Cyclic AMP, accumulation

Daum, P. R., Hill, S. J. Young, J. M. (1982). Histamine Hl-agonist potentiation of adenosine-stimulated cyclic AMP accumulation in slices of guinea-pig cerebral cortex comparison of response and binding parameters. Br. J. Pharmacol. 77, 347-57. 

The P-site of adenylyl cyclase inhibits cyclic AMP accumulation 308 There are four adenosine receptor subtypes 308 Xanthines block P2 but not P2 receptors 309... 

The P-site of adenylyl cyclase inhibits cyclic AMP accumulation. Since P, and P2 receptors are located on the cell surface, they bind purines or pyrimidines in the extracellular space. There also is an adenosine binding site located intracellularly on the enzyme adenylyl cyclase (see Ch. 21). This is referred to as the P-site of adenylyl cyclase. Binding of adenosine and other purines, notably 3 AMP, 2 deoxy-3 -ATP and 2, 5 -dideoxyadenosine to this site, inhibits adenylyl cyclase activity [8]. The P-site of adenylyl cyclase and other intracellular purine binding sites are not classified as purinergic receptors. 

P2Y receptors are activated by adenine and uridine nucleotides. Most of the known P2Y receptors have been detected in the nervous system [21]. The majority of P2Y receptors inhibit neuronal N-type Ca2+ channels and M-type K+ channels. P2Y1 receptors are found exclusively on platelets, on their precursor megakaryocyte cells and on certain other cultured hematopoietic cells, such as K562 leukemia cells. They can be distinguished from other P2 receptors in that ADP is the most potent natural agonist and ATP is a competitive antagonist. ADP acts via a G protein to inhibit cyclic AMP accumulation, mobilize intracellular Ca2+ and stimulate granule secretion. ADP... 

Carrero I, Perez-Albarsanz MA, Carmena MJ, et al. 1990. Lindane inhibits b-adrenergic stimulation of cyclic AMP accumulation in rat prostatic epithelial cells. Pesticide Biochem Physiol 38 197-203. 

Ebstein R, Belmaker R, Grunhaus L, et al Lithium inhibition of adrenaline-stimulated adenylate cyclase in humans. Nature 259 411-413, 1976 Ebstein RP, Hermoni M, Belmaker RH The effect of lithium on noradrenahne-in-duced cyclic AMP accumulation in rat brain inhibition after chronic treatment and absence of supersensitivity. J Pharmacol Exp Ther 213 161-167, 1980 Ebstein RP, Lerer B, Shlaufman M, et al The effect of repeated electroconvulsive shock treatment and chronic lithium feeding on the release of norepinephrine from rat cortical vesicular preparations. Cell Mol Neurobiol 3 191-201, 1983 Ebstein RP, Moscovich D, Zeevi S, et al Effect of lithium in vitro and after chronic treatment on human platelet adenylate cyclase activity prosreceptor modification or second messenger signal amplification. Psychiatry Res 21 221-228, 1987 Eccleston D, Cole AJ Calcium-channel blockade and depressive illness. Br J Psychiatry 156 889-891, 1990... 

Newman M, Klein E, Birmaher B, et al Lithium at therapeutic concentrations inhibits human brain noradrenaline sensitive cyclic AMP accumulation. Brain Res 278 380-381, 1983... 

HeLa cells were treated with 5 mM butyrate for 48 h or with 1 yM GM1 for 1 h. Both types of treated cells bound similar amounts of 125I-choleragen and about 60-fold more than did control cells (Fig. 6a). When the cells were exposed to a saturating dose of toxin, the time course and extent of cyclic AMP accumulation were similar for both the butyrate-treated and the GM1-treated HeLa cells and more rapid than in the control cells (Fig. 6b). Thus, butyrate induces choleragen receptors in HeLa cells that are functionally equivalent to those created by incorporation of exogenous GM1. 

