The Sodium Pump : Structure Mechanism, Hormonal Control and its Role in Disease

The sodium of animal cell membranes converts the chemical energy obtained from the hydrolysis of adenosine 5' -triphosphate into a movement of the cations Na + and K + against an electrochemical gradient. The gradient is used subse­ quently as an energy source to drive the uptake of metabolic substrates in polar epithelial cells and to use it for purposes of communications in excitable cells. The biological importance of the sodium pump is evident from the fact that be­ tween 20-70% of the cell's metabolic energy is consumed for the pumping pro­ cess. Moreover, the sodium pump is an important biological system involved in regulatory processes like the maintenance of the cells' and organism's water me­ tabolism. It is therefore understandable that special cellular demands are han­ dled better by special isoforms of the sodium pump, that the expression of the sodium pump and their isoforms is regulated by hormones as is the activity of the sodium pump via hormone-regulated protein kinases. Additionally, the sodium pump itself seems to be a receptor for a putative new group of hormones, the endogenous digitalis-like substances, which still have to be defined in most cases in their structure. This group of substances has its chemically well known coun­ terpart in steroids from plant and toad origin which are generally known as "car­ diac glycosides". They are in medical use since at least 200 years in medicine in the treatment of heart diseases.

Gene organization, analysis of the sodium pump by molecular biology.- Transcription factors regulating the Na+/K+-ATPase genes.- Expression of functional Na+/K+-ATPase in yeast.- Expression of functional Na+/K+-ATPase in insect cells using baculovirus.- Sp1 and an E-box binding protein regulate Na+/K+-ATPase ?2-subunit gene.- Cloning and analysis of the 5?-flanking region of the rabbit Na+/K+-ATPase al subunit gene.- Positive and negative transcriptional elements in the chicken Na+/K+-ATPase ?1-subunit gene.- Transcriptional regulation of the Na+/K+-ATPase al gene expression by 8-bromo-cyclic AMP in renal cells.- Cloning of the dog Na +/K + ATPase al-subunit.- Cloning and characterization of a new member of the family of Na +/K+-ATPase genes.- The cloning of homologous Na+/K+-ATPase genes from new species.- Functional expression of the gastric H, K-ATPase in Xenopus oocytes.- Over-expression of the peptide containing the ATP-binding site in Na +/K+-ATPase ?-subunit.- Expression of Na+/K+-ATPase in Saccharomyces cervisiae.- Regulation of Na+/K+-ATPase al and ?1 expression in epithelial cells.- The ?-subunit of the Na+/K+-ATPase has catalytic activity independent of the ß-subunit.- Functional expression of Na+/K+-ATPase a and ? isoforms.- Ca2+/cahnoduIin-sensitive Na+/K+-ATPase activity expressed in chimeric molecules between the plasma membrane Ca2+-ATPase and the Na +IK+-ATPase a-subunit.- Expression of Na+/K+-ATPase and H+/K+-ATPase fusion proteins Sf-9 insect cells.- In vitro synthesis of H+/K+-ATPase polypeptides in insect cells using the baculovirus expression system.- Molecular biology and structure of the calcium pump of sarcoplasmic reticulum.- Functional domains of sarcoplasmic reticulum Ca2+-ATPase studied by site-directed mutagenesis.- Conservation patterns define interactions between transmembrane helices of P-type ion pumps.- Structural studies of Ca2+-ATPase by cryoelectron microscopy.- The topology of sarcoplasmic Ca2+-ATPase and Na+/ K+-ATPase in the M5/M6 region.- Changes of molecular structure and interaction in the catalytic cycle of sarcoplasmic reticulum Ca2+-ATPase. Infrared difference spectra of Ca2+-binding, nucleotide binding, phosphorylation and phosphoenzyme conversion.- Ca2+-binding to sarcoplasmic reticulum Ca2+-ATPase in the absence of chelators.- Electrogenicity and countertransport properties of reconstituted sarcoplasmic reticulum Ca2+-ATPase.- Cell Biology.- Endo-exocytotic sorting of Na+/K+-pumps in developing oocytes and embryos of Xenopus laevis.- Determinants of cell surface distributions of Na+/K+-ATPase in polarized epithelial cells.- Physiologic relevance of the ?2 isoform of Na+/K+-ATPase in muscle and heart.- Na+/K+-ATPase of neurons and glia.- Expression of a truncated ? subunit of the Na+/K+-ATPase (?-1-T) in smooth muscle cells.