THE CLUSTER-ARRANGED COOPERATIVE MODEL - A MODEL THAT ACCOUNTS FOR THE KINETICS OF BINDING TO A(1) ADENOSINE RECEPTORS

To explain the equilibrium binding and binding kinetics of ligands to membrane receptors, a number of models have been proposed, none of whi ch is able to adequately describe the experimental findings, in partic ular the apparent negative cooperativity of ligand binding. In this pa per, a new model, the cluster-arranged cooperative model, is presented whose main characteristic is that it explains the existence of negati ve cooperativity in the binding of ligands to the receptor molecule. T he model is based on our findings of agonist binding to Al adenosine r eceptors and of ligand-induced clustering of these receptors on the ce ll surface. The model assumes the existence of two conformational form s of the receptor in an equilibrium which depends on the concentration of the ligand. In this way, negative cooperativity is explained by th e transmission of the information between receptor molecules through t he structure of the membrane. The model is able to predict the thermod ynamic binding and binding kinetics of [H-3]-(R)-(phenylisopropyl)aden osine to A(1) adenosine receptors in the presence and absence of guany lyl imidodiphosphate. In the presence of the guanine nucleotide analog ue, the linear Scatchard plots obtained for [H-3]-(R)-(phenylisopropyl )adenosine binding are explained by the disappearance of cooperativity , thus suggesting that G proteins are important for the existence of n egative cooperativity in ligand binding. Among other predictions, the model justifies early events in homologous desensitization since high ligand concentrations would lead to the saturation of the receptor in a low-affinity conformation that does not signal. Our model can likely explain the behavior of a number of heptaspanning and tyrosine-kinase receptors exhibiting complex binding kinetics.