Cyclic Adenyl cyclase

FIGURE 2.6 Production of cyclic AMP from ATP by the enzyme adenylate cyclase. Cyclic AMP is a ubiquitous second messenger in cells activating numerous cellular pathways. The adenylate cyclase is activated by the a subunit of Gs-protein and inhibited by the a-subunit of Gj-protein. Cyclic AMP is degraded by phosphodiesterases in the cell. 

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. 

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. 

ETEC young children > adults in developing world/travelers to tropics 10-72h acute watery CFA-I-IV - colonization LT-I and -II - adenylate cyclase - secretion STa - guanylate cyclase - secretion STb - cyclic nucleotide-independent HCO] secretion... 

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. 

Fig. 2. An adrenaline molecule (1) binds to its binding site on the extracellular site of an adrenaline receptor (2). Thereby, the exchange of GDP by GTP in the Ga subunit of a hetero-trimeric G protein (3) is induced, followed by the dissociation of the Ga and Gpr subunits. G now binds and stimulates its effector adenylate cyclase (4), which produces cyclic AMP (5) from ATP (6). This second messenger starts a cascade of enzymatic reactions, which alter the behavior of the cell via several phosphorylation steps... 

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... 

We have tested the hypothesis that insulin inhibits the stimulatory effect of parathyroid hormone (PTH) on calcium reabsorption in the distal nephron. PTH is known to enhance calcium transport in renal cells, probably by stimulation of adenylate cyclase and subsequent increases in 3 5 cyclic AMP productoin. Since insulin had been observed to inhibit PTH-stimulated increases in kidney cyclic AMP levels in vitro (24) we investigated whether insulin-mediated hypercalciuria was dependent on the presence of PTH in vivo. 

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). 

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. 

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. 

Adenylate cyclase the enzyme that catalyzes the formation of cyclic AMP (cAMP). 

Glucagon stimulates adenylate cyclase activity and this increases the concentration of cyclic AMP. Insulin antagonises this effect via an increase in the activity of cyclic AMP phosphodiesterase, which hydrolyses cyclic AMP to AMP, which results in a decrease in the concentration of cyclic AMP (Figure 6.34). 

Figure 6.34 Effects of glucagon and insulin on the cyclic AMP level. Glucagon increases the activity of adenylate cyclase, which increases the concentration of cyclic AMP whereas insulin activates the phosphodiesterase which hydrolyses cyclic AMP to form AMP. Cyclic AMP activates protein kinase A.

The action of adrenaline (or noradrenaline) involves binding to an extracellular receptor, of which there are two classes, the a- and p-receptor. When the hormone binds to the P-receptor, the hormone-receptor complex activates adenyl cyclase, which catalyses the formation of cyclic AMP from ATP. 

Figure 12.13 Action and effects of glucagon. Glucagon binds to its receptor on the plasma membrane of the liver which activates adenyl cyclase. The resultant cyclic AMP activates protein kinase which results in phosphorylation and activation of ...

Receptors are located on non-motile cilia that project from the dendrite of the neurone into the mucus layer. It is the cilia that possess the receptor for the pheromone and respond to it via an effector system that results in opening of a Na" ion channel. This depolarises the membrane across the sensory cell which, if of sufficient magnitude, leads to generation of action potential along the axon with which it forms a synapse. The effector system is adenyl cyclase and the generation of cyclic AMP, a process that involves the G-protein (Figure 12.15). 

The adenyl cyclase reaction is zero order, that is, it is saturated with ATP. The phosphodiesterase reaction is first order, at least at the concentrations of cyclic AMP normally found in the ceU, and the maximum activity is greater than that of adenyl cyclase. 

Figure 14.13 The kinetic sequence of reactions that control the cyclic AMP concentration, and its binding to the effector system, and the kinetic sequence that controls the concentration of a neurotransmitter and its binding to the receptor on the postsyn-aptic membrane. Processes (1) are reactions catalysed by adenyl cyclase, and exocytosis. Reactions (2) are catalysed by phosphodiesterase and, for example, acetylcholinesterase. Reactions (3) are the interactions between the messenger and the effector system both the latter are equilibrium binding processes. (See Chapter 12 (p. 266) for discussions of equilibrium binding.)...

Relaxation of smooth mnscles is controlled by the concentration of cyclic GMP in the muscle. This is regulated by the activities of the enzyme that forms cyclic GMP (i.e. gnanyl cyclase) and the enzyme that degrades cyclic GMP, that is, cyclic GMP phosphodiesterase (see Box 12.2). This is analogons to the enzyme system that regulates the concentration of cyclic AMP, by the activities of adenyl cyclase and phosphodiesterase ... 

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