Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The liberation of arachindonate in the thyroid occurs at the expense of two distinct pools of precursors. (1) the phosphatidylinositol through a process Ca2+-dependent and cyclic AMP-independent; and (2) the triglycerides by a cyclic AMP-dependent lipase, in which the involvement of cyclic AMP-dependent protein kinase has not yet been determined. The "PI pool" or "paracyclic AMP pool" is mobilized very rapidly by large doses of TSH but its physiological significance can be discussed. The "triglyceride pool" or "post-cyclic AMP pool" is mobilized more slowly by small doses of TSH and seems not to be implicated in the acute TSH stimulation of adenylate cyclase. The "post-cyclic AMP pool" of prostaglandins would be very important as third messenger or as "long-acting TSH hormone". Some recent works of Boeynaems and Van Sande (16) and Madaoui et al. (17) on the thyroid support this hypothesis, as aspirin or indomethacin inhibits DBc-AMP stimulation of glucose oxydation, iodine organification, or thyroid hormone secretion. On the other hand, in the absence of prostaglandin synthesis, TSH still stimulates the adenylate cyclase, which means that prostaglandins are not obligatory intermediates of hormonal action on cyclic AMP production. In conclusion, these results show a TSH action in the thyroid on the release of fatty acids, precursors of PG's, from their lipidic stores. Nevertheless, a second control step is not excluded in conversion of cyclic endoperoxide to PGE or PGFalpha.
Adv Prostaglandin Thromboxane Res 1976
PMID:Stimulation by TSH of prostaglandin synthesis in pig thyroid. 18 42

The prostaglandin endoperoxide PGH2 antagonized basal and hormone-stimulated adenylate cyclase activity in an adipocyte ghost preparation. The inhibition was readily reversible, and demonstrable on initial rates of cAMP synthesis. It is suggested that PGH2 may be an endogenous feedback regulator of lipolysis in adipose tissue.
Adv Prostaglandin Thromboxane Res 1976
PMID:Inhibition of adenylate cyclase in adipocyte ghosts by the prostaglandin endoperoxide PGH2. 18 45

Thromboxane A2 plays an important role in arachidonic acid- and prostaglandin H2-induced platelet aggregation. Agents that stimulate platelet adenylate cyclase (prostaglandin I2, prostaglandin I1 and prostaglandin E1) and dibutyryl cyclic AMP inhibit both thromboxane A2 formation and arachidonate-induced aggregation in platelet-rich plasma. Despite complete suppression of aggregation with agents that elevate cyclic AMP, considerable thromboxane A2 is still formed. Prostaglandin H2-induced aggregations which bypass the cyclooxygenase regulatory step are also inhibited by agents that elevate cyclic AMP without any measurable effect on thromboxane A2 production. These data demonstrate that cyclic AMP can inhibit platelet aggregation by a mechanism independent of its ability to suppress the cyclooxygenase enzyme. Parallel experiments with washed platelet preparations suggest that they may be an inadequate model for studying the relationship between the platelet cyclooxygenase and platelet function.
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PMID:Regulatory role of cyclic adenosine 3',5'-monophosphate on the platelet cyclooxygenase and platelet function. 21 15

Elevated eicosanoid biosynthesis characterizes certain forms of human and experimental glomerular proliferative disease. Thromboxane A2 (TxA2) and other prostaglandins (PG) act through specific receptors and mechanisms of intracellular signal transduction in human mesangial cells. We studied the actions of U-46619, a TxA2 mimetic which stimulates mesangial phospholipase C, and of the PGI2 analogue, Iloprost, a potent activator of adenylate cyclase, on proliferation of cultured human mesangial cells. When applied alone to quiescent cells, U-46619 had only weak mitogenic activity, as assessed by [3H]thymidine [( 3H]-TdR) incorporation and cell counts. On the other hand, addition of U-46619 10 minutes prior to stimulation of the cells with 1 to 17% fetal bovine serum (FBS) for 24 hours, potently and dose-dependently inhibited FBS-stimulated [3H]-TdR incorporation. Similarly, U-46619 inhibited the effects of 10 ng/ml platelet-derived growth factor (PDGF), epidermal growth factor or basic fibroblast growth factor on [3H]-TdR incorporation, by 55, 79 and 88%, respectively. The effects of U-46619 were not mimicked by another stimulus of phospholipase C, angiotensin II. Iloprost also inhibited FBS-activated proliferation. Neither eicosanoid inhibited the rise of cytosolic Ca2+ induced by FBS or PDGF. The actions of TxA2 and Iloprost in cultured cells point to multiple functional interactions between eicosanoids and growth factors in the control of mesangial cell proliferation.
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PMID:Regulation of human mesangial cell growth in culture by thromboxane A2 and prostacyclin. 169 33

