Hormone-receptor interactions are noncooperative: application to the beta-adrenergic receptor.

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Abstract
Kinetic methods were developed with which the negatively cooperative hormone-binding model was demonstrated to be untenable for the insulin receptor system. These methods have led others to the same conclusion for the thyrotropin and nerve growth factor receptors. The application of these methods to the study of (l)-[propyl-2,3-3H]dihydroalprenolol[(l)-[3H]DHA] binding at 15.degree. C to the .beta.-adrenergic receptor of the frog erythrocyte, the remaining and most extensively characterized hormone receptor-cyclase system in which negatively cooperative site-site interactions have been reported, is discussed. Scatchard analysis of the equilibrium binding data for (l)-[3H]DHA in this system is linear. In addition, increasing concentrations of (l)-[3H]DHA during the binding reactions resulted in increasing receptor occupancy but no enhancement of the subsequent dilution-induced dissociation of bound hormone, demonstrating directly that the dissociation rate is independent of occupancy. Analysis of the time course of the approach-to-equilibrium for this system at different hormone concentrations was consistent with reversible hormone binding to a homogeneous class of noncooperative receptors, and the analysis yielded a kinetically estimated equilibrium constant consistent with that derived from the linear equilibrium data. Negatively cooperative site-site interactions are not a significant factor for the .beta.-adrenergic receptor of the frog erythrocyte. For all known hormone receptor systems, the hormone binds noncooperatively to 1 or more classes of independent receptor sites. The need for critical reinterpretation of detailed thermodynamic, clinical and hormone analog studies based on the negative cooperativity model is discussed.