- The C-terminus of Na+/K+-ATPase ß-subunit contains a hydrophobic assembly domain.- Synthesis and secretion of the extracellular domain of the ß1 subunit isoform of Na +/K+-ATPase into the culture medium of CHO cells.- The amino-terminal transmembrane region of the ? subunit is important for Na +/K+-ATPase complex stability.- Construction and expression of chimeric cDNAs of Na+/K+- and H+/K+-ATPase ?-subunits.- Segregation of maternal Na+/K+-pump al and ß3 mRNAs to animal blastomeres of early Xenopus embryos.- Isoform specific antisera for the Na+/K+-ATPase ßl and ß2 subunits: Localization in fetal rat tissues.- Polyclonal antibodies to extramembrane domains of Na+/K+-ATPase ?l and ?3 isoforms.- Differential axonal transport of individual Na+/K+-ATPase ? subunit isoforms in rat sciatic nerve.- Differential expression of Na+/K+-ATPase isoforms in cultured rodent cardiac and skeletal muscle cells.- Na+/K+-ATPase abundance and activity in HeLa cells transfected with rat ? isoforms.- Aldosterone induces a delayed parallel increase in total and cell-surface Na+/K+-ATPase in A6 kidney cells.- Differential aldosterone effects on two epithelial cell pools of [3H]ouabain binding sites.- Branchial Na+/K+-ATPase expression in the European eel (Anguilla anguilla) following saltwater acclimation.- Differentiation of Na+/K+-ATPase by digoxigenin-labeled lectins on blots. Evidence for organ-typical glycoforms.- Structure and reaction mechanisms of the sodium pump.- Structural requirements for the interaction between the Na+/K+-ATPase ?- and ?-subunits.- Structure and function of ion pumps studied by atomic force microscopy and gene-transfer experiments using chimeric Na+/K+- and Ca2+-ATPases.- Na+/K+-ATPase: Cardiac glycoside binding and functional importance of negatively charged amino acids of transmembrane regions.- Functional analysis of the disulfide bonds of Na+/K+-ATPase ?-subunit by site-directed mutagenesis.- Purified renal Na+/K+-ATPase; subunit structure and structure-function relationships of the N-terminus of the al-subunit.- Organization of the cation binding domain of the Na+/K+-pump.- The stabilization of cation binding and its relation to Na+/K+-ATPase structure and function.- Is the sodium pump a functional dimer.- Atomic force microscopy of crystallized Na+/K+-ATPase.- Scanning force microscopical studies of the Na+/K+-ATPase.- Molecular imaging of purified Na+/K+-ATPase molecules in canine kidney membranes using atomic force microscopy.- Cytoplasmic and extracellular domains in two-dimensional crystals of Ma+/K+-ATPase.- Membrane topology of the a subunit of Na+/K+-ATPase.- Identification of epitopes recognized by Na+/K+-ATPase-directed antibodies.- Probing the ?-subunit folding by dot-sandwich immunochemical analysis.- Determination of sidedness of COOH-terminus of Na+/K+-ATPase ?-subunit by vectorial labeling.- Approaches to disulfide bonds identification in the Na+/K+-ATPase ?-subunit.- Is the cysteine104 part of the sugar binding subsite of the cardiac glycoside receptor of Na +/K+-ATPase.- Towards understanding the molecular mechanism of the inhibitory cardiac glycoside interaction with the receptor enzyme Na+/K+-transporting ATPase.- Palytoxin induces K + release from yeast cells expressing Na+/K+-ATPase.- Bafilomycin and concanamycin derivatives as specific inhibitors of P- and V-type ATPases.- Tertiary amines as cytosolic K+-antagonists of gastric H+/K+-ATPase.- Probing the cation binding site of Na+/K+-ATPase with competitive Na + antagonists.- Structure of the cation occlusion domain of Na+/K+-ATPase studied by proteolysis, interaction with Ca2+ ions and thermal denaturation.- Functional consequences of alterations to Glu329 and other residues in the transmembrane sector of Na+/K+-ATPase.- Identification of Glu779 as an essential part of the cation binding site of the sodium pump.- Rearrangements of the membrane-associated segments of Na+/K+-ATPase upon phosphorylation, ion-occlusion and ouabain binding.- Na+/K+-ATPase: Regulation of K+ access channels by K+.- The ribose conformation of ATP affects the kinetic properties of Na+/K+-ATPase.- ATP accelerates phosphorylation of the Na+/K+-ATPase acting with low apparent affinity.- Effects of ATP on the steady-state level of the phosphoenzyme of pig kidney Na+/K+-ATPase.- A phase-change model of transient kinetics of phosphoenzyme of Na+/K+-ATPase.