Hormone messenger systems

Figure 10.1 ThecyclicAMPsecondmessengersystem.Themostcommonsecond messenger system activated by the protein/peptide hormones and the catecholamines involves the formation of cAMP. This multistep process is initiated by binding of the hormone (the first messenger) to its receptor on the cell surface. The subsequent increase in the formation of cAMP (the second messenger) leads to the alteration of enzyme activity within the cell. A change in the activity of these enzymes alters cellular metabolism.

As with signal transduction and second messenger systems, the mechanism of gene activation allows for amplification of the hormone s effect. 

Hormonal actions on target neurons are classified in terms of cellular mechanisms of action. Hormones act either via cell-surface or intracellular receptors. Peptide hormones and amino-acid derivatives, such as epinephrine, act on cell-surface receptors that do such things as open ion-channels, cause rapid electrical responses and facilitate exocytosis of hormones or neurotransmitters. Alternatively, they activate second-messenger systems at the cell membrane, such as those involving cAMP, Ca2+/ calmodulin or phosphoinositides (see Chs 20 and 24), which leads to phosphorylation of proteins inside various parts of the target cell (Fig. 52-2A). Steroid hormones and thyroid hormone, on the other hand, act on intracellular receptors in cell nuclei to regulate gene expression and protein synthesis (Fig. 52-2B). Steroid hormones can also affect cell-surface events via receptors at or near the cell surface. 

FIGURE 52-2 There are two modes of hormonal action. (A) Activation of cell-surface receptors and coupled second-messenger systems, with a variety of intracellular consequences. (B) Entry of hormone into the target cell, binding to and activation of an intracellular receptor and binding of the receptor-hormone complex to specific DNA sequences to activate or repress gene expression. DAG, diacylglycerol HRE, hormone-response element. 

The effects of Li+ upon this system have been reviewed in depth by Mork [131]. Animal studies originally demonstrated that Li+ inhibits cAMP formation catalyzed by adenylate cyclase in a dose-dependent manner [132]. The level of cAMP in the urine of manic-depressive patients changes with mental state, being abnormally elevated during the switch period between depression and mania it is proposed that Li+ s inhibitory effect upon adenylate cyclase activity may correct this abnormality. Subsequent research, in accord with the initial experiments, have shown that Li+ s interference with this second messenger system involves more than one inhibitory action. At therapeutic levels, Li+ inhibits cAMP accumulation induced by many neurotransmitters and hormones, both in... 

Water-soluble hormones must transmit signals to affect metabolism and gene ejcpression without themselves entering the cytoplasm. They often do so via second messenger systems that, in turn, activate protein kinases. 

The effector systems result in changes in messenger systems that then cause the effects of the hormone. Not surprisingly, the effects of the hormone depend on which hormone is being considered. To illustrate this four hormones - insulin, cortisol, adrenaline and glucagon - are discussed. 

New drug targets have been generated by characterizing the importance of hormones and second messenger systems in the pathophysiology and treatment of anxiety disorders. Neuropeptides and neuroactive steroids are at least in part synthesized and released in the brain independent from their peripheral activity. 

Because lithium affects second-messenger systems involving both activation of adenylyl cyclase and phosphoinositol turnover, it is not surprising that G proteins are also found to be affected. Several studies suggest that lithium may uncouple receptors from their G proteins indeed, two of lithium s most common side effects, polyuria and subclinical hypothyroidism, may be due to uncoupling of the vasopressin and thyroid-stimulating hormone (TSH) receptors from their G proteins. 

The outline of another important second-messenger system was elucidated during the last few years. Chemical messengers that act via this system include a variety of hormones (e.g., catecholamines, vasopressin, and angiotensin) as well as some neurotransmitters (e.g., acetylcholine acting on pancreatic acinar cells to stimulate secretion of digestive... 

An example of a hormone that exerts its effects through a surface receptor-second messenger system is ACTH.36 ACTH is a polypeptide that binds to a surface receptor on adrenal cortex cells. The surface receptor then stimulates the adenylate cyclase enzyme to increase production of cAMP, which acts as a second messenger (the hormone was the first messenger), and increases the activity of other enzymes within the cell to synthesize adrenal steroids such as cortisol. For a more detailed description of surface receptor-second messenger systems, see Chapter 4. 

In no model pheromone biosynthetic system is the molecular mechanism of hormonal regulation completely understood. The mechanism of action of JH and the nature of its receptor remain one of the mysteries of insect science, and the clear-cut action of JH by itself in inducing specific genes in pheromone production in bark beetles offers an excellent model for study. A better understanding of the PBAN receptor and the second messenger system it triggers as well as the steps regulated in pheromone biosynthesis is also needed. The next several years should see some of the key questions answered in model insects. 

Most hormones influence cell metabolism through second messengers, as already stated. There are two major forms the cyclic AMP (see Chapter 10) and the Ca2+ systems. The various hormones, neurotransmitters, and other metabolic mediators elicit the activation of either one or the other system by binding to their specific receptors. Table 16.6 summarizes the second messenger systems used by the various hormones. The details of the mode of action of each second messenger system are discussed here. 

In the past few years our understanding of a new second messenger system involving inositol phospholipids has developed rapidly. It is clear the action of many hormones and neurotransmitters depends on the hydrolysis of membrane phosphoin-ositides. Agonists induce the cleavage of Ptdlns 4,5-P2, resulting in the formation... 

On the basis of results obtained from studies in adrenal glomerulosa, vascular smooth muscle and hepatic cells, it is evident that the major effects of All on cell function are mediated via an activation of the calcium messenger system. Furthermore, the data, although far from complete, provide convincing evidence that a temporal and spatial pattern of events underlies hormonal action. 

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