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Thermodynamics of the interaction between oxytocin and its myometrial receptor in sheep: a stepwise binding mechanism.
Journal article

Thermodynamics of the interaction between oxytocin and its myometrial receptor in sheep: a stepwise binding mechanism.

  • Pliska V Collegium Helveticum, Swiss Federal Institute of Technology (ETH-Zürich) and University of Zurich, Schmelzbergstrasse 25, CH-8092 Zürich, Switzerland; Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH-Zürich), Campus Hönggerberg, CH-8093 Zürich, Switzerland. Electronic address: pliska@collegium.ethz.ch.
  • Folkers G Collegium Helveticum, Swiss Federal Institute of Technology (ETH-Zürich) and University of Zurich, Schmelzbergstrasse 25, CH-8092 Zürich, Switzerland; Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH-Zürich), Campus Hönggerberg, CH-8093 Zürich, Switzerland.
  • Spiwok V Department of Biochemistry and Microbiology, Institute of Chemical Technology (VŠCHT-Prague), Technická 5, CZ-166 28 Praha 6, Czech Republic.
  • 2014-07-11
Published in:
  • Biochemical pharmacology. - 2014
Arginine vasopressin
Atosiban: [1-mercaptopropionic acid, 2-D-(O-ethyl)-tyrosine,4-threonine, 8-ornithine]oxytocin
G protein-coupled receptors
GTP-γS: guanosine-5′-O-(3-thiotriphosphate)
Ligand-receptor thermodynamics
Myometrium cell membranes
Oxytocin
Oxytocin inhibitors
Oxytocin receptor
Receptor models
Tritium-labeled arginine vasopressin: [8-arginine, 3-phenylalanine-3,4,5-(3)H]vasopressin
Tritium-labeled oxytocin: [2-tyrosine-2,6-(3)H]oxytocin
Animals
Arginine Vasopressin
Binding Sites
Cell Membrane
Female
Myometrium
Oxytocin
Receptors, Oxytocin
Sheep
Temperature
Thermodynamics
Vasotocin
English Entropy (ΔS), enthalpy (ΔH) and heat capacity (ΔCp) changes attending the oxytocin interaction with its two binding sites on myometrial cell membranes in sheep were derived from the temperature dependence of Kd values. The high affinity oxytocin site (Kd on the order of 10(-9)mol l(-1), 25 °C), ascribed to the oxytocin receptor (OXTR), is entropy-driven in the temperature range 0-37 °C. Enthalpy component prevails as a driving force in the binding to the low affinity site (Kd ≈ 10(-7)) within the higher temperature range. ΔCp values in both cases do not differ significantly from zero but become highly relevant in the presence of a GTP analog (10(-4)M GTP-γS). Under these conditions, ΔCp in the low site interaction becomes negative and ΔS is shifted toward negative values (enthalpy drift); ΔCp of the high affinity site rises to a high positive value and the interaction is even more strongly entropy driven. Atosiban, a competitive antagonist of oxytocin at OXTR displays a single significant binding site on myometrial cells (Kd about 10(-7)mol l(-1)). Thermodynamic profiles of atosiban and the low affinity oxytocin site show conspicuous similarities, indicating that the inhibitor is bound to the low affinity site, and not, with a lower affinity, to the putative receptor protein. It is suggested that the interaction of oxytocin with its responding system on myometrial membranes follows in two distinct steps that are likely to be associated with several independent binding domains in the GPCR receptor.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://sonar.ch/global/documents/143400
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