Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Steroidogenesis by Y-1 adrenal tumor cells in culture is stimulated by ATP, adenyl-5'-yl imidodiphosphate (App(NH)), adenosine 5'(beta, alpha-methylene)triphosphate (App(CH2)p), ADP, AMP, NAD, FAD, and adenosine but not by adenine or other nucleoside triphosphates. ATP, App(NH)p, App(CH2)p, and adenosine are active in the micromolar range. Like adrenocorticotropic hormone (ACTH), the onset of stimulation is immediate and occurs to the same extent. Also active are 2'- and 5'-deoxyadenosine and 2-chloroadenosine whereas adenine xyloside, L-riboside, or arabinoside have very low activity. Stimulation is accompanied by rounding of the cells. Dipyridamole, an inhibitor of adenosine transport, increased the response to low concentrations of adenosine, suggesting that adenosine acts externally. Stimulation of steroidogenesis by adenosine or phosphorylated adenosine compounds fails to occur in the presence of crystalline adenosine deaminase, and the effect of the enzyme on adenosine, ATP, or NAD stimulation is reversed by the competitive inhibitor erythro-9-[3-(nonane-2-ol)]adenine. This suggests that the enzyme acts specifically on adenosine and a requirement for the conversion of the above compounds to adenosine seems probable. The inhibition of cAMP effects by adenosine deaminase suggests that some of its effects are also mediated by conversion to adenosine. Similar stimulation is seen in I-10 Leydig tumor cells, but an ACTH-resistant mutant of Y-1 cells, called OS-3, is relatively resistant to adenosine. Adenosine and 2-chloroadenosine stimulate adenylate cyclase in membranes from Y-1 and I-10 cells at concentrations slightly greater than are effective for steroidogenesis. Other nucleosides are ineffective. Like the NH2-terminal 24 residues of adrenocorticotropic hormone (1-24 ACTH), the adenosine effect in Y-1 membranes is rapid and is on the Vmax intercept (versus ATP) and not on the Km. In contrast to steroidogenesis, adenosine is only a partial agonist for adenylate cyclase. It effect occurs in the presence of ITP, GTP, or guanyl-5'-yl imidodiphosphate (Gpp(NH)p). Theophylline inhibits adenosine-stimulated steroidogenesis. Inhibition of adenylate cyclase occurs in the same concentration range but is of the mixed type.
...
PMID:Activation of steroidogenesis and adenylate cyclase by adenosine in adrenal and Leydig tumor cells. 18 24

Experimental atherosclerosis in rabbits induced by feeding a standard atherogenic diet for 4 months resulted in an increased sensitivity of platelets to the proaggregatory action of collagen and ADP. Treatment with dipyridamole (3 x 10 mg/day i.m.) for 4 weeks normalized platelet loss in atherosclerotic rabbits and abolished the increased sensitivity to proaggregatory collagen, but not to ADP. Dipyridamole treatment lowered basal as well as PGI2-induced cAMP levels below values seen in platelets from normal rabbits, but the stimulation by PGI2 relative to basal cAMP levels was not affected or even increased by dipyridamole treatment. Dipyridamole did not affect the increased sensitivity of platelets from atherosclerotic rabbits to the antiaggregatory action of PGI2, indicating that dipyridamole decreased absolute cAMP levels, probably due to reduction of the adenine nucleotide pool in platelets without affecting the adenylate cyclase function. Dipyridamole enhanced atherosclerotic plaque formation in arterial walls. Basal as well as PGI2-stimulated cAMP content was lower in homogenates from atherosclerotic than from normal aortic tissue. Dipyridamole-treated animals showed a further decrease in basal as well as PGI2-stimulated cAMP content of the aortic tissue, suggesting that this decrease in cAMP content may be linked to the enhanced proliferative activity seen in artherosclerotic plaque formation.
...
PMID:Effects of dipyridamole in experimental atherosclerosis. Action on PGI2, platelet aggregation and atherosclerotic plaque formation. 22 6

