Phosphorylation-type ATPases (EC 3.6.3.-) are associated with membranes and the transport of ions or phospholipids. A characteristic is the interconversion between E1 and E2 conformations in the activity cycle of the transporters.
Na+/K+-ATPase
The cell-surface Na+/K+-ATPase is an integral membrane protein which regulates the membrane potential of the cell by maintaining gradients of Na+ and K+ ions across the plasma membrane, also making a small, direct contribution to membrane potential, particularly in cardiac cells. The active enzyme is a heteromultimer with incompletely defined stoichiometry, possibly as tetramers of heterodimers, each consisting of one of four large, ten TM domain catalytic α subunits and one of three smaller single TM domain glycoprotein β-subunits (see table). Additional protein partners known as FXYD proteins (e.g. FXYD2, ENSG00000137731) appear to associate with and regulate the activity of the pump.
Unless otherwise stated all data refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
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Na+/K+-ATPases are inhibited by ouabain and cardiac glycosides, such as digoxin, as well as potentially endogenous cardiotonic steroids [1].
Ca2+-ATPases
The sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) is an intracellular membrane-associated pump for sequestering calcium from the cytosol into intracellular organelles, usually associated with the recovery phase following excitation of muscle and nerves.
The plasma membrane Ca2+-ATPase (PMCA) is a cell-surface pump for extruding calcium from the cytosol, usually associated with the recovery phase following excitation of cells. The active pump is a homodimer, each subunit of which is made up of ten TM segments, with cytosolic C- and N-termini and two large intracellular loops.
Secretory pathway Ca2+-ATPases (SPCA) allow accumulation of calcium and manganese in the Golgi apparatus.
Unless otherwise stated all data refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
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The fungal toxin ochratoxin A has been described to activate SERCA in kidney microsomes [2]. cyclopiazonic acid [6], thapsigargin [4] and BHQ are widely employed to block SERCA. Thapsigargin has also been described to block the TRPV1 vanilloid receptor [7].
The stoichiometry of flux through the PMCA differs from SERCA, with the PMCA transporting 1 Ca2+ while SERCA transports 2 Ca2+.
Loss-of-function mutations in SPCA1 appear to underlie Hailey-Hailey disease [3].
H+/K+-ATPase
The H+/K+ ATPase is a heterodimeric protein, made up of α and β subunits. The α subunit has 10 TM domains and exhibits catalytic and pore functions, while the β subunit has a single TM domain, which appears to be required for intracellular trafficking and stabilising the α subunit. The ATP4A and ATP4B subunits are expressed together, while the ATP12A subunit is suggested to be expressed with the β1 (ATP1B1) subunit of the Na+/K+-ATPase [5].
Unless otherwise stated all data refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
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The gastric H+/K+-ATPase is inhibited by (R)-lansoprazole and a metabolite of esomeprazole.
Cu2+-ATPase
Copper-transporting ATPases convey copper ions across cell-surface and intracellular membranes. They consist of eight TM domains and associate with multiple copper chaperone proteins (e.g. ATOX1, ENSG00000177556).
Unless otherwise stated all data refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
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Phospholipid-transporting ATPase
These transporters are thought to translocate the aminophospholipids phosphatidylserine and phosphatidylethanolamine from one side of the phospholipid bilayer to the other.
Unless otherwise stated all data refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
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Loss-of-function mutations in ATP8B1 are associated with type I familial intrahepatic cholestasis.
A further series of structurally-related proteins have been identified in the human genome, with as yet undefined function, including ATP13A1 (ENSG00000105726), ATP13A2 (ENSG00000159363), ATP13A3 (ENSG00000133657), ATP13A4 (ENSG00000127249) and ATP13A5 (ENSG00000187527).
