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- P-type ATPases
Overview
Phosphorylation-type ATPases (EC 3.6.3.-) are associated with membranes and the transport of ions or phospholipids. Characteristics of the family are the transient phosphorylation of the transporters at an aspartate residue and the interconversion between E1 and E2 conformations in the activity cycle of the transporters, taken to represent ‘half-channels’ facing the cytoplasm and extracellular/luminal side of the membrane, respectively.
Sequence analysis across multiple species allows the definition of five subfamilies, P1-P5. The P1 subfamily includes heavy metal pumps, such as the copper ATPases. The P2 subfamily includes calcium, sodium/potassium and proton/potassium pumps. The P4 and P5 subfamilies include putative phospholipid flippases.
Further reading
* Key recommended reading is highlighted with an asterisk
* Aperia A, Akkuratov EE, Fontana JM, Brismar H. (2016) Na+-K+-ATPase, a new class of plasma membrane receptors. Am J Physiol, Cell Physiol, 310 (7): C491-5. [PMID:26791490]
Argüello JM, Raimunda D, González-Guerrero M. (2012) Metal transport across biomembranes: emerging models for a distinct chemistry. J Biol Chem, 287 (17): 13510-7. [PMID:22389499]
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]
* Brini M, Carafoli E, Calì T. (2017) The plasma membrane calcium pumps: focus on the role in (neuro)pathology. Biochem Biophys Res Commun, 483 (4): 1116-1124. [PMID:27480928]
* Bruce JIE. (2018) Metabolic regulation of the PMCA: Role in cell death and survival. Cell Calcium, 69: 28-36. [PMID:28625348]
Bublitz M, Musgaard M, Poulsen H, Thøgersen L, Olesen C, Schiøtt B, Morth JP, Møller JV, Nissen P. (2013) Ion pathways in the sarcoplasmic reticulum Ca2+-ATPase. J Biol Chem, 288 (15): 10759-65. [PMID:23400778]
Bueno-Orovio A, Sánchez C, Pueyo E, Rodriguez B. (2014) Na/K pump regulation of cardiac repolarization: insights from a systems biology approach. Pflugers Arch, 466 (2): 183-93. [PMID:23674099]
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]
Cereijido M, Contreras RG, Shoshani L, Larre I. (2012) The Na+-K+-ATPase as self-adhesion molecule and hormone receptor. Am J Physiol, Cell Physiol, 302 (3): C473-81. [PMID:22049208]
Contreras-Ferrat A, Lavandero S, Jaimovich E, Klip A. (2014) Calcium signaling in insulin action on striated muscle. Cell Calcium, 56 (5): 390-6. [PMID:25224502]
Crambert G. (2014) H-K-ATPase type 2: relevance for renal physiology and beyond. Am J Physiol Renal Physiol, 306 (7): F693-700. [PMID:24431203]
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]
* Diederich M, Muller F, Cerella C. (2017) Cardiac glycosides: From molecular targets to immunogenic cell death. Biochem Pharmacol, 125: 1-11. [PMID:27553475]
* Dubois C, Prevarskaya N, Vanden Abeele F. (2016) The calcium-signaling toolkit: Updates needed. Biochim Biophys Acta, 1863 (6 Pt B): 1337-43. [PMID:26658643]
* Dyla M, Basse Hansen S, Nissen P, Kjaergaard M. (2019) Structural dynamics of P-type ATPase ion pumps. Biochem Soc Trans, 47 (5): 1247-1257. [PMID:31671180]
* Dyla M, Kjærgaard M, Poulsen H, Nissen P. (2020) Structure and Mechanism of P-Type ATPase Ion Pumps. Annu Rev Biochem, 89: 583-603. [PMID:31874046]
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]
Galougahi KK, Liu CC, Bundgaard H, Rasmussen HH. (2012) β-Adrenergic regulation of the cardiac Na+-K+ ATPase mediated by oxidative signaling. Trends Cardiovasc Med, 22 (4): 83-7. [PMID:23040838]
Gupta SP. (2012) Quantitative structure-activity relationship studies on Na+,K(+)-ATPase inhibitors. Chem Rev, 112 (6): 3171-92. [PMID:22360614]
Inesi G, Pilankatta R, Tadini-Buoninsegni F. (2014) Biochemical characterization of P-type copper ATPases. Biochem J, 463 (2): 167-76. [PMID:25242165]
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]
