Cyclic AMP formation

Fig. 11. Dose—response curves for (A,A) inhibition of cyclic AMP formation and stimulation of IP formation by carbachol (A,D) before and (A,H) after reduction of receptor number by irreversible alkylation (carbachol) is in M. Error bars ( ) are shown for some studies.

Kozawa et al, 2000a and b). In both cell types, the p38 MAPK-specific inhibitor, SB203580, blocks SIP hsp27 induction and amplification of inositol phosphates, hi osteoblastic cells, PGE shmulates cyclic AMP formation and inhibits apoptosis. This appears to be mediated by a cyclic AMP-dependent modulation of SPHK and S IP production (Machwate etal., 1998)... 

Although many effector systems utilise ATP or the equivalent, directly or indirectly, the rate at which ATP is used by such processes is trivial in comparison with many other processes. For example, in rat heart, the rate of cyclic AMP formation and degradation represents only 0.05 per cent of the normal rate of ATP turnover. 

Young, L.T., Li, P.P., Kish, S.J., Siu, K.P., Kamble, A., Hornykiewicz, O., and Warsh, J.J. (1993) Cerebral cortex Gs alpha protein levels and forskolin-stimulated cyclic AMP formation are increased in bipolar affective disorder. / Neurochem 61 890-889. 

Whitworth P, Kendall DA Effects of lithium on inositol phospholipid hydrolysis and inhibition of dopamine D, receptor-mediated cyclic AMP formation by carbachol in rat brain slices. J Neurochem 53 536-541, 1989 Whybrow PC The therapeutic use of triiodothyronine and high dose thyroxine in psychiatric disorder. Acta Med Austriaca 21 44-47, 1994 Whybrow PC Update on thyroid axis approaches to treatment of rapid cycling bipolar disorder. Paper presented at the annual meeting of the New Clinical Drug Evaluations Unit (NCDEU), Boca Raton, EL, May 30, 1996... 

The A2A receptors modulating neurotransmitter release are known to couple to Gs, causing stimulation of adenylate cyclase, an increase in cyclic AMP formation and... 

Since cyclic AMP derivatives and inhibitors of cyclic nucleotide phosphodiesterase stimulate prolactin release (17, 37, 38) and dopamine is a potent inhibitor of prolactin secretion (1, ly 39), it is not surprising that the catecholamine does not stimulate the adenylate cyclase system. On the contrary, the data summarized above show that the pituitary DA receptor is negatively coupled to adenylate cyclase. The pituitary DA receptor is thus a typical DA -receptor (40, 41). In view of the multiplicity of factors involved in the control of prolactin secretion, including sex steroids, it is likely that mechanisms other than cyclic AMP are involved (39, 42). It does however appear that inhibition of cyclic AMP formation by dopamine is a key element in a multifactorial control system responsible for the fine tuning of prolactin secretion. 

Our data have shown that the non-aromatlsable androgen DHT and progestins can act directly at the pituitary level at physiological concentrations to inhibit spontaneous PRL secretion and reverse the well-known stimulatory effect of E (39, 40, 42, 51). In addition, the effect of E2, DHT and progestins is observed, not only on spontaneous and IRH-induced PRL secretion, but also in the presence of IBMX. This last observation suggests that the marked modulatory effects of sex steroids are exerted at a step following cyclic AMP formation. 

Dopamine can thus be added to the list of hormones and neurotransmitters which can stimulate or inhibit cyclic AMP formation, depending upon their tissue of action. Thus, while dopamine stimulates cyclic AMP formation in parathyroid cells, superior cervical ganglia, retina and striatal tissue (27, 58-61), it inhibits the accumulation of the cyclic nucleotide in cells of the intermediate and anterior lobes of the pituitary gland. Opposite effects on the cyclic AMP system are also found with LHRH which stimulates and inhibits cyclic AMP levels in the anterior pituitary gland (62) and ovary (63), respectively. Similarly, alpha-adrenergic agents show opposite effects on cyclic AMP formation in brain (64) and platelets (65). PGE, stimulates cyclic AMP formation in the anterior pituitary gland (62) while it inhibits the same parameter in fat cells (66). 

Figure 4. Representation of the classification of the dopamine receptor based on its coupling with adenylate cyclase activity. DA+ receptors (left) are coupled to adenylate cyclase through the Ns GTP-binding protein (91) with secondary activation of adenylate cyclase. DA. receptors (middle) are coupled through the Ni GTP-binding protein, thus resulting in inhibition of cyclic AMP formation. DA0 receptors (right) are those uncoupled to cyclic AMP formation, the example being possibly some autoreceptors on nigrostriatal dopaminergic neurons.

Dopamine induces biochemical and physiological effects in the mammalian neostriatum. The occurrence of a D-l dopamine receptor (in the classification scheme of Kebabian and Caine) accounts for the ability of dopamine to enhance cyclic AMP formation. The occurrence of a D-2 dopamine receptor accounts for the ability of dopamine to inhibit cyclic AMP formation brought about by stimulation of a D-l dopamine receptor. Dopamine receptors mediate the regulation of (1) the release or turnover of acetylcholine (postsynaptic dopamine receptor) and (2) the release or turnover of dopar mine (presynaptic autoreceptor). Both receptors can be classified as D-2 dopamine receptors. Indications for the occurrence of dopamine receptors affecting the release or turnover of GABA, glutamate, serotonin and several neuropeptides are evaluated. 