The role of cyclic AMP as modulator of prolactin secretion was first suggested by the finding of a stimulatory effect of cyclic AMP derivatives (17-22) and inhibitors of cyclic nucleotide phosphodiesterase activity such as theophylline and IBMX (22-26) on the secretion of this hormone. More convincing evidence supporting a role of cyclic AMP in the action of dopamine on prolactin secretion had to be obtained, however, by measurement of adenohypophysial adenylate cyclase activity or cyclic AMP accumulation under the influence of the catecholamine. As illustrated in Fig. 1, addition of 100 nM dopamine to male rat hemipituitaries led to a rapid inhibition of cyclic AMP accumulation, a maximal effect (30% inhibition) being already obtained 5 min after addition of the catecholamine. Thus, while dopamine is well known to stimulate adenylate cyclase activity in the striatum (27, 28), its effect at the adenohypophysial level in intact cells is inhibitory. Dopamine has also been found to exert parallel inhibitory effects on cyclic AMP levels and prolactin release in ovine adenohypophysial cells in culture (29) and purified rat mammotrophs (30). Using paired hemipituitaries obtained from female rats, Ray and Wallis (22) have found a rapid inhibitory effect of dopamine on cyclic AMP accumulation to approximately 75% of control. 

Figure 1. Time course of the effect of dopamine (100 nM) on cyclic AMP accumulation in male rat anterior pituitaries (5A). Key O—O, control and...

Since the adenylate cyclase system has been well demonstrated to play a mediatory role in controlling the action of B-adrenergic and dopaminergic agents in pars intermedia cells (5-13, 41), we have studied the possibility of a similar role of cyclic AMP in CRF action. After a 10-min incubation with increasing CRF concentrations, an approximately 6-fold increase in cyclic AMP content is measured at an ED q value of 6 nM (Fig. 5A). A maximal stimulatory effect of CRF on cyclic AMP accumulation is observed 2 min after addition of CRF. As observed on a-MSH secretion, preincuba-... 

The above-described data show that CRF added to cells of the rat Intermediate lobe In culture causes a rapid stimulation of oe-MSH release and cyclic AMP accumulation, thus demonstrating a direct action of the peptide on pars intermedia cells (15). It is however difficult, using intact cells, to dissociate between increases in cyclic AMP levels due to stimulation of adenylate cyclase activity or to Inhibition of cyclic nucleotide phosphodiesterase or to a combination of both effects. Definitive proof of the role of adenylate cyclase In the action of CRF In the intermediate lobe of the pituitary gland is provided by the following findings of a CRF-lnduced stimulation of adenylate cyclase activity in homogenate of rat and bovine pars Intermedia cells. 

As Illustrated in Fig. 7, 3 yM CRF and 1 yM (-)Isoproterenol cause a 190 and 110% stimulation of adenylate cyclase activity In rat pars intermedia particulate fraction, respectively. An additive effect Is observed when both stimulatory agents are present. Dopamine (30 yM), on the other hand, has no significant effect alone. However, In the presence of GXP, the catecholamine causes a 40 to 60% Inhibition of adenylate cyclase activity stimulated by CRF, ISO or CRF + ISO. It can also be seen that while 0.3 mM GXP alone causes a 100% increase In basal adenylate cyclase activity, it leads to a marked potentiation of the effect of ISO and CRF on [ 2P] cyclic AMP accumulation. It should be noticed that In the absence of the guanyl nucleotide, dopamine has no Inhibitory effect on adenylate cyclase activity In any of the groups studied. 

The present data clearly demonstrate that the 41-amino acid ovine CRF Is a potent stimulator of adenylate cyclase activity In rat and bovine pars Intermedia tissue. Our previous data have shown that CRF causes a rapid and marked stimulation of cyclic AMP accumulation in rat pars Intermedia cells in culture (15). The final proof of the role of adenylate cyclase in the observed changes of cyclic AMP levels had to be obtained by direct measurement of adenylate cyclase activity. 

