Influence of tetracaine on the structure and function of estrogen receptors

The local anesthetic agent tetracaine has been shown to relax the affinity of estrogen receptors for estradiol and unidentified ligands in uterine cytosols. This effect is dependent on both the temperature of the exchange reaction and the concentration of tetracaine. Increasing the concentration of tetracaine in the system from 0 to 6 mM while keeping the temperature at 10 C results in a stepwise increase in the fractions of receptors that engage in a rapid exchange. Increasing the temperature of the exchange reaction from 0 to 17 C in the presence of 4 mM tetracaine similarly results in a stepwise increase in the fraction of receptors exhibiting the rapid exchange. The combination of 4 mM tetracaine and 10 C achieves the displacement of [3H]estradiol by unlabeled estradiol from the majority of the receptors in 30 min. In addition, tetracaine appears to relax the specificity of the receptors so as to facilitate the displacement of [3H]estradiol from the receptor by otherwise low affinity ligands, such as tamoxifen, nafoxidine, and 17 alpha-(2',3'-dihydroxypropyl)17 beta-estradiol. Tetracaine also dissociates estrogen receptors from other macromolecules in the cytosol, so that the receptors sediment in low salt sucrose gradients an 4S complexes. The data support the view that estrogen receptors of uterine cytosols are functionally microheterogeneous, possibly by virtue of their interactions with other components of the cytosol, and that set fractions of receptors are transformed to a state with a lower affinity for estradiol by specific concentrations of tetracaine at a given temperature. A concept of receptor action is discussed in which the ability of receptors to mediate the interaction of macromolecules may regulate the activity of multienzyme systems or the function of specific chromatin complexes.