Inhibition cAMP

A critical component of the G-protein effector cascade is the hydrolysis of GTP by the activated a-subunit (GTPase). This provides not only a component of the amplification process of the G-protein cascade (63) but also serves to provide further measures of dmg efficacy. Additionally, the scheme of Figure 10 indicates that the coupling process also depends on the stoichiometry of receptors and G-proteins. A reduction in receptor number should diminish the efficacy of coupling and thus reduce dmg efficacy. This is seen in Figure 11, which indicates that the abiUty of the muscarinic dmg carbachol [51 -83-2] to inhibit cAMP formation and to stimulate inositol triphosphate, IP, formation yields different dose—response curves, and that after receptor removal by irreversible alkylation, carbachol becomes a partial agonist (68). 

Preferentially inhibits cAMP formation Preferentially inhibits cAMP formation Preferentially inhibits cAMP formation Preferentially inhibits cAMP formation (in recombinant system). Preferentially inhibits cAMP formation (in recombinant system). 

The 5-HTx receptor class comprises five receptors (5-HT1a, 5-HT1b, 5-HTiD, 5-ht1E> and 5-HT1F) which, in humans, share 40-63% overall sequence identity and couple somewhat preferentially to Gi/o to inhibit cAMP formation (see Tables 1-3). The 5-htiE receptors are given a lower case appellation to denote that... 

Dipyridamole exerts its effect by inhibition of platelet phosphodiesterase E5, increasing cyclic guanosine monophosphate and cyclic adenosine monophosphate (cAMP). By inhibiting its uptake and metabolism by erythrocytes, dipyridamole also increases the availability of adenosine within blood vessels, promoting inhibition of platelet aggregation and local vasodilatation. " Dipyridamole may also inhibit cAMP phosphodiesterase in platelets, which further increases cAMP levels and may enhance endothelial nitric oxide production, contributing to its antithrombotic effect. Existing trials of dipyridamole in stroke have focused on secondary prevention and will be discussed briefly. 

The multiplicity of G proteins coupled to opiate receptors may explain how different opiates can bind to the same receptor yet induce different cellular responses. For example, morphine binds to the cloned rat fi receptor expressed in HEK 293, CHO and COS-7 cells and inhibits cAMP accumulation [80-82]. Morphine can be continuously applied to the cells for up to 16 h, and the potency and magnitude of morphine inhibition of adenylyl cyclase does not diminish [80, 81]. In contrast, the opiate sufentanil can bind to the same cloned fi receptor in HEK 293 cells to inhibit cAMP accumulation. However, sufentanil s actions rapidly desensitize [83]. Since both compounds bind to the same receptor, and the fi receptor is the only receptor these drugs can interact with in these cells, the ability of these two full agonists to differentially regulate the fi receptor must be due to their abilities to affect separate adaptive processes in these cells. 

Mutagenesis studies have shown that morphine and sufentanil bind differently to the jj, receptor [83, 85]. Mutation of an aspartic acid at residue 114 of the // receptor to an asparagine resulted in a mutant that did not bind morphine and morphine was ineffective in inhibiting adenylyl cyclase via that receptor. In contrast, sufentanil bound to the mutant and wild-type receptors equally well and it effectively inhibited cAMP accumulation via the mutant receptor. These findings demonstrate that morphine and sufentanil have different requirements for binding to the // receptor. By binding differentially, these two agonists may induce the ft receptor to interact with different G proteins to induce distinct cellular effects. 

While chronic morphine treatment uncouples the // receptor from K+ channels, it did not affect the coupling of ft receptors to adenylyl cyclase. Pretreatment of the cloned ft receptor expressed in HEK 293, AtT-20, CHO and COS cells with morphine or DAMGO for up to 16h did not alter the subsequent ability of fi agonists to inhibit cAMP accumulation [25, 65, 80-82]. These findings suggest that morphine treatment induces a selective desensitization of the coupling of the fi receptor to K+ channels. 