- The E2 conformation of Na+/K+-ATPase during the Na+-ATPase activity.- Parallel pathway models for electric organ Na+- and Na+/K+-ATPases.- Enzymic activities of solubilized and dissociated (? + ?) chains and of soluble ?? protomers of pig kidney Na+/K+-ATPase.- One phosphorylation site per ??-protomer in reconstituted shark Na+/K+-ATPase.- Protomer association of solubilized Na+/K+-ATPase induced by ATP.- Arginine appears not to be located in the active site of Na+/K+-ATPase.- Does the ?-subunit of the red cell membrane Na+/K+-ATPase exist as a homodimer.- Functional diversity of tissue-specific Na+/K+-pumps delivered from exogenous sources into erythrocytes.- Two-sided bi-directional Na+/K+-ATPase-liposomes. Structure and function.- Electrogenicity and voltage dependence.- Voltage sensitivity of the Na+/K+ pump: Structural implications.- Electrogenic properties of the endogenous and of modified Torpedo Na+/K+-pumps in Xenopus oocytes: The access channel for external cations.- Electrogenic and electroneutral partial reactions in Na+/K+-ATPase from eel electric organ.- Flexibility and constraint in the interpretation of Na +/K + pump electrogenicity: What is an access channel.- Partial reactions in Na+/K+- and H+/K+-ATPase studied with voltage-sensitive fluorescent dyes.- Changes of membrane capacitance coupled with electrogenic transport by the Na+/K+-ATPase.- Reversal potential of Na + pump current in cardioballs at various ?G of ATP hydrolysis.- Characteristics of sodium pump current in guinea-pig and rat dorsal root ganglion neurons.- Kinetic analysis and voltage dependency of ?-3 Na+/K+-pump.- Access channel model for Na + and K + translocation by the Na+/K+-pump.- Na+/K+-pump mutant with a slow charge translocating step.- Analyzing the Na+/K+-pump in outside-out giant membrane patches of Xenopus oocytes.- The role of putative intramembraneous glutamic acid residues of the ?-subunit of the sodium pump in external cation binding.- Conformational states of Na+/K+-ATPase probed with RH-421 and eosin.- Do lipophilic anions affect the spatial organization of the ATP binding site of the Na+/K+-ATPase.- Na+/K+-ATPase: Probing for a high affinity binding site for Na+ by spectrofluorometry.- Interaction between cytoplasmic sodium binding sites and cardiotonic steroids.- Dielectric coefficients of the extracellular release of sodium ions.- Spectroscopy as a tool in Na+/K+-ATPase.- Changes in the conformational state of probe-labeled Na+/K+-ATPase in real time.- Mechanism of the conformational change in fluorescein 5? -isothiocyanate-modified Na +/K+-ATPase.- Relaxation spectroscopy applied to determination of rate constants for ligand binding and dissociation.- Does eosin treat all P-type ATPases equally.- Kinetic analyses of conformational changes and charge transfer by Na+/K+-ATPase.- Reassignment of cation-induced population of main conformational states of FITC-Na+/K+-ATPase as detected by fluorescence spectroscopy and characterized by equilibrium binding studies.- Caged Na + and K + ligands: Photochemical properties, application for membrane transport studies and selective fluorimetric detection of alkali ions.- Kinetic and spectroscopic characterization of the cardiac glycoside binding site of Na+/K+-ATPase employing a dansylated ouabain derivative.- Kinetics and mechanism of cation-binding to Na+/K+-ATPase.- Comparison of E1 and E2 conformers of membrane bound Na+/K+-ATPase using time-resolved phosphorescence anisotropy measurements.- Application of time-resolved phosphorescence anisotropy measurements for the study of rotational mobility of eosin-labeled Na+/K+-ATPase and Ca2+-ATPase.- Pyridoxal-5?-phosphate probe at Lys 480 can monitor conformational events induced by acetyl phosphate in Na+/K+-ATPase.- Phosphorylation of Na+/K+-ATPase by p-nitrophenylphosphate and other phosphatase substrates.- Estimation of distance changes between Cys-964 and Lys-501 in Na+/K+-ATPase intermediates and the orientation of transmembrane segment containing Cys 964.- Hormonal regulation of the sodium pump.- Heterogeneity of distribution and of the regulation by corticosteroids of transport ATPases along the rat collecting tubule.- Hormonal regulation of Na+/K+-ATPase activity.- Regulation of the Na+/K+-pump by insulin.- Phosphorylation of Na+/K+-ATPase by protein kinases: structure-functions relationship.