RECEPTOR ACTIVATION BY 2 AGONISTS - ANALYSIS BY NONLINEAR-REGRESSION AND APPLICATION TO N-METHYL-D-ASPARTATE RECEPTORS

The activation of a receptor by two agonists is described by a mathematical model based on the assumption that the response of the receptor is a linear function of its occupancy. The model has six parameters: The basal response, three efficacies corresponding to two binary and one ternary complexes, the affinities of the two agonists, and a parameter describing mutual changes in the affinity of the agonists. A method is described to determine the parameters of the model by two successive fittings to the logistic sigmoidal function using nonlinear regression. This method was applied to study the activation of N-methyl-D-aspartate receptors by glutamate and glycine, measured with [3H]dizocilpine binding under nonequilibrium conditions. Experimental data fitted the model well, and consistent parameter values were obtained in three independent experiments. The efficacies with one agonist (glutamate or glycine) were very low compared with the efficacy with the two agonists combined, indicating that both glutamate and glycine are required for the activation of N-methyl-D-aspartate receptors. Glutamate and glycine also mutually increased their affinities for the receptor. This method may be useful for characterizing partial agonists, antagonists, and inverse agonists of receptors with multiple modulatory sites. © 1994 Academic Press, Inc. All rights reserved.