Activation of ionotropic receptors and thermodynamics of binding

The structure, thermodynamics and activation mechanism of Cys-loop ionotropic receptors such as glycine, nicotinic acetylcholine, 5-HT3-type serotonin and A-type gamma-aminobutyric acid receptors are discussed. Based on the interrelationship of receptor binding and ionophore function, a ternary displacement mechanism of binding including the activation of ionophores is outlined. This displacement model can explain the enigmatic thermodynamic discrimination of agonists versus antagonists of Cys-loop ionotropic receptors. Binding of both agonists and antagonists is exothermic while activation is endothermic driven by large increases in entropy. Closure of the binding cavities around agonists in concert with subunit rotations and/or removal of water-filled crevices between transmembrane (TM) regions can account for entropy increases. Recombinant glycine and gamma-aminobutyric acidA receptors and their point mutations support the predominant role of entropy in receptor activation.