Adenylate cyclase-cyclic adenosine

Glucagon appears to exert its effects on liver cells by a classic adenyl cyclase-cyclic adenosine monophosphate (cAMP) second messenger system (see Chapter 4).93 Glucagon binds to a specific receptor located on the hepatic cell membrane. This stimulates the activity of the adenyl cyclase enzyme that transforms adeno-... 

Receptors act by inactivation of adenylate cyclase cyclic AMP (adenosine-monophosphate) levels within the cell decrease. 

P2-Agonists cause airway smooth muscle relaxation by stimulating adenyl cyclase to increase the formation of cyclic adenosine monophosphate (cAMP). Other non-bronchodilator effects have been observed, such as improvement in mucociliary transport, but their significance is uncertain.11 P2-Agonists are available in inhalation, oral, and parenteral dosage forms the inhalation route is preferred because of fewer adverse effects. 

The effect of receptor stimulation is thus to catalyze a reaction cycle. This leads to considerable amplification of the initial signal. For example, in the process of visual excitation, the photoisomerization of one rhodopsin molecule leads to the activation of approximately 500 to 1000 transdudn (Gt) molecules, each of which in turn catalyzes the hydrolysis of many hundreds of cyclic guanosine monophosphate (cGMP) molecules by phosphodiesterase. Amplification in the adenylate cyclase cascade is less but still substantial each ligand-bound P-adrenoceptor activates approximately 10 to 20 Gs molecules, each of which in turn catalyzes the production of hundreds of cyclic adenosine monophosphate (cAMP) molecules by adenylate cyclase. 

Gs Noradrenaline and fi2 Dopamine Di and D5 Histamine H2 Serotonin 5-HT4 Stimulates adenylate cyclase increasing the concentration of cAMP (cyclic-adenosine-3, 5 -monophosphate)... 

Adenyl cyclase The enzyme (also known as adenylate, or adenylyl cyclase) that catalyses the formation of the second messenger cyclic adenosine-.l A -monophosphate (cAMP) from ATP following the activation of a Gs protein-coupled receptor. 

Abnormal G protein functioning dysregulates adenylate cyclase activity, phosphoinositide responses, sodiurrypotassiunVcalcium channel exchange, and activity of phospholipases. Abnormal cyclic adenosine monophosphate and phosphoinositide secondary messenger system activity. 

The short-acting / -agonists (Table 80-1) are the most effective broncho-dilators available. /J2-Adrenergic receptor stimulation activates adenyl cyclase, which produces an increase in intracellular cyclic adenosine monophosphate. This results in smooth muscle relaxation, mast cell membrane stabilization, and skeletal muscle stimulation. 

Selective sympathomimetics cause relaxation of bronchial smooth muscle and bronchodilation by stimulating the enzyme adenyl cyclase to increase the formation of cyclic adenosine monophosphate. They may also improve mucociliary clearance. 

Alprostadil, or prostaglandin E1 stimulates adenyl cyclase to increase production of cyclic adenosine monophosphate, a neurotransmitter that ultimately enhances blood flow to and blood filling of the corpora. 

NE and EPI stimulate a- and (TAR on the cell surface of target tissues. P2-AR are expressed on almost all types of immune cells, with the notable exception of T-helper (Th)2 clones [3], P-AR on immunocytes are coupled with Gs proteins and adenylate cyclase, with subsequent activation increasing intracellular adenosine 3 , 5 -cyclic monophosphate (cAMP) and protein kinase A (PKA). Under normal conditions, P-AR cell surface expression up- and down-regulates in response to reduced and increased catecholamine... 

Metabotropic receptors, in contrast, create their effects by activating an intracellular G protein. The metabotropic receptors are monomers with seven transmembrane domains. The activated G protein, in turn, may activate an ion channel from an intracellular site. Alternately, G proteins work by activation or inhibition of enzymes that produce intracellular messengers. For example, activation of adenylate cyclase increases production of cyclic adenosine monophosphate (cAMP). Other effector mechanisms include activation of phospholipases, diacylglycerol, creation of inositol phosphates, and production of arachidonic acid products. Ultimately, these cascades can result in protein phosphorylation. 

For example, the stimulation of )6-adrenoceptors by noradrenaline results in the activation of adenylate cyclase on the irmer side of the nerve membrane. This enz)nne catalyses the breakdown of ATP to the very labile, high-energy compound cyclic 3,5-adenosine monophosphate (cyclic AMP). Cyclic AMP then activates a protein kinase which, by phosphorylating specific membrane proteins, opens an ion charmel to cause an efflux of potassium and an influx of sodium ions. Such receptors are termed metabotropic receptors. 

The nucleotide cyclic AMP (3, 5 -cyclic adenosine monophosphate, cAMP) is a cyclic phosphate ester of particular biochemical significance. It is formed from the triester ATP by the action of the enzyme adenylate cyclase, via nucleophilic attack of the ribose 3 -hydroxyl onto the nearest P=0 group, displacing diphosphate as leaving group. It is subsequently inactivated by hydrolysis to 5 -AMP through the action of a phosphodiesterase enzyme. 

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). 

A) Inhibition of platelet phosphodiesterases (PDEs) [91]. Quercetin and myricetin potentiated the anti-aggregatory action of prostacyclin (PGI2), a potent stimulator of platelet adenylate cyclase synthesised by the vascular endothelium, on ADP-induced platelet aggregation in washed human platelets, and the elevation of platelet cyclic adenosine monophosphate (cAMP) elicited by PGI2 [89,92,93]. These effects are probably due to an inhibition of PDEs. As suggested by Ferrell and co-workers [92], this inhibition arises from the similarity between the pyranone ring of flavonoids and the pyrimidine ring of adenine. 

Adenylate cyclase. The enzyme that catalyzes the formation of cyclic 3, 5 -adenosine monophosphate (cAMP) from ATP. 

ACTH activates adenylate cyclase and elevates the cyclic adenosine monophosphate level. 

Two of the more studied effector proteins of G-proteins are adenylate cyclase (AC) and phospholipase C (PLC). AC converts adenosine triphosphate (ATP, 5.4) into 3, 5 -cyclic adenosine monophosphate (cAMP, 5.5) (Scheme 5.4). cAMP is a secondary messenger that can activate certain kinases (phosphorylation enzymes) and stimulate the breakdown of fats and glycogen. PLC hydrolyzes phosphatidylinositol 3,4-bisphosphate (PIP2, 5.6) to form two secondary messengers, diacylglycerol (DAG, 5.7) and inositol... 

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