* Krebs J. (2015) The plethora of PMCA isoforms: Alternative splicing and differential expression. Biochim Biophys Acta, 1853 (9): 2018-24. [PMID:25535949]
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]
* Little R, Cartwright EJ, Neyses L, Austin C. (2016) Plasma membrane calcium ATPases (PMCAs) as potential targets for the treatment of essential hypertension. Pharmacol Ther, 159: 23-34. [PMID:26820758]
Lopez-Marques RL, Theorin L, Palmgren MG, Pomorski TG. (2014) P4-ATPases: lipid flippases in cell membranes. Pflugers Arch, 466 (7): 1227-40. [PMID:24077738]
Lopreiato R, Giacomello M, Carafoli E. (2014) The plasma membrane calcium pump: new ways to look at an old enzyme. J Biol Chem, 289 (15): 10261-8. [PMID:24570005]
López-Marqués RL, Holthuis JC, Pomorski TG. (2011) Pumping lipids with P4-ATPases. Biol Chem, 392 (1-2): 67-76. [PMID:21194369]
* López-Marqués RL, Poulsen LR, Bailly A, Geisler M, Pomorski TG, Palmgren MG. (2015) Structure and mechanism of ATP-dependent phospholipid transporters. Biochim Biophys Acta, 1850 (3): 461-475. [PMID:24746984]
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]
Mattle D, Sitsel O, Autzen HE, Meloni G, Gourdon P, Nissen P. (2013) On allosteric modulation of P-type Cu(+)-ATPases. J Mol Biol, 425 (13): 2299-308. [PMID:23500486]
Michelangeli F, East JM. (2011) A diversity of SERCA Ca2+ pump inhibitors. Biochem Soc Trans, 39 (3): 789-97. [PMID:21599650]
* Migocka M. (2015) Copper-transporting ATPases: The evolutionarily conserved machineries for balancing copper in living systems. IUBMB Life, 67 (10): 737-45. [PMID:26422816]
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]
* Padányi R, Pászty K, Hegedűs L, Varga K, Papp B, Penniston JT, Enyedi Á. (2016) Multifaceted plasma membrane Ca(2+) pumps: From structure to intracellular Ca(2+) handling and cancer. Biochim Biophys Acta, 1863 (6 Pt B): 1351-63. [PMID:26707182]
Palmgren MG, Nissen P. (2011) P-type ATPases. Annu Rev Biophys, 40: 243-66. [PMID:21351879]
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]
Pittman JK. (2011) Vacuolar Ca(2+) uptake. Cell Calcium, 50 (2): 139-46. [PMID:21310481]
Pizzo P, Lissandron V, Capitanio P, Pozzan T. (2011) Ca(2+) signalling in the Golgi apparatus. Cell Calcium, 50 (2): 184-92. [PMID:21316101]
* Pomorski TG, Menon AK. (2016) Lipid somersaults: Uncovering the mechanisms of protein-mediated lipid flipping. Prog Lipid Res, 64: 69-84. [PMID:27528189]
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]
Reinhard L, Tidow H, Clausen MJ, Nissen P. (2013) Na(+),K (+)-ATPase as a docking station: protein-protein complexes of the Na(+),K (+)-ATPase. Cell Mol Life Sci, 70 (2): 205-22. [PMID:22695678]
* Retamales-Ortega R, Vio CP, Inestrosa NC. (2016) P2C-Type ATPases and Their Regulation. Mol Neurobiol, 53 (2): 1343-54. [PMID:25631710]
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]
Sebastian TT, Baldridge RD, Xu P, Graham TR. (2012) Phospholipid flippases: building asymmetric membranes and transport vesicles. Biochim Biophys Acta, 1821 (8): 1068-77. [PMID:22234261]
Sikkel MB, Hayward C, MacLeod KT, Harding SE, Lyon AR. (2014) SERCA2a gene therapy in heart failure: an anti-arrhythmic positive inotrope. Br J Pharmacol, 171 (1): 38-54. [PMID:24138023]
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]
* Tadini-Buoninsegni F, Smeazzetto S. (2017) Mechanisms of charge transfer in human copper ATPases ATP7A and ATP7B. IUBMB Life, 69 (4): 218-225. [PMID:28164426]
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]
How to cite this family page
Database page citation:
P-type ATPases. Accessed on 12/07/2025. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=138.
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Kelly E, Mathie A, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Pawson AJ, Sharman JL, Southan C, Davies JA; CGTP Collaborators. (2019) The Concise Guide to PHARMACOLOGY 2019/20: Transporters. Br J Pharmacol. 176 Issue S1: S397-S493.
