Adenylate cyclase metabolism

Group II assays consist of those monitoring cellular second messengers. Thus, activation of receptors to cause Gs-protein activation of adenylate cyclase will lead to elevation of cytosolic or extracellularly secreted cyclic AMP. This second messenger phosphorylates numerous cyclic AMP-dependent protein kinases, which go on to phosphorylate metabolic enzymes and transport and regulatory proteins (see Chapter 2). Cyclic AMP can be detected either radiometrically or with fluorescent probe technology. 

Figure 11.6 Initiation of a metabolic response to the binding of glucagon to its receptor. (1) glucagon cell surface receptor (2) G protein (3) adenylate cyclase. (See text for further detail)...

Li+ causes malformation and affects regeneration in some protozoans, for example Tetrahymenapyriformis [231], by inhibiting both DNA and RNA synthesis by affecting regeneration in Hydra [232], planarians [233], and annelids [234] and by affecting cell signaling mediated by both inositol phosphate metabolism [235] and adenylate cyclase [236] in slime molds. 

Mehorta and coworkers (1989) observed that isolated fractions of brain and heart cells from rats orally administered 0.5-10 mg endrin/kg showed significant inhibition of Ca+2 pump activity and decreased levels of calmodulin, indicating disruption of membrane Ca+2 transport mechanisms exogenous addition of calmodulin restored Ca+2-ATPase activity. In vitro exposure of rat brain synaptosomes and heart sarcoplasmic reticuli decreased total and calmodulin-stimulated calcium ATPase activity with greater inhibition in brain preparations (Mehorta et al. 1989). However, endrin showed no inhibitory effects on the calmodulin-sensitive calcium ATPase activity when incubated with human erythrocyte membranes (Janik and Wolf 1992). In vitro exposure of rat brain synaptosomes to endrin had no effect on the activities of adenylate cyclase or 3, 5 -cyclic phosphodiesterase, two enzymes associated with synaptic cyclic AMP metabolism (Kodavanti et al. 1988). 

Kacew S, Singhal RL. 1973. The influence of p,p-DDT, a-chlordane, heptachlor, and endrin on hepatic and renal carbohydrate metabolism and cyclic AMP-adenyl cyclase system. Life Sci 13 1363-1371. 

Although details will vary, in each case an agonist at its receptor activates adenylate cyclase and the second messenger cAMP is produced from ATP. cAMP activates protein kinase A and a cascade of reactions may follow. These may be metabolic reactions, as in the cases just described, or activation of a cAMP response-element protein, CREB. CREB is a transcription factor with affinity for specific sites on DNA. Control of protein synthesis follows. 

The induction of this operon responds to the intracellular concentration of cAMP, which is determined by the carbon source available to the cell. When cells are grown on cellobiose or cellulose that do not inhibit adenylate cyclase, cAMP is made in sufficient quantities for induction of cellulase. On the contrary, when cells are grown on glucose or other readily metabolized carbohydrates that do inhibit adenylate cyclase. 

Metabolism. The nucleotide cAMP (adenosine 3, 5 -cyclic monophosphate) is synthesized by membrane-bound adenylate cyclases [1] on the inside of the plasma membrane. The adenylate cyclases are a family of enzymes that cyclize ATP to cAMP by cleaving diphosphate (PPi). The degradation of cAMP to AMP is catalyzed by phosphodiesterases [2], which are inhibited by methylxanthines such as caffeine, for example. By contrast, insulin activates the esterase and thereby reduces the cAMP level (see p. 388). 

An ADP-ribosyltransferase that permanently activates the Gs regulatory protein in the adenylate cyclase pathway. Because ADP-ribosylated Gs GTP complex cannot be converted to its metabolic inactive form, the adenylate cyclase remains in its activated state. The following are recent reviews on the molecular and physical properties of this ADP-ribosylating enzyme. 

