Adenylate cyclase, inhibition

Ehlert, F. J. (1985). The relationship between muscarinic receptor occupancy and adenylate cyclase inhibition in the rabbit myocardium. Mol. Pharmacol. 28 410-421. 

Signal transduction was studied most precisely for the 5-HTiA receptor in rat amygdala (Koyama et al. 1999). The receptor operated through a N-methyl maleimide-sensitive mechanism and by adenyl cyclase inhibition rather than any change in K+ or Ca2+ channels. The fall in cyclic AMP presumably was followed by decrease in the phosphorylation of synaptic vesicle proteins and, finally, in a decrease of exocytosis. 

There are three important ADP receptors on the platelet surface (16). The P2X, inotrophic receptor is responsible for rapid influx of calcium into the cytosol. The P2Y, receptor mediates mobilization of calcium through activation of PLC and shape change. The P2Y,2 receptor is coupled to adenyl cyclase inhibition mediated by a G-protein with subsequent decrease in the cAMP The decrease in cAMP stimulates dephosphorylation of VASP that is closely correlated with the GPIIb/llla activation. 

Anand-Srivstava MB. 1992. Enhanced expression of inhibitory guanine nucleotide regulatory proteins (Gia) in spontaneously hypertensive rats relationship to adenylate cyclase inhibition. Biochem J 288 79-85. 

In contrast to adrenal and hepatic tissue, adenylate cyclase inhibition may be physiologically relevant in renal vasculature, since pertussis toxin attenuates All-induced vasoconstriction [23]. The physiological role for adenylate cyclase inhibition may therefore depend upon the differential response of the three tissues to the second messenger, cAMP. In vascular smooth muscle, adenylate cyclase inhibition should enhance All-induced contraction by reducing cellular cAMP, the messenger of relaxation, while in the adrenal and the hepatocyte cAMP mediates a stimulatory response and adenylate cyclase inhibition would be expected to oppose All action. 

Maurice DH, HaSLAM RJ. Molecular basis of the synergistic inhibition of platelet function by nihovasodilators and activators of adenylate cyclase inhibition of cyclic AMP breakdown by cyclic GMP. Mol Pharmcolil 671-681,1991. 

Murayama T, and Ui M. (1987). Ihosphatidic add may stimulate menibrane receptors mediating adenylate cyclase inhibition and phospholipid breakdown in 3T3 fibroblasts. J. Biol. Chem. 262, 5522-5529. 

Lactate accumulation Stimulation Adenylate cyclase Inhibition... 

K. Aktories, G. Schultz, and K.H. Jakobs, Islet-activating protein prevents nicotinic acid-induced GTPase stimulation and GTP but not GTPS-induced adenylate cyclase inhibition in rat adipocytes, FEBS Lett., 1983, 156, 88-92. 

Bito H, Mori M, Sakanaka C, Takano T, Honda Z, Gotoh Y, Nishida E, Shimizu T (1994) Functional coupling of SSTR4, a major hippocampal somatostatin receptor, to adenylate cyclase inhibition, arachidonate release, and activation of the mitogen-activated protein kinase cascade. J Biol Chem 269 12722-12730 Bodenant C, Leroux P, Gonzalez BJ, Vaudry H (1991) Transient expression of somatostatin receptors in the rat visual system during development. Neuroscience 41 595-606... 

In eukaryotic cells, cyclic AMP is synthesized from ATP by the plasma membrane-bound adenylate cyclase, and modulates, through a cAMP-dependent protein kinase, metabolism and proliferation. A plasma membrane-associated adenylate cyclase from T. brucei has been purified and characterized (45). The enzyme from bloodstream forms has a neutral pH optimum, and kinetic analysis revealed a for ATP of 1.75 mM and a for Mg of 4mM. Inhibition studies indicated no effect with cAMP, but a profound inhibition by PPj, which was competitive with respect to ATP. This observation suggests that the T. brucei adenylate cyclase interacts with the phosphate portion of the ATP molecule, in contrast to adenylate cyclase in rat liver plasma membranes. Other differences between the T. brucei and mammalian adenylate cyclases were observed. For instance, the parasite enzyme activity was not stimulated by glucagon or epinephrine. Furthermore, fluoride, a potent activator of mammalian adenylate cyclase, inhibited the activity of the T. brucei enzyme. 

Inhibition of Forskolln-Stimulated Activation of Adenylate Cyclase -Inhibition of forskolin-stlmulated adenylate cyclase in membranes and cells has been observed with a2 80 l8ts In platelets, and adipocytes 36,64 muscarinic-cholinergic agonists In cardiac cells Aj -adenoslne agonists and insulin in rat adipocytes 35 somatostatin in S49 lymphoma cells29,66,67 pituitary and dopamine D2-agonists in pituitary.68 The Inhibition varies between 50 and 75%. 

Breivogel, C.S. and Childers, S.R. (2000) Cannabinoid signal transduction in rat brain comparison of cannabinoid agonists in receptor binding, G-protein activation and adenylate cyclase inhibition, J. Pharmacol. Plxp. Ther. 295 328-336. 

Murayama T, Ui M (1985) Differential susceptibility to islet-activating protein, pertussis toxin, of multiple effects of thrombin on 3T3 fibroblasts including adenylate cyclase inhibition and arachidonic acid release. J Biol Chem 260 7226-7233... 

It remains unknown how GTP-bound a or py of G-proteins interacts with the effector system such as phospholipase C or ion chaimels. In the case of adenylate cyclase, the activation involves direct interaction of the GTP-bound a-subunit of G s with the adenylate cyclase catalyst. The inhibition of adenylate cyclase, however, results from combined effects of direct and indirect interactions between some a-subunits, Py -subunits and the catalytic protein of adenylate cyclase as follows. Firstly, Py liberated from Gi, Go and Go may form a trimeric complex with the a-subunit of Gs, thereby decreasing the concentration of free as, the direct activator of the cyclase catalyst (31). The inhibition by this mechanism could be expected to occur in a number of mammalian cell types, since these lAP substrates are much more abundant than Gs in these cells (37). Secondly, the a-subunit of Gi competes with the a-subunit of Gs for the activation site on the cyclase catalyst, though the affinity of Gi was much lower than the affinity of Gs for this site (38). No competition was observed, however, between the a-subunit of G s and a-subimits of Go, Go and G hl. Thirdly, py is capable of direct interaction with the adenylate cyclase catalyst in such a manner as to lower the cyclase activity (38). The interaction was observed at rather higher concentrations of Py. Fourthly, Py binds to calmodulin with a high affinity (39). Calmodulin is a potent activator of the adenylate cyclase catalyst as such, but is not so after it is bound by Py of G-proteins. Thus, the inhibition of adenylate cyclase by Py of G-proteins was biphasic in the presence of calmodulin the inhibition by lower concentrations of Py was due to prevention of calmodulin activation of the cyclase and the inhibition by the higher concentrations reflected the direct interaction with the cyclase. The relative importance of these multiple mechanisms for adenylate cyclase inhibition will be the subject of future investigations. 

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