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Chapter: Biology of Disease: Disorders of the Endocrine System

Mechanisms of Hormonal Action

Hormones act by binding to specific receptors of target cells to form a complex (Figure 7.6) that elicits a cellular response.

MECHANISMS OF HORMONAL ACTION

Hormones act by binding to specific receptors of target cells to form a complex (Figure 7.6) that elicits a cellular response. Only the target tissue will express the receptor for a given hormone and be able to respond to it. Hormone receptors may be located on the surface of the cell or within the cell respectively. Hormones that bind to the former function through what are called second messenger systems, the hormone being the primary or first messenger. Second messengers are small Mr water-soluble molecules and ions that are generally able to move freely throughout the cell. The most common secondary messengers are cyclic adenosine monophosphate (cAMP), the structurally related cyclic guanosine monophosphate (cGMP), Ca2+, inositol triphosphate (IP3), and diacylglycerol (DAG) whose structures are shown in Figure 7.7.






Extracellular receptors are transmembrane proteins that have an extracellular and an intracellular portion joined by a transmembrane domain. Binding of the hormone to the extracellular portion changes the conformation or shape of the complex, such that the intracellular part can catalyze changes to the concentration of the second messenger in the cytosol and amplify the initial signal, that is the binding of the hormone, to produce marked changes in the activities of existing proteins in the target cell.


Amine and peptide and protein hormones are water soluble and cannot easily cross the lipid layer of the plasma membrane. These hormones bind to surface receptors on the plasma membrane (Figure 7.8). G-protein-coupled receptors are the most common cell surface receptors and binding to these results in the activation of adenylate kinase, through a number of proteins whose conformations are changed in turn. Activated adenylate kinase catalyzes the conversion of ATP to the secondary messenger cAMP, whose concentration in the cytoplasm therefore increases.

ATP  +  H2® cAMP  +  PPi

Cyclic AMP, in turn, stimulates protein kinase which then catalyzes the phosphorylation of specific enzymes in the cytosol. Depending on the enzyme, phosphorylation can cause an increase or decrease in activity. A phosphodiesterase inactivates cAMP by hydrolyzing it to AMP and prevents its accumulation in the cytoplasm.

Hormones that recognize intracellular receptors function in an entirely different fashion. Such hormones are able directly to enter the cell where


they regulate the synthesis of proteins. For example, steroid hormones are hydrophobic and lipid soluble and so diffuse directly through the plasma membrane into the cytoplasm of target cells. Thyroid hormones enter their target cells by facilitated diffusion. In the cytoplasm, steroid and thyroid hormones bind to intracellular receptors forming hormone–receptor complexes (Figure 7.10). The complex then interacts with the DNA of specific genes in the nucleus to switch their transcription on or off, allowing or preventing the production of appropriate mRNA molecules respectively. Thus the cell’s production of proteins, such as enzymes, is regulated to produce a physiological response to the hormone.





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