Membrane-Bound Steroid Hormone Receptors

Some cellular responses occur too rapidly following steroid hormone exposure to involve the multi-step process of nuclear receptor activation. For example, 17/6-estradiol can rapidly stimulate adenylate cyclase and cause a near-instantaneous increase in intracellular cAMP in cultured prostate cells. These effects are mediated by the interaction of steroid hormones with cell surface proteins. 

Xenobiotics have the ability to disrupt hormone activity through a variety of mechanisms, though the predominant mechanisms appear to involve binding to the hormone receptor, either as an agonist or antagonist, or by modulating endogenous steroid hormone levels. 

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Figure 17.4 Intracellular steroid receptor activation by hormone ligands, (a) Steroid hormones diffuse across the cell membrane into the cell. (b) Steroid hormone receptors in the basal state bound to accessory proteins, (c) Steroid hormones bind to receptors and accessory proteins are dissociated from the receptors. (d) Hormone receptor complexes dimerize. (e) Dimer complexes enter the nucleus and initiate transcription of responsive genes.

Steroid hormones are produced by the adrenal cortex, testes, ovaries, and placenta. Synthesized from cholesterol, these hormones are lipid soluble therefore, they cross cell membranes readily and bind to receptors found intracellularly. However, because their lipid solubility renders them insoluble in blood, these hormones are transported in the blood bound to proteins. Furthermore, steroid hormones are not typically preformed and stored for future use within the endocrine gland. Because they are lipid soluble, they could diffuse out of the cells and physiological regulation of their release would not be possible. Finally, steroid hormones are absorbed easily by the gastrointestinal tract and therefore may be administered orally. 

Amine hormones include the thyroid hormones and the catecholamines. The thyroid hormones tend to be biologically similar to the steroid hormones. They are mainly insoluble in the blood and are transported predominantly (>99%) bound to proteins. As such, these hormones have longer half-lives (triiodothyronine, t3, = 24 h thyroxine, T4, = 7 days). Furthermore, thyroid hormones cross cell membranes to bind with intracellular receptors and may be administered orally (e.g., synthryoid). In contrast to steroid hormones, however, thyroid hormones have the unique property of being stored extra-cellularly in the thyroid gland as part of the thyroglobulin molecule. 

In the absence of steroid hormones, the receptors remain in an inactive complex, designated the aporeceptor complex. In the aporeceptor complex the receptor is bound to proteins belonging to the chaperone dass. Chaperones are proteins whose levels are increased as a result of a stress situation, such as a rise in ambient temperature. The chaperones assume a central function in the folding process of proteins in the cell. Chaperones aid proteins in avoiding incorrectly folded states. They partidpate in the folding of proteins during and after ribosomal protein biosynthesis, during membrane transport of proteins, and in the correct assembly of protein complexes. 

Metabolism and interactions of metabolic pathways are strongly influenced by hormones and hormonal balance. Therefore, it is worthwhile to examine the effects of hormones on metabolism as well as the potential mechanism of action of the hormones. The mechanism of three major hormones (i.e., insulin, glucagon, and epinephrine) discussed previously are examined as well as others, such as steroid hormones. Many hormones, including those discussed earlier, which cause acute effects on metabolism, do not enter the cell, but must have a transduction to cause intracellular effects, although the hormone itself is bound to a receptor on the membrane. Others, such as steroid and thyroid hormones, enter the cell and have effects in the nucleus. 

Fig. 11.7. Intracellular vs. plasma membrane receptors. Plasma membrane receptors have extracellular binding domains. Intracellular receptors bind steroid hormones or other messengers able to diffuse through the plasma membrane. Their receptors may reside in the cytoplasm and translocate to the nucleus, reside in the nucleus bound to DNA, or reside in the nucleus bound to other proteins.

Most hormones are water-soluble, the main exceptions being the steroid and thyroid hormones. These are more or less insoluble in water and are carried in the bloodstream bound to special carrier proteins. Being hydrophobic, once they have been released from their carrier, they are able to pass through the plasma membrane and bind to specific receptor proteins inside the cell. Whereas water-soluble hormones are usually removed from the bloodstream or broken down within a few minutes, the steroid hormones may remain in the blood for hours and the thyroid hormones for days, so that their effects are usually of relatively long duration. 

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