At present it is not known if all H3 receptor isoforms similarly activate the wide array of signaling pathways. In transfected cells, the rat H3(413) and H3(397) isoforms both inhibit adenylate cyclase more efficiently than does the hill length rat H3 receptor isoform (445 amino acids), but the former are less efficient in activating the MAPK pathway. Much less information is available for the human H3 receptor isoforms but shorter isoforms seem to couple more efficiently to G -proteins to inhibit cAMP production in transfected cells [40],... 

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... 

Wagner, J. A., T. V. McDonald, P. T. Nghiem, A. W. Lowe, H. Schulman, D. C. Gruenert, L. Stryer, and P. Gardner. 1992. Antisense oligodeoxynucleotides to the cystic fibrosis transmembrane conductance regulator inhibit cAMP-activated but not calcium-activated chloride currents. Proc Natl Acad Sci USA 89(15) 6785-9. 

Schwiebert, E. M., N. Kizer, D. C. Gruenert, and B. A. Stanton. 1992. GTP-binding proteins inhibit cAMP activation of chloride channels in cystic fibrosis airway epithelial cells. Proc Natl Acad Sci USA 89(22) 10623-7. 

The third group is that of compounds which may potentially be transported by the PTS and inhibit cAMP production. Cellulase synthesis is initiated after these compounds are consumed for cell growth. This group includes D-glucose, D-fructose, maltose, mannitol, glycerol, sorbitol, and -methyl glucoside. The presence of these compounds in Solka Floe fermentations, enhanced enzyme yields (132 to 254%) but the time required to complete cellulase synthesis took longer (106 to 148%) than the control. 

Less is known about GABAg receptor structure. GABAg receptors are coupled indirectly to K+ channels. These receptors, which are always inhibitory, are coupled to G-proteins. When activated, GABAg receptors decrease Ca + conductance and inhibit cAMP production. The GABA, receptor is probably little more than a subtype of the GABA receptor. It contains the p subunit peptide and is located primarily, if not exclusively, in the retina. 

Competitive antagonism of adenosine receptors xanthines are potent inhibitors at adenosine receptors these may stimuiate or inhibit cAMP and Ca2+ influx. 

Theophylline is found in coffee and in tea in very small amounts, but it has a stronger effect on the heart and breathing than does CF. Along with CF, TP is used as a medicine to treat emphysema and bronchitis (254,255). Caffeine and TP inhibit cAMP phosphodiesterase. In their presence the effects of cAMP, and thus the stimulatory effects of the hormones that lead to its production, are prolonged and intensified. 

The release of Ca2+ in response to such second messengers is known to activate the phosphorylation of a range of cytosolic proteins by Ca2+-dependent protein kinases, for example in hepatocytes,417 adrenal cortex418 and other cells.419 Ca2+ inhibits cAMP-activated protein kinase in parathyroid glands.420 Phosphorylation of proteins produced in the pancreatic /8-cell in response to enhanced [Ca2+] may involve calmodulin, while the stimulus produced by glucose is potentiated by cAMP 421 A calmodulin-activated NAD kinase is present in the outer mitochondrial membrane of com.422... 

PDE3 cGMP-inhibited cAMP-selective Heart, lung, liver, platelets, adipose tissue, immunocytes... 

Carson MJ, Thomas EA, Danielson PE, Sutcliffe JG. The 5HT5A serotonin receptor is expressed predominantly by astrocytes in which it inhibits cAMP... 

Although earlier studies failed to find consistent effects of DA on cAMP levels or adenylate cyclase activity in anterior pituitary cells [13], intact pituitary gland [14,15] or homogenates [13,16], a functional connection between the two is now supported by many experimental approaches. DA and DA agonists inhibit cAMP levels in cultured rat pituitary cells at concentrations in the nanomolar range, comparable to those which inhibit PRL release [17-21], DA also inhibits cAMP accumulation stimulated by VIP or TRH [20]. Inhibition is also seen in human prolactinoma cells [22]. 

Similar to the D2 and D4 receptors, the D3 receptor inhibits cAMP accumulation through coupling to G proteins. In addition, the D3 receptor inhibits Ca2+ currents and promotes mitogenesis, probably via tyrosine phosphorylation and activation of mitogen-activated protein kinases (Sokoloff and Schwartz, 2003). 

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