Lithium blocks the release of thyroxine (T4) and triiodothyronine (T3) mediated by thyrotropin (Kleiner et ah, 1999). This results in a decrease in circulating T4 and T3 concentrations and a feedback increase in serum thyrotropin concentration. It also inhibits thyrotropin-stimulated adenylate cyclase activity (Kleiner et ah, 1999). Lithium has varying effects on carbohydrate metabolism. Increased and decreased glucose tolerance and decreased sensitivity to insulin have been observed (Van derVelde Gordon, 1969). In animals, lithium decreases hepatic cholesterol and fatty acid synthesis. 

Theoretical explanations for the stimulatory activity of the methyl xanthines. These compounds inhibit phosphodiesterase reaulting in the prolonged activ of metabolic enzymes.Adenylate cyclase activity is modulated by the bindin free adenosine. The methyl xanthines are antagonists to adenosine but the bindings do not produce its modulating (inhibitory, attenuating) response. Therefore the end result is stimulatory in relation to cAMP activity. 

Vanadium. Vanadium is essential in rats and chicks. Estimated human intake is less than 4 mg/d. In animals, deliciency results in impaired growth, reproduction, and lipid metabolism, and altered thyroid peroxidase activities. Vanadium may play a role in the regulation of INaK)-ATPase. phosphoryl transferases, adenylate cyclase, and protein kinases. 

It appears that cyclic AMP does not mediate the action of GA (83). Two reports (85, 86) rule out the involvement of cyclic adenosine 3 ,5 -monophosphate and adenylate cyclase in the hormonal regulation of plant growth processes. Although barley aleurone cells metabolize GA s, attempts to isolate GA-binding proteins have not been successful (84). 

The enzymes responsible for the platelet metabolism are distributed in different platelet structures, For example, the plasma membrane contains adenylate cyclase in contrast, phospholipase (PL) A2, diglycerol lipase, cyclooxygenase... 

Adenosine, in addition to serving as a substrate for the generation of cAMP plays a physiologic role as a platelet inhibitor and a vasodilator and may attenuate neutrophil-mediated damage to endothelial cells, Adenosine diphosphate (ADP)— a potent platelet agonist—is converted to adenosine, which is taken up rapidly by cells, especially erythrocytes and endothelial cells, A small proportion is metabolized to the aforementioned cyclic nucleotides. The remainder is broken down to inosine and subsequently to xanthine. Dipyridamole inhibits the active transport of adenosine into cells, but does not interfere with the passive diffusion. Since the platelet inhibitory effects of adenosine proceed via stimulation of adenylate cyclase, these effects can also be amplified by dipyridamole, In circulating blood, the largest amount of adenosine is found in red blood cells, This may, in part, help explain why dipyridamole is much more effective in whole blood than in plasma. 

All the pharmacological and behavioural effects elicited by dopamine agonists and antagonists in the brain can only be explained if such an interaction occurs at the level of the dopamine receptor (D2 receptor site) the site still remains in search of a function. Bovine parathyroid cells were reported to possess dopamine sites which should be involved in the control of parathormone secretion. However, the very poor pharmacological characterization and the lack of in vivo evidence do not allow to assess the dopaminergic nature of this hormone secretion. Dopamine-sensitive adenylate cyclase is thus not a receptor directly implicated in the dopaminergic neurotransmission it is an enzyme which could have an important role in the control of long term metabolic effects such as the synthesis of neuronal constituents. 

The observation that victims of the Japanese Minamata disaster had suffered considerable damage to plasma membranes has led to investigation of possible reaction mechanisms whereby such damage may result from MeHg+ poisoning. It has been demonstrated that methylmercury is the most potent inhibitor of the enzyme adenyl cyclase yet reported.284 The enzyme occurs in liver plasma membranes and plays a part in the metabolism of mammalian cells. 

Recently Exton and co-workers [93] have proposed that adrenergic responsiveness in skeletal muscle is regulated by thyroid hormones at two levels, i.e., 1) stimulation of /3-adrenergic receptors and adenylate cyclase activity and 2) increased activity of phosphoprotein phosphatases. Such results would explain the effect of thyroid hormones on glycogen metabolism in muscle although the primary mechanism of these actions remains unknown. 

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