar 

  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. 1981

    Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  51. Therien, A, and Blostein R. Mechanisms of sodium pump regulation Am. J. Physiol. Cell. Physiol. 279: C541–C566, 2000.

    Google Scholar 

  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, 2001

    Article  PubMed  CAS  Google Scholar 

  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. 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.

    PubMed  CAS  Google Scholar 

  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. 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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacology, Medical College of Ohio, Toledo, OH, 43614, USA

    Gail Adams, Manoranjani Tillekeratne, Nikolay B. Pestov & Nikolai N. Modyanov

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  1. Gail Adams
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  2. Manoranjani Tillekeratne
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  3. Nikolay B. Pestov
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  1. Graduate School of Pharmaceutical Science, The University of Tokyo, Japan

    Tetsuro Urushidani

  2. Dept. of Molecular & Cell Biology, University of California at Berkeley, USA

    John G. Forte

  3. Center for Ulcer Research & Education, University of California, Los Angeles, USA

    George Sachs

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Adams, G., Tillekeratne, M., Pestov, N.B., Modyanov, N.N. (2002). Human Nongastric H,K-ATPase: Current View On Structure And Functional Properties. In: Urushidani, T., Forte, J.G., Sachs, G. (eds) Mechanisms and Consequences of Proton Transport. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-0971-4_2

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