Receptor Activation Upregulation and Downregulation

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Figure 21.18 Steroid receptor gene superfamily. T3, triiodothyronine; RA, retinoic acid; D3, dihydroxy vitamin D ; E2, estradiol; 3
CORT, cortisol; ANDR, androgen; PROG, progesterone; ALDO, aldosterone. Figure shows roughly the relative sizes of the genes for these receptors. Information derived from the laboratories of R. Evans, K. Yamamoto, P. Chambon, and others. In some cases there is high homology in DNA­binding domains and lower homology in ligand­binding domains.
Thyroid hormone and retinoic acid receptors are also members of the same superfamily of receptors although their ligands are not steroids. They do contain six­
membered rings as shown in Figure 21.19. For some steroid receptors the A ring is the prominent site of recognition by the receptor, presenting the likelihood that the A ring inserts into the binding pocket of the receptor. In some cases, derivatives of the structures with a six­membered ring bind to the estradiol and glucocorticoid receptors. Thus the ring structures of thyroid hormone and retinoic acid have structural similarities not unlike many of the steroidal ligands involved in binding.
The receptors in this large gene family may act as transcriptional activators that together with other transcriptional regulators bring about gene activation.
21.8— Receptor Activation: Upregulation and Downregulation
Little is known about activation of steroid receptors. Activation converts a non­DNA­binding form (unactivated–nontransformed) of the receptor to a form (activated–
transformed) that is able to bind nonspecific DNA or specific DNA (hormone­responsive element). The likelihood that certain receptors are cytoplasmic (glucocorticoid receptor and possibly the mineralocorticoid receptor) while others seem to be nuclear (progesterone, estradiol, vitamin D3, and androgen receptors) may have a bearing on the significance of the activation phenomena. Most information is available for cytoplasmic receptors. The current view is that the non­DNA­
binding form is a heteromeric trimer consisting of one molecule of receptor and a dimer of 90­kDa heat shock protein, as shown in Figure 21.20. The DNA­binding site of the receptor is blocked by the heteromeric proteins or by some other factor or by a combination of both. Upon activation–transformation a stepwise disaggregation of this complex could occur, leading to the activated receptor having its DNA­binding site fully exposed. The reaction may be initiated by the binding of steroid to the ligand­binding site that produces a conformational change in the receptor protein.
Figure 21.19 Structures of retinoic acid (vitamin A acid) and 3,5,3 ­triiodothyronine.
Although the conditions required to induce activation in vitro are well known, the primary signal within the cell is not. Many believe that the binding of ligand alone is not sufficient to cause the activation process. Clearly, elevated temperature is a requirement for this conformational change, since incubation of target cells with appropriate steroids at low temperatures fails to result in in vivo activation and subsequent translocation. Once the liberated receptor is free in the cytoplasm it crosses the perinuclear membrane, perhaps through a nucleopore, to enter the nucleus. It binds nonspecifically and specifically to