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Abstract:

This study examined how the quaternary organic ammonium ion, benzyltriethylamine (BTEA), binds to the Na,K-ATPase to produce membrane potential (VM)-dependent inhibition and tested the prediction that such a VM-dependent inhibitor would display electrogenic binding kinetics. BTEA competitively inhibited K+ activation of Na,K-ATPase activity and steady-state 86Rb+ occlusion. The initial rate of 86Rb+ occlusion was decreased by BTEA to a similar degree whether it was added to the enzyme prior to or simultaneously with Rb+, a demonstration that BTEA inhibits the Na,K-ATPase without being occluded. Several BTEA structural analogues reversibly inhibited Na,K-pump current, but none blocked current in a VM-dependent manner except BTEA and its para-nitro derivative, pNBTEA. Under conditions that promoted electroneutral K+-K+ exchange by the Na,K-ATPase, step changes in VM elicited pNBTEA-activated ouabain-sensitive transient currents that had similarities to those produced with the K+ congener, Tl+. pNBTEA- and Tl+-dependent transient currents both displayed saturation of charge moved at extreme negative and positive VM, equivalence of charge moved during and after step changes in VM, and similar apparent valence. The rate constant (ktot) for Tl+-dependent transient current asymptotically approached a minimum value at positive VM. In contrast, k tot for pNBTEA-dependent transient current was a "U"-shaped function of VM with a minimum value near 0 mV. Homology models of the Na,K-ATPase alpha subunit suggested that quaternary amines can bind to two extracellularly accessible sites, one of them located at K+ binding sites positioned between transmembrane helices 4, 5, and 6. Altogether, these data revealed important information about electrogenic ion binding reactions of the Na,K-ATPase that are not directly measurable during ion transport by this enzyme. © 2009 American Chemical Society.

Registro:

Documento: Artículo
Título:Quaternary benzyltriethylammonium ion binding to the Na,K-ATPase: A tool to investigate extracellular K+ binding reactions
Autor:Peluffo, R.D.; González-Lebrero, R.M.; Kaufman, S.B.; Kortagere, S.; Orban, B.; Rossi, R.C.; Berlin, J.R.
Filiación:Department of Pharmacology and Physiology, UMDNJ-New Jersey Medical School, Newark, NJ 07101, United States
Instituto de Química Y Fisicoquímica Biológicas, Departamento de Química Biológica, Universidad de Buenos Aires, C1113AAD Buenos Aires, Argentina
Department of Microbiology and Immunology, Drexel University School of Medicine, Philadelphia, PA 19129, United States
Schering-Plough Research Institute, Summit, NJ 07901, United States
Department of Pharmacology and Physiology, UMDNJ-New Jersey Medical School, 195 S. Orange Ave., Newark, NJ 07101-1709, United States
Palabras clave:Ammonium ions; ATP-ase activity; Binding kinetics; Binding reactions; Extracellular; Homology models; Initial rate; Ion binding; Ion transports; Membrane potentials; Minimum value; Pump current; Quaternary amines; Similar degree; Step changes; Structural analogue; Transient current; Transmembrane helices; Amines; Ammonium compounds; Binding energy; Binding sites; Electric fault currents; Enzymes; Ions; Optical devices; Rate constants; Ion exchange; adenosine triphosphatase (potassium sodium); benzyltriethylamine; potassium ion; quaternary ammonium derivative; rubidium ion; unclassified drug; amino acid sequence; animal cell; article; binding competition; controlled study; enzyme activation; enzyme binding; heart muscle fiber membrane; nonhuman; patch clamp; potassium transport; priority journal; rat; transport kinetics; Animals; Binding Sites; Dogs; Electric Conductivity; Enzyme Inhibitors; Extracellular Space; Membrane Potentials; Models, Biological; Models, Molecular; Nitro Compounds; Potassium; Protein Binding; Protein Conformation; Quaternary Ammonium Compounds; Rabbits; Rats; Rubidium; Sodium-Potassium-Exchanging ATPase; Time Factors; Strophanthus gratus
Año:2009
Volumen:48
Número:34
Página de inicio:8105
Página de fin:8119
DOI: http://dx.doi.org/10.1021/bi900687u
Título revista:Biochemistry
Título revista abreviado:Biochemistry
ISSN:00062960
CODEN:BICHA
CAS:potassium ion, 24203-36-9; rubidium ion, 22537-38-8; Enzyme Inhibitors; Nitro Compounds; Potassium, 7440-09-7; Quaternary Ammonium Compounds; Rubidium, 7440-17-7; Sodium-Potassium-Exchanging ATPase, 3.6.3.9
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00062960_v48_n34_p8105_Peluffo

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Citas:

---------- APA ----------
Peluffo, R.D., González-Lebrero, R.M., Kaufman, S.B., Kortagere, S., Orban, B., Rossi, R.C. & Berlin, J.R. (2009) . Quaternary benzyltriethylammonium ion binding to the Na,K-ATPase: A tool to investigate extracellular K+ binding reactions. Biochemistry, 48(34), 8105-8119.
http://dx.doi.org/10.1021/bi900687u
---------- CHICAGO ----------
Peluffo, R.D., González-Lebrero, R.M., Kaufman, S.B., Kortagere, S., Orban, B., Rossi, R.C., et al. "Quaternary benzyltriethylammonium ion binding to the Na,K-ATPase: A tool to investigate extracellular K+ binding reactions" . Biochemistry 48, no. 34 (2009) : 8105-8119.
http://dx.doi.org/10.1021/bi900687u
---------- MLA ----------
Peluffo, R.D., González-Lebrero, R.M., Kaufman, S.B., Kortagere, S., Orban, B., Rossi, R.C., et al. "Quaternary benzyltriethylammonium ion binding to the Na,K-ATPase: A tool to investigate extracellular K+ binding reactions" . Biochemistry, vol. 48, no. 34, 2009, pp. 8105-8119.
http://dx.doi.org/10.1021/bi900687u
---------- VANCOUVER ----------
Peluffo, R.D., González-Lebrero, R.M., Kaufman, S.B., Kortagere, S., Orban, B., Rossi, R.C., et al. Quaternary benzyltriethylammonium ion binding to the Na,K-ATPase: A tool to investigate extracellular K+ binding reactions. Biochemistry. 2009;48(34):8105-8119.
http://dx.doi.org/10.1021/bi900687u