1. Exposure of platelets to exogenous arachidonic acid results in aggregation and secretion, which are inhibited at high arachidonate concentrations. The mechanisms for this have not been elucidated fully. In our studies in platelet suspensions, peak aggregation and secretion occurred at 2-5 microM-sodium arachidonate, with complete inhibition around 25 microM. 2. In platelets loaded with quin2 or fura-2, the cytoplasmic Ca2+ concentration, [Ca2+]i, rose in the presence of 1 mM-CaCl2 from 60-80 nM to 300-500 nM at 2-5 microM-arachidonate, followed by inhibition to basal values at 25-50 microM. Thromboxane production was not inhibited at 25 microM-arachidonate. Cyclic AMP increased in the presence of theophylline, from 3.5 pmol/10(8) platelets in unexposed platelets to 8 pmol/10(8) platelets at 50 microM-arachidonate; all platelet responses were inhibited with doubling of cyclic AMP contents. 3. The adenylate cyclase inhibitor 2',5'-dideoxyadenosine attenuated the inhibitory effect of arachidonate, suggesting that it is mediated by increased platelet cyclic AMP and that it is unlikely to be due to irreversible damage to platelets. 4. Aspirin or the combined lipoxygenase/cyclo-oxygenase inhibitor BW 755C did not prevent the inhibition by arachidonate of either [Ca2+]i signals or aggregation induced by U46619. 5. Thus high arachidonate concentrations inhibit Ca2+ mobilization in platelets, and this is mediated by stimulation of adenylate cyclase. High arachidonate concentrations influence platelet responses by modulating intracellular concentrations of two key messenger molecules, cyclic AMP and Ca2+.
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PMID:High concentrations of exogenous arachidonate inhibit calcium mobilization in platelets by stimulation of adenylate cyclase. 245 17

We suggest that regression of the corpus luteum is an active process induced by PGF2 alpha, GnRH, and a peptide of ovarian origin whose action GnRH mimics (20). The initial events involved in luteolysis occur within minutes, and they are intimately linked to inhibition of LH action. Membrane receptor binding of luteolytic hormones activates production of a second messenger (such as a product of PI turnover) that stimulates release of sequestered, intracellular Ca2+ by a mechanism linked to inhibition of microsomal Ca2+-ATPase activity. The increase in cytosolic Ca2+ inhibits adenylate cyclase activity by blocking GTP-dependent activation of adenylate cyclase. As a result, the cell response to LH is abolished and function is lost.
Adv Prostaglandin Thromboxane Leukot Res 1985
PMID:Luteolytic hormones are calcium-mediated, guanine nucleotide antagonists of gonadotropin-sensitive adenylate cyclase. 293 78

Separate receptors for LTC4 and LTD4 have been identified and characterized by physiologic and radioligand binding criteria. LTD4 receptors appear to be plasma-membrane-associated and to display characteristics previously described for many hormone receptors, such as inhibition of agonist binding by guanine nucleotides and Na+, suggesting a postreceptor linkage to adenylate cyclase of an inhibitory nature. LTC4 receptors have a substantial subcellular distribution; agonist binding to the receptor is not influenced by monovalent ions or guanine nucleotides but is enhanced by divalent cations. Within these two major subclass receptors with specificity for LTC4 and LTD4, respectively, there is an additional heterogeneity in terms of affinities. It is considered likely that a third receptor mediates the distinct actions of LTE4 on a guinea pig tracheal spirals, where this agonist exhibits greater contractile potency than LTD4 and LTC4 and elicits hyperreactivity to histamine that is not a nonspecific response to a prior contraction.
Adv Prostaglandin Thromboxane Leukot Res 1985
PMID:Subclass-specific receptors for sulfidopeptide leukotrienes. 300 42