Bagrov, AY; Shapiro, JI; Fedorova, OV. (2009) Endogenous cardiotonic steroids: physiology, pharmacology, and novel therapeutic targets. Pharmacol. Rev., 61 (1): 9-38. [PMID:19325075]
Benarroch, EE. (2011) Na+, K+-ATPase: functions in the nervous system and involvement in neurologic disease. Neurology, 76 (3): 287-93. [PMID:21242497]
Bers, DM; Despa, S. (2009) Na/K-ATPase--an integral player in the adrenergic fight-or-flight response. Trends Cardiovasc. Med., 19 (4): 111-8. [PMID:19818946]
Brini, M. (2009) Plasma membrane Ca(2+)-ATPase: from a housekeeping function to a versatile signaling role. Pflugers Arch., 457 (3): 657-64. [PMID:18548270]
Brini, M; Carafoli, E. (2009) Calcium pumps in health and disease. Physiol. Rev., 89 (4): 1341-78. [PMID:19789383]
Cartwright, EJ; Oceandy, D; Neyses, L. (2009) Physiological implications of the interaction between the plasma membrane calcium pump and nNOS. Pflugers Arch., 457 (3): 665-71. [PMID:18228035]
Di Leva, F; Domi, T; Fedrizzi, L; Lim, D; Carafoli, E. (2008) The plasma membrane Ca2+ ATPase of animal cells: structure, function and regulation. Arch. Biochem. Biophys., 476 (1): 65-74. [PMID:18328800]
Fedorova, OV; Shapiro, JI; Bagrov, AY. (2010) Endogenous cardiotonic steroids and salt-sensitive hypertension. Biochim. Biophys. Acta, 1802 (12): 1230-6. [PMID:20347967]
Floyd, R; Wray, S. (2007) Calcium transporters and signalling in smooth muscles. Cell Calcium, 42 (4-5): 467-76. [PMID:17624426]
Folmer, DE; Elferink, RP; Paulusma, CC. (2009) P4 ATPases - lipid flippases and their role in disease. Biochim. Biophys. Acta, 1791 (7): 628-35. [PMID:19254779]
Inesi, G; Prasad, AM; Pilankatta, R. (2008) The Ca2+ ATPase of cardiac sarcoplasmic reticulum: Physiological role and relevance to diseases. Biochem. Biophys. Res. Commun., 369 (1): 182-7. [PMID:18068669]
Jaitovich, A; Bertorello, AM. (2010) Salt, Na+,K+-ATPase and hypertension. Life Sci., 86 (3-4): 73-8. [PMID:19909757]
Kaler, SG. (2011) ATP7A-related copper transport diseases-emerging concepts and future trends. Nat Rev Neurol, 7 (1): 15-29. [PMID:21221114]
Kawase, Y; Hajjar, RJ. (2008) The cardiac sarcoplasmic/endoplasmic reticulum calcium ATPase: a potent target for cardiovascular diseases. Nat Clin Pract Cardiovasc Med, 5 (9): 554-65. [PMID:18665137]
Lingrel, JB. (2010) The physiological significance of the cardiotonic steroid/ouabain-binding site of the Na,K-ATPase. Annu. Rev. Physiol., 72: 395-412. [PMID:20148682]
Manunta, P; Messaggio, E; Casamassima, N; Gatti, G; Carpini, SD; Zagato, L; Hamlyn, JM. (2010) Endogenous ouabain in renal Na(+) handling and related diseases. Biochim. Biophys. Acta, 1802 (12): 1214-8. [PMID:20226856]
Morth, JP; Pedersen, BP; Buch-Pedersen, MJ; Andersen, JP; Vilsen, B; Palmgren, MG; Nissen, P. (2011) A structural overview of the plasma membrane Na+,K+-ATPase and H+-ATPase ion pumps. Nat. Rev. Mol. Cell Biol., 12 (1): 60-70. [PMID:21179061]
Muthusamy, BP; Natarajan, P; Zhou, X; Graham, TR. (2009) Linking phospholipid flippases to vesicle-mediated protein transport. Biochim. Biophys. Acta, 1791 (7): 612-9. [PMID:19286470]
Patel, S; Docampo, R. (2010) Acidic calcium stores open for business: expanding the potential for intracellular Ca2+ signaling. Trends Cell Biol., 20 (5): 277-86. [PMID:20303271]
Poulsen, H; Morth, P; Egebjerg, J; Nissen, P. (2010) Phosphorylation of the Na+,K+-ATPase and the H+,K+-ATPase. FEBS Lett., 584 (12): 2589-95. [PMID:20412804]
