Hormone Action

In plasma, steroids dissociate from the carrier protein and diffuse through the plasma membrane into the nucleus. Several mechanisms have been identified by which steroids and their receptors may cause cellular responses. These mechanisms appear to be hormone-, receptor-, and cell-specific, and they include ligand-dependent and -independent activation of intracellular receptors in addition to the activation of a putative membrane-bound receptor.

Traditional steroid signaling

The effects of steroids are primarily mediated by their receptors, acting as steroid-activated transcription factors to regulate the expression of a variety of genes. In the absence of ligand, steroid receptors are functionally inactive. These receptors exist in complexes that include one or more receptor molecules, a dimer of the 90-kDa hsp, and a monomer of the 70-kDa hsp. Once bound to the steroid, the receptor dissociates from each of the hsp and undergoes a conformational change that results in posttranslational modifications (Fig. 3). The steroid receptor complex subsequently binds to DNA at SREs within the regulatory regions of target genes. The steroid receptor DNA complex interacts with general transcrip-tional machinery including cofactors, coactivators, or corepressors, resulting in the positive or negative regulation of target gene transcription. Newly synthesized mRNA leaves the nucleus and undergoes translation, which will ultimately result in a biological response by that cell or other cells.[2,6,7]

Novel steroid signaling

In addition to the traditional genomic receptor, functional membrane-bound receptors have been identified for progesterone and estrogen, suggesting the possibility of nongenomic mechanisms of action.[8] Similar findings have been reported for estrogen for which the cell membrane and genomic receptors originate from a single transcript.[8] The rapid, nongenomic effects of steroids appear to be transmitted by nongenomic membrane receptors. Investigators postulate that the activity of these receptors is associated with an influx of intracellular Ca+, suggesting that a membrane receptor or a fragment of one is involved in nongenomic signaling for some steroids.[9] The mechanism is unclear however.

In addition to the ligand-induced actions described previously, some steroid receptors, such as those for

Fig. 3 Steroid dependent gene transactivation. Steroid hormones (S) diffuse through the plasma membrane and bind to specific intracellular proteins called receptors (SR) that are found primarily within the nucleus of target cells, although minute amounts have been localized elsewhere within the cell. Binding of the hormone induces conformational changes in the receptor, resulting in the release of heat shock proteins (70 and 90) from the receptor. The steroid receptor complexes dimerize and bind to specific sites on the DNA, called the steroid response elements (SRE), resulting in the regulation of target gene transcription (mRNA). (From Ref. 7.)

Fig. 3 Steroid dependent gene transactivation. Steroid hormones (S) diffuse through the plasma membrane and bind to specific intracellular proteins called receptors (SR) that are found primarily within the nucleus of target cells, although minute amounts have been localized elsewhere within the cell. Binding of the hormone induces conformational changes in the receptor, resulting in the release of heat shock proteins (70 and 90) from the receptor. The steroid receptor complexes dimerize and bind to specific sites on the DNA, called the steroid response elements (SRE), resulting in the regulation of target gene transcription (mRNA). (From Ref. 7.)

progesterone, can be activated in the absence of the ligand by phosphorylation pathways that modulate the interaction of these receptors with cofactors.[10] In this model, steroid receptor coactivators, such as the steroid receptor coactivator-1 (SRC-1), are activated after phosphorylation is induced by neurotransmitters. The activated coactivator recruits the receptors, forming a hyperphosphorylated transcriptional complex that binds to the SRE in the absence of the steroid. This interaction regulates the transcription of target genes.[11]

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