- Stimulation by phorbol 12-myristate 13-acetate (PMA) of Na+/K+-pump mediated 86Rb+-influx into human lymphocytes.- Regulation of the sodium pump by fatty acids and acylglycerols.- Relations of Na+/K+-pump kinetics to polyunsaturated molecular species of plasmalogen-phosphatidylethanolamine in intact human erythrocytes.- Inhibitory actions of monoclonal antibody to phosphatidylserine on Na+/K+-ATPase.- Regulation of sodium pump with physiologically active ligands (prostaglandins, galanin).- Characterization of the molecular isoforms of Na+/K+-ATPase subunits along the rat nephron by polymerase chain reaction.- Increase in Na pump activity of brain-type isoforms via increased turnover rate after glutamate excitation of cerebral neurons.- The ?3 isoform protein of the Na+/K+-ATPase is associated with the sites of neuromuscular and cardiac impulse transmission.- Direct correlation of Na+/K+-ATPase-isoform abundance and myocardial contractility in mouse heart.- Endogenous digitalis-like substances.- Discovery of endogenous ouabain — a new mammalian hormone.- Structure and biological activity of the Na+/K+-ATPase inhibitor isolated from bovine hypothalamus: Difference from ouabain.- Identification and physiological significance of Na+/K+-pump inhibitors in rats.- Endogenous digitalis-like factor from umbilical cord and ouabain: Comparision of biochemical properties.- New steroidal digitalis-like compounds in human cataractous lenses.- Large scale purification of an endogenous Na+/K+-pump inhibitor from bovine adrenal glands.- Demonstration of inhibitors of the sodium pump in human plasma and bovine adrenals cross-reacting with proscillaridin A antibodies.- A labile endogenous Na-pump inhibitor in man.- Ouabain-like immunoreactivity in the brain and the adrenal medulla is increased in DOCA-salt hypertensive rats.- Changes in the endogenous ouabain-like substance in the brain and cerebrospinal fluid after cold-induced vasogenic brain edema.- Modulation of the Ca2+/Mg2+-ATPase activity of synaptosomal plasma membrane vesicles by the hypothalamic hypophysary Na+/K+-ATPase inhibitory factor (HHIF).- Endogenous digitalis in acute myocardial ischemia.- Role of P-type ATPases in disease.- Sensitivity of the failing and nonfailing human heart to cardiac glycosides.- Autoimmune gastritis and H+/K+-ATPase.- Na + modulation of K+ transport by Na+/K+-pump in red eells of salt-sensitive and salt-resistant Dahl rats.- Biochemical characterization of the Na+/K +-ATPase isoforms in human heart.- The canine cardiac ?3 isoform of Na+/K+-ATPase is highly sensitive to digitoxigenin.- Heterogeneous Na+ sensitivities of Na+/K+-ATPase isoenzymes in membranes; modulation by anaesthesia and diets.- Na+/K+-ATPase isoforms in human heart; variation with mammalian species and pathophysiological states.- Non effectiveness of ouabain and decrease in Na+/K+-ATPase affinity for ouabain in failing rabbit heart.- Digoxin treatment and congestive heart failure in light of human cardiac and skeletal muscle digitalis glycoside receptor studies.- Age-related changes in Na+/K+-ATPase and Ca2+-ATPase concentration in rat heart ventricle.- Digoxin induced dysfunction of skeletal muscle potassium homeostasis during exercise.- Na+/K+-ATPase isoform expression in cardiac muscle from Dahl salt-sensitive and salt-resistant rats.- Na+/K+-ATPase from spontaneously hypertensive rats.- Na+/K+-pump ?3 isoform in rat vascular smooth muscle and its physiological role.- Hormonal effects on the expression of Na+/K+-ATPase ?-subunit during pregnancy.- Does human skeletal muscle Na+/K+-ATPase concentration correlate with capacity for muscle performance.- Regulation of the Na+/K+-pump proteins in skeletal muscle: Acute effects of insulin on ?2 distribution and muscle fibre-type specific expression of ? subunits.- Insulin as regulator of skeletal muscle Na+/K+-ATPase concentration in rats with experimental diabetes and patients with diabetes mellitus.- The maximum capacity for active sodium-potassium transport in the slow and fast skeletal muscle of obese (ob/ob) and lean mice.- Alterations in Na+/K+-ATPase isoforms of different tissues in streptozotocin induced diabetes mellitus.- Properties of the oxidized Na+/K+-ATPase.- Modification of Na+/K+-ATPase in a model of epilepsy in the rat.- Tumor development and changes in Na+/K+-pump parameters.- Distinct int...