Prassas, I; Diamandis, EP. (2008) Novel therapeutic applications of cardiac glycosides. Nat Rev Drug Discov, 7 (11): 926-35. [PMID:18948999]
Puts, CF; Holthuis, JC. (2009) Mechanism and significance of P4 ATPase-catalyzed lipid transport: lessons from a Na+/K+-pump. Biochim. Biophys. Acta, 1791 (7): 603-11. [PMID:19233312]
Rasmussen, HH; Hamilton, EJ; Liu, CC; Figtree, GA. (2010) Reversible oxidative modification: implications for cardiovascular physiology and pathophysiology. Trends Cardiovasc. Med., 20 (3): 85-90. [PMID:21130951]
Rosenberg, PB. (2009) Calcium entry in skeletal muscle. J. Physiol. (Lond.), 587 (Pt 13): 3149-51. [PMID:19567752]
Scarpignato, C; Hunt, RH. (2008) Proton pump inhibitors: the beginning of the end or the end of the beginning?. Curr Opin Pharmacol, 8 (6): 677-84. [PMID:18840545]
Tadini-Buoninsegni, F; Bartolommei, G; Moncelli, MR; Fendler, K. (2008) Charge transfer in P-type ATPases investigated on planar membranes. Arch. Biochem. Biophys., 476 (1): 75-86. [PMID:18328799]
Taub, M; Springate, JE; Cutuli, F. (2010) Targeting of renal proximal tubule Na,K-ATPase by salt-inducible kinase. Biochem. Biophys. Res. Commun., 393 (3): 339-44. [PMID:20152810]
Toyoshima, C. (2009) How Ca2+-ATPase pumps ions across the sarcoplasmic reticulum membrane. Biochim. Biophys. Acta, 1793 (6): 941-6. [PMID:19010358]
Weidemüller, C; Hauser, K. (2009) Ion transport and energy transduction of P-type ATPases: implications from electrostatic calculations. Biochim. Biophys. Acta, 1787 (6): 721-9. [PMID:19265666]
Wray, S; Burdyga, T. (2010) Sarcoplasmic reticulum function in smooth muscle. Physiol. Rev., 90 (1): 113-78. [PMID:20086075]
Zhang, L; Zhang, Z; Guo, H; Wang, Y. (2008) Na+/K+-ATPase-mediated signal transduction and Na+/K+-ATPase regulation. Fundam Clin Pharmacol, 22 (6): 615-21. [PMID:19049666]
1. Bagrov, AY; Shapiro, JI; Fedorova, OV. (2009) Endogenous cardiotonic steroids: physiology, pharmacology, and novel therapeutic targets. Pharmacol. Rev., 61 (1): 9-38. [PMID:19325075]
2. Chong, X; Rahimtula, AD. (1992) Alterations in ATP-dependent calcium uptake by rat renal cortex microsomes following ochratoxin A administration in vivo or addition in vitro. Biochem. Pharmacol., 44 (7): 1401-9. [PMID:1417961]
3. Hu, Z; Bonifas, JM; Beech, J; Bench, G; Shigihara, T; Ogawa, H; Ikeda, S; Mauro, T; Epstein, EH. (2000) Mutations in ATP2C1, encoding a calcium pump, cause Hailey-Hailey disease. Nat. Genet., 24 (1): 61-5. [PMID:10615129]
4. Lytton, J; Westlin, M; Hanley, MR. (1991) Thapsigargin inhibits the sarcoplasmic or endoplasmic reticulum Ca-ATPase family of calcium pumps. J. Biol. Chem., 266 (26): 17067-71. [PMID:1832668]
5. Pestov, NB; Korneenko, TV; Shakhparonov, MI; Shull, GE; Modyanov, NN. (2006) Loss of acidification of anterior prostate fluids in Atp12a-null mutant mice indicates that nongastric H-K-ATPase functions as proton pump in vivo. Am. J. Physiol., Cell Physiol., 291 (2): C366-74. [PMID:16525125]
6. Seidler, NW; Jona, I; Vegh, M; Martonosi, A. (1989) Cyclopiazonic acid is a specific inhibitor of the Ca2+-ATPase of sarcoplasmic reticulum. J. Biol. Chem., 264 (30): 17816-23. [PMID:2530215]
7. Tóth, A; Kedei, N; Szabó, T; Wang, Y; Blumberg, PM. (2002) Thapsigargin binds to and inhibits the cloned vanilloid receptor-1. Biochem. Biophys. Res. Commun., 293 (2): 777-82. [PMID:12054538]
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