In intact cells or in membranes prepared from intact cells that were preincubated with PGE1, subsequent PGI2-stimulation is attenuated. Preincubation of cells with PGI2 does not induce desensitization of PGI2-stimulated adenylate cyclase. These data suggest that HFF cells must be constantly exposed to a biologically active prostaglandin for desensitization to occur. The intrinsic chemical lability of PGI2 may be a biochemical protection mechanism against desensitization in cells that normally respond to PGI2.
Adv Prostaglandin Thromboxane Res 1980
PMID:PGE1 but not PGI2 desensitizes the PGI2 receptor-adenylate cyclase complex in human foreskin fibroblasts. 624 90

We examined the role of prostaglandins in three pivotal events of the female reproductive cycle: ovulation, luteolysis, and menstruation. Four general approaches were adopted, using in vivo and in vitro models: use of inhibitors of cyclooxygenase and of PG action; immunoneutralization of individual prostaglandins; administration of exogenous prostaglandins; and attempts to correlate PG levels in tissues and body fluids to physiologic events. It can be concluded that prostaglandins or related metabolites of arachidonic acid are essential in laboratory rodents for follicular rupture and the release of a fertilizable oocyte, but not for other LH actions on the follicle that are mimicked by PG or for the neuroendocrine triggering of ovulation. PGs control the cyclic regression of the corpus luteum and appear also to be implicated in the decidual reaction and in the menstrual shedding of the endometrium in primates. Some aspects of the control of follicular PG formation and of PG action were analyzed. Gonadotropins stimulate follicular PG synthesis by a steroid-independent cyclic nucleotide-mediated induction of cyclooxygenase. Both the thecal and granulosa cell compartments show this response. An effect of the phytolectin conconalavin A on ovarian PG synthesis is described. The response of follicular cells to prostaglandin E2 exhibits the phenomenon of desensitization and is influenced by agents modifying the structure and function of cytoskeletal elements. Evidence is put forward for the view that abrogation by PGF2 alpha of the stimulatory action of LH on luteal adenylate cyclase is the biochemical basis of the luteolytic action of this prostaglandin. While the precise mechanism of PG action on the endometrium remains to be defined, PG-synthetase inhibitors have already found useful applications in the management of menstrual disorders, such as functional dysmenorrhea and menorrhagia. The role in ovarian and uterine physiology of the more recently discovered labile arachidonate metabolites, such as the endoperoxides, prostacyclin, and thromboxanes, has not yet been adequately explored.
Adv Prostaglandin Thromboxane Res 1980
PMID:Significance of prostaglandins in the regulation of cyclic events in the ovary and uterus. 737 86

Thromboxane A2 (TXA2), the major cyclooxygenase (COX) product of arachidonic acid (AA), activates platelets and is a potent vasoconstrictor. The functional importance of this eicosanoid has been demonstrated in syndromes of acute coronary ischaemia. The cellular response to this agonist is tightly regulated. The liberation of AA from membrane phospholipids is conventionally thought to be the rate limiting step in TXA2 biosynthesis. However, the discovery of a second, highly regulated COX gene (COX-2) and the demonstration of product-based inactivation of COX and thromboxane synthase suggest a more complex regulation of TXA2 formation. TXA2 signalling is mediated by a G-protein linked receptor (PGH2/TXA2 receptor) which activates phospholipase C (PLC). Pharmacological studies suggest two distinct binding sites on platelets, but receptor heterogeneity has yet to be documented at a molecular level. The PGH2/TXA2 receptors are linked via a pertussis and cholera toxin-insensitive G-protein which has not been fully characterized, but is thought to belong to the Gq class of G-proteins. The diversity of G-protein alpha subunits, and growing evidence suggesting functional roles for the beta-gamma subunit, support a possible dual signalling mechanism of cellular activation. This may be of particular importance in regulating the response to eicosanoids with contrasting actions. A receptor for prostacyclin (PGI2) has not yet been cloned but biochemical studies suggest that it is linked to the activation of adenylate cyclase via Gs. At least three distinct prostaglandin E receptors have been identified. Desensitization of the cellular responses to the activation of TXA2, PGI2 and PGE receptors have been demonstrated and potential phosphorylation sites in their COOH terminal ends may be important in mediating this effect.
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PMID:Cellular activation by thromboxane A2 and other eicosanoids. 813 96


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