Ebersole BJ, Diglio CA, Kaufman DW, Berg KA. 5-Hydroxytryptaminerlike receptors linked to increases in intracellular calcium concentration and inhibition of cyclic AMP accumulation in cultured vascular smooth muscle cells derived from bovine basilar artery. J Pharmacol Exp Ther 1993 266 692-699. 

Schoeffter P, Bobimac I. 5-Hydroxytryptamine 5-HT1D receptors mediating inhibition of cyclic AMP accumulation in Madin-Darby canine kidney (MDCK) cells. Naunyn Schmiedebergs Arch Pharmacol 1995 352 256-262. 

Gamovskaya MN, Nebigil CG, Arthur JM, Spumey RF, Raymond JR. 5-Hydroxy-tryptamine2A receptors expressed in rat renal mesangial cells inhibit cyclic AMP accumulation. Mol Pharmacol 1995 48 230-237. 

Berg KA, Clarke WP, Chen Y, Ebersole BJ, McKay RD, Maayani S. 5-Hydroxy-tryptamine type 2A receptors regulate cyclic AMP accumulation in a neuronal cell line by protein kinase C-dependent and calcium/caknodulin-dependent mechanisms. Mol Pharmacol 1994 45 826-836. 

Wong YH, Conklin BB, Bourne HR. 1992. Gz-mediated hormonal inhibition of cyclic AMP accumulation. Science 255 339-342. 

In fat cells epinephrine stimulation of cyclic AMP accumulation and lipolysis is markedly reduced in hypothyroidism but enhanced in hyperthyroidism (see Ref. 79). Similar effects of altered thyroid status on the response to two other lipolytic hormones, ACTH and glucagon, have been reported suggesting that thyroid hormones regulate similarly either the different receptors of the various lipolytic hormones and/or a common step of the lipolytic pathway [80],... 

MILL OV, Johnson RA, Gorman RR. inhibition of PGE,-stimulated cyclic AMP accumulation by thromboxane Aj. Prostaglandins 13 599-609,1977. 

Ca " (Xa 2.3 /J.M) stimulates beef heart phosphodiesterase [49], and a Ca " - and Mg " -dependent phosphodiesterase has been isolated from brain [50,51]. This suggests that increased Ca concentrations in cells may lead to a suppression of the increased rate of cyclic AMP accumulation, thus preventing a prolonged increase in cyclic AMP. 

There have been frequent difficulties relating physiological effects to cyclic AMP levels. For example, adenosine inhibits the effect of noradrenaline on cyclic AMP accumulation in rat fat cells but does not interfere with the lipolytic effect of the catecholamine [58]. Both ACTH and its o-nitrophenyl sulphenyl derivative stimulate corticosterone synthesis in isolated rat adrenal cells to the same maximal rate, but the analogue has a 30- to 100-fold smaller effect than ACTH on cyclic AMP accumulation [60]. 

Cyclic AMP accumulation by catecholamines is generally associated with /3-adrenoceptor stimulation, but there is recent evidence that a adrenoceptor stimulation also can lead to cyclic AMP accumulation. For example, in slices of rat cerebral cortex, the effect of isoprenaline on the cyclic AMP level was inhibited by a /3-adrenoceptor blocking drug and yet inhibition of the effect of noradrenaline required the combination of a P and an a-adrenoceptor blocking drug [65,66]. 

Knoop FC, Thomas DD (1984) Effect of cholera enterotoxin on calcium uptake and cyclic AMP accumulation in rat basophilic leukemia cells. In Int. J. Biochem. 16 275-280. 

ManeufYP, Brotchie JM (1997) Paradoxical action of the cannabinoid WIN 55,212-2 in stimulated and basal cyclic AMP accumulation in rat globus pallidus slices. Br J Pharmacol 120 1397-1398... 

Fain, Effect of nicotinamide and nicotinic acid on cyclic AMP accumulation by fat cells. Naunyn-Schmiedebergs Arch. 

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