Hormones second messenger system

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. 

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... 

Thyroxine and catecholamine are examples of hormones that are derived from amino acids they are water soluble and circulate in plasma either bound to proteins (thyroxine) or free (catecholamines). Thyroxine binds avidly to three binding proteins and has a half-life of about 7 to 10 days, and the free and unbound catecholamines such as epinephrine have a very short half-life of a minute or less. As do the water-soluble peptide and protein hormones, these hormones interact with membrane-associated receptors and use a second messenger system. 

Norepinephrine (NE) and epinephrine (EPI) act as neurotransmitters and hormones in both the peripheral and central nervous systems (CNS). NE is released from neurons throughout the CNS and periphery to participate in a variety of physiological fimctions, while both NE and EPI are released from the adrenal medulla in response to stress. NE and EPI modulate fluid homeostasis, cardiac fimction, energy metabolism, and may play a role in depression. At the cellular level, these actions are mediated by multiple adrenergic receptor (AR) subtypes and second messenger systems. 

G-proteins. Studies have demonstrated endogenous ADP-ribosylation of G-proteins in various mammalian tissues (Duman et al., 1991), and recent experiments have shown that endogenous ADP-ribosylation is under the control of specific hormones and second messenger systems (Prune et al., 1990). These findings suggest that regulation of ADP-ribosylation may represent a mechanism by which receptor-coupled signal transduction systems modulate cell function. 

See also Second Messenger Systems, Hormone Receptors, Oncogenes and Cell Signalling, Diabetes, Action of Insulin... 

Lithium is one of the group lA alkali metals (like potassium and sodium) and is not normally present in the body. It acts predominantly through the phosphatidylinositol (PI) second messenger system, causing alterations in calcium- and protein kinase C (PKC)-mediated processes. Lithium can also alter the adenylate cyclase (AC) system, but this action is probably related to its toxic effects. Many calcium-dependent systems may be affected by lithium, among them regulation of receptor sensitivity, parathyroid hormone release, and proper functioning of intracellular microtubule structures. - ... 

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