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NEUROPHARMACOLOGY

Modeling the Binding and Function of Metabotropic Glutamate Receptors

Grup Biomatemàtic de Recerca, Institut de Neurociències and Unitat de Bioestadística, Universitat Autònoma de Barcelona, Bellaterra, Spain (X.R., D.R., J.S., J.G.); Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5203, Institut de Génomique Fonctionnelle, Université Montpellier, Montpellier, France (J.K., J.-P.P.); and Institut National de la Santéet de la Recherche Médicale, Unité 661, Université Montpellier, Montpellier, France (J.K., J.-P.P.)

A mathematical model for the binding and function of metabotropic glutamate receptors was developed, with the aim to gain new insights into the functioning of these complex receptors. These receptors are homodimers, and each subunit is composed of a ligand binding [Venus flytrap (VFT)] domain and a heptahelical domain (HD) responsible for G-protein activation. Our mechanistic model integrates all structural information available so far: the various states of the VFT dimer (open-open, closed-open, and closed-closed), as well as the fact that a single HD is active at a time. To provide the model with parameters with biological meaning, two published experimental studies were reanalyzed. The first one reports a negative cooperativity in agonist binding (J Biol Chem 279:35526–35534, 2004), whereas the other indicates a positive cooperativity in agonist-mediated response (Nat Struct Mol Biol 11:706–713, 2004). The former study allowed us to explain the mechanistic features associated with VFT recognition by agonists and antagonists integrating a negative allosteric interaction for agonist binding. The second study helped us to quantitatively describe the functional dynamics of transduction of the VFT occupation into functional response, confirming a putative positive cooperativity at the level of receptor coupling efficacy. This model will help both to better understand the functioning of these receptors and to characterize the mechanism of action of various types of allosteric modulators. Moreover, this model may be of general utility for oligomeric systems in which the ligand binding and effector domains correspond to distinct structural domains.

Address correspondence to: Jesús Giraldo, Grup Biomatemàtic de Recerca, Institut de Neurociències and Unitat de Bioestadística, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain. E-mail: jesus.giraldo{at}uab.es