Hormone binding and coupled response relationships in systems dependent on the generation of secondary mediators.

The relationship between hormone binding and biological response curves is discussed for instances in which the response is dependent upon the generation of a secondary mediator of hormone action. In the simplest model, where the rate of mediator generation is directly proportional to the level of hormone receptor occupancy, and degradation of the secondary mediator follows first-order kinetics, the form of the biological response curve is identical to that for hormone receptor occupancy, but the curve is displaced to the left such that a half-maximal biologic response occurs at less than 50% hormone receptor occupancy (spare-receptor phenomenon). The same is shown to be the case when the model is iterated to include a sequence of coupled intermediate binding reactions intervening between initial hormone binding and the final biological response. When, in contrast, the degradation of one or more of these coupled intermediates is not strictly first order, but instead shows standard Michaelis-Menten kinetics, the response curve, while again remaining parallel to the curve for hormone binding, can now move to the right of the binding curve such that a high threshold is observed for the biological effect, and a half-maximal response may not occur until the level of hormone receptor occupancy is well over 50%. Some consequences of this model are discussed with special reference to the sensitivity and speed of reversibility of the biological response, implications for responses at pharmacological as opposed to physiological concentrations of hormone, and parallels which can be extended to coupled enzymatic reactions of the Michaelis-Menten type.