A metactoid sensitization model to describe multiple receptors linked to a common response: application to histamine receptors coupled to [3H]cyclic AMP accumulation in guinea pig cortex

MN Gannon, LB Hough and H Weinstein

Department of Pharmacology, Mount Sinai School of Medicine, City University of New York, New York 10029.

A metactoid sensitization model was developed to describe and resolve the activities of different receptor subtypes coupled to second messenger interactions. The model was formulated for a system in which activation of one receptor potentiates the measured response to activation of another receptor but does not produce the same direct response on its own. For a case in which both direct and indirect components of the response could be activated by the same agonist, simulations based on the model reveal that the overall agonist EC50 of the measured response cannot be less than the EC50 of the direct response. Unless the indirect receptor is fully activated before agonist occupancy of the direct receptor, the EC50 of the overall response must be greater than the EC50 at the direct receptor. Inhibition of the response by antagonists acting at the direct receptor may not reveal the indirect component, even if the entire response is dependent on simultaneous activation of both receptors. The pattern of inhibition seen with competitive antagonists acting at the indirect receptor would be critically dependent on the difference between agonist affinities for its two receptors. These conditions may thus lead to the misclassification of the receptors through conventional pharmacological techniques. The model was applied to pharmacological data of histamine (HA)-stimulated [3H]cAMP accumulation in a vesicular preparation of guinea pig cerebral cortex. In this system, H1 receptors potentiate the [3H]cAMP response to H2 and/or adenosine receptor activation but have no measurable effect alone. Fitted HA EC50 values at both H1 and H2 receptors agreed well with independent experimental observations in this system. Values were similar in both the presence and absence of an interaction between the response to adenosine and the action of HA on H1 receptors. Similarly, affinity constants for both types of HA receptor antagonists, determined from fitting the pharmacological data to this model, were in agreement with literature values for these drugs. Thus, the metactoid sensitization model adequately describes this system, predicts the experimental data, and indicates experimental conditions for further testing and refinement of the model.

Volume 35, Issue 2, pp. 205-213, 02/01/1989
Copyright © 1989 by American Society for Pharmacology and Experimental Therapeutics