Intracellular Receptors And Hormone Signaling

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The intracellular receptors, in contrast to the plasma membrane-bound receptors, can be located in either the cytosol or the nucleus and are distinguished by their mode of acti vation and function. The ligands for these receptors must be lipid soluble because of the plasma membranes that must be traversed for the ligand to reach its receptor. The main result of activation of the intracellular receptors is altered gene expression.

Steroid and Thyroid Hormone Receptors Are Intracellular Receptors Located in the Cytoplasm or Nucleus

For the activation of intracellular receptors to occur, lig-ands must cross the plasma membrane. The hormone lig-ands that belong to this group include the steroids (e.g., estradiol, testosterone, progesterone, cortisone, and aldosterone), 1,25-dihydroxy vitamin D3, thyroid hormone, and retinoids. These hormones are typically delivered to their target cells bound to specific carrier proteins. Because of their lipid solubility, these hormones freely diffuse through both plasma and nuclear membranes. These hormones bind to specific receptors that reside either in the cytoplasm or the nucleus. Steroid hormone receptors are located in the cytoplasm and are usually found complexed with other proteins that maintain the receptor in an inactive conformation. In contrast, the thyroid hormones and retinoic acid bind to receptors that are already bound to response elements in the DNA of specific genes. The unoccupied receptors are inactive until the hormone binds, and they serve as repressors in the absence of hormone. These receptors are discussed in Chapters 31 and 33. The model of steroid hormone action shown in Figure 1.17 is generally applicable to all steroid and thyroid hormones.

All steroid hormone receptors have similar structures, with three main domains. The N-terminal regulatory domain regulates the transcriptional activity of the receptor and may have sites for phosphorylation by protein kinases that may also be involved in modifying the transcriptional activity of the receptor. There is a centrally located DNA-binding domain and a carboxyl-terminal hormone-binding and dimerization domain. When hormones bind, the hormone-receptor complex moves to the nucleus, where it binds to specific DNA sequences in the gene regulatory (promoter) region of specific hormone-responsive genes. The targeted DNA sequence in the promoter is called a hormone response element (HRE). Binding of the hormone-receptor complex to the HRE can either activate or repress transcription. The end result of stimulation by steroid hormones is a change in the readout or transcription of the genome. While most effects involve increased production of specific proteins, repressed production of certain proteins by steroid hormones can also occur. These newly synthesized proteins and/or enzymes will affect cellular metabolism with responses attributable to that particular steroid hormone.

Hormones Bound to Their Receptors Regulate Gene Expression

The interaction of hormone and receptor leads to the activation (or transformation) of receptors into forms with an increased affinity for binding to specific HRE or acceptor sites on the chromosomes. The molecular basis of activation in vivo is unknown but appears to involve a decrease in apparent molecular weight or in the aggregation state of receptors, as determined by density gradient cen-trifugation. The binding of hormone-receptor complexes to chromatin results in alterations in RNA polymerase activity that lead to either increased or decreased transcription of specific portions of the genome. As a result, mRNA is produced, leading to the production of new cellular proteins or changes in the rates of synthesis of preexisting proteins (see Fig. 1.17).

The molecular mechanism of steroid hormone-receptor activation and/or transformation, how the hormone-receptor complex activates transcription, and how the hormone-receptor complex recognizes specific response elements of the genome are not well understood but are under active investigation. Steroid hormone receptors are also known to undergo phosphorylation/dephosphorylation reactions. The effect of this covalent modification is also an area of active research.

Carrier

Carrier

Steroid Mechanism Action

JBflflHHHP^ The general mechanism of action of steroid ^HllllHHIvhormones. Steroid hormones (S) are lipid soluble and pass through the plasma membrane, where they bind to a cognate receptor in the cytoplasm. The steroid hormone-receptor complex then moves to the nucleus and binds to a hormone response element in the promoter-regulatory region of specific hormone-responsive genes. Binding of the steroid hormone-receptor complex to the response element initiates transcription of the gene, to form messenger RNA (mRNA). The mRNA moves to the cytoplasm, where it is translated into a protein that participates in a cellular response. Thyroid hormones are thought to act by a similar mechanism, although their receptors are already bound to a hormone response element, repressing gene expression. The thyroid hormone-receptor complex forms directly in the nucleus and results in the activation of transcription from the thyroid hormone-responsive gene.

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Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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