Cyclic nucleotides, hormone action

Volume XXXVIII. Hormone Action (Part C Cyclic Nucleotides) Edited by Joel G. Hardman and Bert W. O Malley... 

When the hormonal stimulus stops, the intracellular actions of cAMP are terminated by an elaborate series of enzymes. cAMP-stimulated phosphorylation of enzyme substrates is rapidly reversed by a diverse group of specific and nonspecific phosphatases. cAMP itself is degraded to 5 -AMP by several cyclic nucleotide phosphodiesterases (PDE Figure 2-13). Competitive inhibition of cAMP degradation is one way caffeine, theophylline, and other methylxanthines produce their effects (see Chapter 20). 

Volume XXXVIII. Hormone Action (Part C Cyclic Nucleotides)... 

The role of cyclic AMP as modulator of prolactin secretion was first suggested by the finding of a stimulatory effect of cyclic AMP derivatives (17-22) and inhibitors of cyclic nucleotide phosphodiesterase activity such as theophylline and IBMX (22-26) on the secretion of this hormone. More convincing evidence supporting a role of cyclic AMP in the action of dopamine on prolactin secretion had to be obtained, however, by measurement of adenohypophysial adenylate cyclase activity or cyclic AMP accumulation under the influence of the catecholamine. As illustrated in Fig. 1, addition of 100 nM dopamine to male rat hemipituitaries led to a rapid inhibition of cyclic AMP accumulation, a maximal effect (30% inhibition) being already obtained 5 min after addition of the catecholamine. Thus, while dopamine is well known to stimulate adenylate cyclase activity in the striatum (27, 28), its effect at the adenohypophysial level in intact cells is inhibitory. Dopamine has also been found to exert parallel inhibitory effects on cyclic AMP levels and prolactin release in ovine adenohypophysial cells in culture (29) and purified rat mammotrophs (30). Using paired hemipituitaries obtained from female rats, Ray and Wallis (22) have found a rapid inhibitory effect of dopamine on cyclic AMP accumulation to approximately 75% of control. 

Dopamine can thus be added to the list of hormones and neurotransmitters which can stimulate or inhibit cyclic AMP formation, depending upon their tissue of action. Thus, while dopamine stimulates cyclic AMP formation in parathyroid cells, superior cervical ganglia, retina and striatal tissue (27, 58-61), it inhibits the accumulation of the cyclic nucleotide in cells of the intermediate and anterior lobes of the pituitary gland. Opposite effects on the cyclic AMP system are also found with LHRH which stimulates and inhibits cyclic AMP levels in the anterior pituitary gland (62) and ovary (63), respectively. Similarly, alpha-adrenergic agents show opposite effects on cyclic AMP formation in brain (64) and platelets (65). PGE, stimulates cyclic AMP formation in the anterior pituitary gland (62) while it inhibits the same parameter in fat cells (66). 

There has been some work on the nature of the second messengers that mediate the mitogenic actions of prolactin on the crop sac. A role for cyclic GMP has been suggested [100]. Injection of this nucleotide with a small quantity of prolactin into the skin above the crop potentiated the actions of the hormone, although when injected alone the cyclic nucleotide had no effect. 

Ascorbate and Cyclic Nucleotides. Many biological activities are potentiated by hormonal actions that utilize cyclic 3 5 -AMP and cyclic 3 5 -GMP as "second messengers." Lewin (195) has reviewed extensive evidence showing that ascorbate potentiates the formation of cyclic 3 5 -AMP and is concerned in the inhibition of processes that reduce the concentration of both cyclic 3 5 -AMP and cyclic 3 5 -GMP by hydrolyzing them to 5 -AMP and 5 -GMP, respectively. The role of these cyclic nucleotides in cancer is uncertain, but diminished adenyl cyclase activity has been noted in polyoma virus-transformed cells (45), and cyclic 3 5 -AMP has been shown to inhibit cell multiplication in vitro (195) and tumor growth in vivo (130). 

Figure 3.1 shows the nucleotides formed from the purine adenine - the adenine nucleotides, adenosine monophosphate (AMP), adenosine diphosphate (ADP) and adenosine triphosphate (ATP) - as well as the nucleotide triphosphates formed from the purine guanine and the pyrimidine uracil (see also section 10.3.2 for a discussion of the role of cyclic AMP in metabolic regulation and hormone action). 

C. Degradation Stimulation and inhibition of cyclic nucleotide degradation (Sites 5 and 6) are very important mechanisms for controlling their intracellular levels, and to date represent the most fertile sources of prototype drugs. The variety of structures that can influence the activity of the phosphodiesterase enzymes (PDE s) and the importance of these enzymes in drug development have been recently reviewed . Since PDE s are influenced by a number of hormones, e.g., insulin and cholecysto-kinin, it is at least theoretically possible that some drugs could block the action of these hormones on PDE s (Site 7). However, no such drug has yet been found. 

It has been proposed that hormones and neurotransmitters as well as other types of regulatory agents control physiological processes by means of protein phosphorylation (Greengard, 1975, 1976). Some of the protein phosphorylation occurs as a consequence of a hormone receptor-adenylate cyclase-cAMP-protein kinase sequence of action. In other cases, different cyclic nucleotides may replace cAMP, while with cyclic nucleotide-independent protein kinases, other signal molecules. 

Cyclic nucleotides such as cyclic adenosine 3, 5 -monophosphate (cAMP) and cyclic guanosine 3, 5 -mono-phosphate (cGMP) play an important role in cellular signalling as second messengers in response to, for instance, neurotransmitters or hormones. The initial action involves the (hormone) interacting with a G protein-coupled... 

Other evidence for the involvement of a G-protein in the action of insulin has come from studies by Walaas and co-workers [104]. They have demonstrated that insulin stimulated the activity of a cyclic AMP-dependent protein kinase activity in sarcolemma membranes. As this effect of insulin was enhanced if micromolar concentrations of GTP-binding protein were present, they suggested that a guanine nucleotide regulatory protein was involved in the hormonal control of this kinase. Indeed, cholera toxin also appeared to obliterate this action of insulin, as it did the effect of insulin on liver adenylate cyclase and the peripheral plasma membrane cyclic AMP phosphodiesterase in liver. 

Nucleosides and nucleotides are found in places other than as part of the structure of DNA and RNA. We have seen, for example, that adenosine units are part of the structures of two important coenzymes, NADH and coenzyme A. The 5 -triphosphate of adenosine is, of course, the important energy source, ATP (Section 22. IB). The compound called 3, 5 -cyclic adenylic acid (or cyclic AMP) (Fig. 25.6) is an important regulator of hormone activity. Cells synthesize this compound from ATP through the action of an enzyme, adenylate cyclase. In the laboratory, 3, 5 -cyclic adenylic acid can be prepared through dehydration of 5 -adenylic acid with dicyclohexylcarbodiimide. 

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