A Postsynaptic Dopamine Receptor Regulating Cyclic AMP Formation... 

Activation of neostriatal tyrosine hydroxylase was observed when cyclic AMP was added to high speed supernatants from rat neostriatum (133). Intraventricular injection of dibutyryl cyclic AMP stimulated tyrosine hydroxylation in the neostriatum (134). However, it is still questionable if under physiological conditions this cyclic AMP involvement in the feedback control of tyrosine hydroxylase activity is mediated by presynaptic dopamine receptors or by presynaptic allo-receptors. In addition, if a dopamine sensitive adenylate cyclase is involved in the regulation of neostriatal tyrosine hydroxylase activity it is relevant to know if this adenylate cyclase is linked to a D-1 and/or a D-2 receptor. At this point in time experimental data are not in favour of the presence of a D-l receptor linked to an adeiylate cyclase on the varicosities of dopaminergic neurons in the neostriatum. E.g. concentrations of dopamine agonists stimulating cyclic AMP formation inhibit tyrosine... 

Apart from mediating a stimulation of cyclic AMP formation no clear physiological functions has been discovered yet for the (postsynaptic) D-1 receptor in the neostriatum or in other... 

Cadogan AK, Kendall DA, Marsden CA. Serotonin 5-HT1A receptor activation increases cyclic AMP formation in the rat hippocampus in vivo. J Neurochem 1994 62 1816-1821. 

McLean PG, Coupar IM. Stimulation of cyclic AMP formation in the circular smooth muscle of human colon by activation of 5-HT4-like receptors. Br J Pharmacol 1996 117 238-239. 

Ford AP, Baxter GS, Eglen RM, Clarke DE. 5-Hydroxytryptamine stimulates cyclic AMP formation in the tunica muscularis mucosae of the rat oesophagus via 5-HT4 receptors. Eur J Pharmacol 1992 211 117-120. 

Collier HO, Roy AC. Morphine-like drugs inhibit the stimulation of E prostaglandins of cyclic AMP formation by rat brain homogenate. Nature 1974 248 24-27. 

Weiss S, Sebben M, Garcia-Sainz JA, Bockaert J (1985) D2-dopamine receptor-mediated inhibition of cyclic AMP formation in striatal neurons in primary culture. Mol Pharmacol 27 595-599. 

Yamada M, Yamada M, Watson MA Richelson E (1993) Neurotensin stimulates cyclic AMP formation in CHO-rNTR-10 cells expressing the cloned rat neurotensin receptor. Eur J Pharmacol 244 99-101. 

Labdanes (core C6 C6 linked to variously reduced furan or pyran moieties) include the Lamiaceae (Labiatae) diterpenes forskolin (C6 C6 pyran) (that activates adenylyl cyclase, the enzyme catalysing cyclic AMP formation from ATP) and premarrubiin (C40L G6 C6 furan-furan) that converts to the bitter non-opiate antinociceptive marrubiin (G4L C6 C6 -(CH2)2-furan). 

Whitworth, P., and Kendall, D.A., 1989, Effects of lithium on inositol phospholipid hydrolysis and inhibition of dopamine D1 receptor-mediated cyclic AMP formation by carbachol in rat brain slices. J. Neurochem. 53 536-541. 

The sympathetic nervous system innervates the major lymphoid organs such as the spleen with nerve fibers reaching both the vasculature and the parenchyma where lymphocytes, primarily T cells (T helper type 1-2, T l, T j2), reside (Friedman and Irwin, 1997). T cells possess receptors for both norepinephrine and neuropeptide Y that are released in response to sympathetic nerve stimulation. The adrenergic receptors are primarily the subtype, which is consistent with data demonstrating that (32 agonists can markedly influence the immune system (Kohm and Sanders, 2001). For example, stimulation of T cell receptors results in increased cyclic AMP formation, which can modulate cytokine expression, i.e., decreasing... 

The multiple drug effects on smooth muscles are also little understood. Thus, isoprenaline relaxes and adrenaline and noradrenaline contract the isolated rat aorta, but all three catecholamines increase cyclic AMP formation [61]. Adrenaline induces relaxation and prostaglandin Ei contraction in the estrogen-treated rat isolated myometrium, but both adrenaline and prostaglandin Ei elevate the cyclic AMP level in the tissue [62]. An example of a critical evaluation of the evidence linking cyclic AMP to a physiological effect (cardiac contractility) is that of Sobel and Mayer [63]. 

Schoepp, D. D., Johnson, B. G. and Monn, J. A. (1992) Inhibition of cyclic AMP formation by a selective metabotropic glutamate receptor agonist. Journal of Neurochemistry, 58, 1184-1186. 

Baba A. Saga H, Hashimoto H (1993) Inhibitory glutamate response on cyclic AMP formation in cultured astrocytes. Neurosci Lett /49 182-184. 

Sagan S, Venance L, Torrens Y, Cordier J, Glowinski J, Giaume C (1999) Anandamide and WIN 55212-2 inhibit cyclic AMP formation through G-protein-coupled receptors distinct from CBl cannabinoid receptors in cultured astrocytes. Eur J Neurosci 11 691-699... 

Murphy MG, Moak CM, Rao BG. Effects of membrane polyunsaturated fatty acids on opiate peptide inhibition of basal and prostaglandin El-stimulated cyclic AMP formation in intact NIE-115 neurometabolism cells. Biochem Pharmacol 1987 36 4079-4084. 

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