The structure and regulatory function(s) of cortisol receptor. 1: Extragenomic effects dependent on the cortisol receptor activation.

Abstract

A large body of recent data is consistent with the idea that steroids, at least sex steroid hormones, regulate gene expression in eucariotic cells via a common two-step molecular mechanism. This two-step model has acquired the status of a “dogma” and has become a generally accepted theoretical framework for experimental research being currently conducted. However, this model (dogma) does not take into consideration the immediate extragenomic effects caused by steroids in responsive tissues, nor does it offer the tentative link between extragenomic and genomic events occurring in target cells. The results of our recent studies on cortisol specific receptor and its regulatory functions lead us to propose a new speculative model, the postulates of which are aimed at integrating both the extragenomic and genomic events occurring in target cells during the course of steroid hormone action. The key concepts of the proposed model are the following: the native cytoplasmic holoreceptor should be a multimer, consisting of several different subunits and comprising the defined “metabolic code” for various multiple cooperative metabolic functions. The “activation” of the receptor, caused by the binding of appropriate steroid hormone, results in the disaggregation of the receptor into the monomeric subunits, which play the role of regulatory proteins The released subunits--various regulatory proteins-then exert their control at different levels of the mechanism of genetic expression, including the post-translational level. They modulate the preformed molecules and the activities of the regulatory mechanisms operative in respective target cells like for instance phosphorylation/dephosphorylation mechanism. These events result in modifications of translations on the preformed mRNA’s and cell membrane transport. The resulting changes are immediate and underlie the steroid-induced extragenomic effects. The subunit(s), which binds the steroid hormone, so called “steroidophilic”-subunits, regulates the rate of transcription, i.e. selective and specific gene expression in target cells. This subunit is a key stone in the macromolecular organization of the receptor. It may be of an isoproteinic nature and may have different affinities towards other subunits thus determining the assembly and nature of other associated subunits, giving rise to the tissue specific .receptor polymorphism and causing variations in the “metabolic code” of receptors. “The activation” of receptor, caused by steroids, and resulting in disaggregation of multimer into the monomeric subunits is the key event in the cell responses to steroids. It triggers, controls and links extragenomlc events with gene expression. These extragenomic and genomic events are included in the “metabohc program” encoded in the molecular structure of the receptors. The steroids, as effecters trigger the receptor activation, which controls the sequential and selective metabolic events, underlying the specific physiological “responses” of steroid responsive tissues. In this paper we will present some of our recent data to further substantiate the proposed “model” of the integral steroid hormone action in target tissues.