Field electrical stimulation (ES), K+ (50 mM) or ionophore X-537A (0.01 mM) induced tritium release from cat cerebral arteries preincubated with [3H]noradrenaline (NA). Adenosine and AMP (0.5 mM) did not modify tritium release caused by ionophore X-537A, but these agents and ATP (0.5 mM) significantly reduced that elicited by ES and K+; this reduction was antagonized by 1-methyl-3-isobutylxanthine (MIX; 0.05 mM). Inosine (0.5 mM) and the agonist of purinergic A2-receptors, 5'N-ethyl-carboxamide adenosine (NECA; 0.5 mM) had no effect, but the agonist of purinergic A2-receptors L-N6-phenylisopropyl adenosine (L-PIA; 0.1 mM) diminished tritium efflux caused by ES and K+. The adenosine inhibition of ES-induced radioactivity release was not affected by indomethacin (0.05 mM). MIX (0.05 mM) increased tritium release evoked by ES and K+. Agents that increase intracellular cyclic (c)AMP levels, such as dibutyryl cAMP (0.5 mM), the phosphodiesterase inhibitor Ro 20-1724 (0.1 mM), and the activators of adenylate cyclase, forskolin (0.005 mM) and NaF (2 mM) reduced tritium secretion elicited by ES and K+. However, the intracellular increase of cyclic GMP (cGMP) caused by 8-Br-cGMP did not affect this secretion. Dipyridamole (0.05 mM) and the adenosine deaminase inhibitor erythro-9-2-hydroxy-3 nonyl adenosine (EHNA; 0.1 mM) also produced inhibition of tritium secretion elicited by ES and K+. Dipyridamole reduced both the uptake of [3H]NA and [3H]adenosine.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Role of presynaptic purinoceptors and cyclic AMP on the noradrenaline release in cat cerebral arteries. 198 Feb 88

2',5'-Dideoxyadenoside (DDA) inhibited both anti-IgE and ionophore A23187 induced histamine secretion from human basophils. Whereas DDA inhibited IgE-dependent histamine secretion when added at all times prior to challenge, release induced by A23187 was inhibited only with simultaneous addition of DDA and secretagogue. Dipyridamole, but not theophylline, abrogated DDA mediated inhibition of histamine release suggesting an intracellular mechanism of action of DDA. The observations that 2'-deoxyadenosine and 9-beta-D-arabinofuranosyladenine also inhibited release suggest that the its inhibitory effect was enhanced by manganese and reversed by islet activating protein from Bordetella pertussis suggest that DDA inhibits basophil histamine release by interacting with a guanine nucleotide binding protein which may be linked to either adenylate cyclase or other second messenger system(s).
...
PMID:Inhibition of immunological and nonimmunological histamine release from human basophils by adenosine analogues that act at P-sites. 242 53

1. Acute effects of dipyridamole, an inhibitor of adenosine transport, direct activators of adenylate cyclase and thirteen adenosine antagonist analogs on fatty acid synthesis have been examined in terms of the control of [1-14C]acetate incorporation into labeled fatty acids in the presence of glucose. 2. This monosaccharide acts as a stimulator of lipogenesis by generating NADPH for the lipid synthesis. 3. The relationship between lipogenesis and lipolysis was compared with a variety of adenylate cyclase stimulators. 4. The data obtained reveals that dipyridamole potentiated the inhibitory or stimulatory effects of isoproterenol and forskolin on lipogenesis and on lipolysis, respectively. 5. In these cases the data show that it exists an inverse relationship between lipogenesis and lipolysis. 6. Dipyridamole and methylxanthine analogs only moderately affect the rate of lipolysis whereas its effects are more potent on lipogenesis and lend further support to the hypothesis that dipyridamole antagonize adenosine actions as well as methyl xanthines. 7. These results suggest that dipyridamole and adenosine antagonists alter lipogenesis independently of the lipolytic process and that it exists an inverse relationship between lipogenesis and lipolysis under some conditions whereas there are not under others.
...
PMID:Regulation of lipid metabolism by dipyridamole and adenosine antagonists in rat adipocytes. 258 56

The effects of ATP, adenosine and N6-substituted adenosines, adenosine receptor agonists, on the twitch contraction of guinea-pig ileum evoked by transmural stimulation were evaluated. Adenosine and ATP produced an immediate and concentration dependent inhibition of the twitch, IC50 being 1.1 X 10(-5) mol/l and 1.2 X 10(-5) mol/l, respectively. N6-l-phenylisopropyl adenosine (L-PIA), N6-cyclohexyl adenosine (CHA) and N6-allyl adenosine also induced inhibitions which were gradual and persistent, IC50 being 2.6 X 10(-8), 2.7 X 10(-8) and 5.4 X 10(-7) mol/l, respectively. Dipyridamole (10(-7) mol/l), an adenosine uptake inhibitor, markedly augmented the inhibition evoked by adenosine and ATP, but not that by three N6-substituted adenosines, while theophylline (10(-4) mol/l) almost completely antagonized the inhibitory effects of all purine compounds. IC50 value of adenosine in the presence of dipyridamole (5 X 10(-7) mol/l) was shifted to the left about 50 times from the control, whereas that of L-PIA was virtually unchanged. Tissue-medium ratios indicating uptake of [3H]adenosine, [3H]ATP and [3H]CHA into the segment were 3.23 (s.e.m. = 0.59), 3.59 (s.e.m. = 0.78) and 0.41 (s.e.m. = 0.04), respectively. These results suggest that not only adenosine and ATP but also these N6-substituted adenosines are potent agonists for the P1 receptor, implying a similarity between P1 and A1 receptor in a functional role and these purine compounds may thereby modulate cholinergic neurotransmission by altering adenylate cyclase activity.
...
PMID:Cholinergic neuromodulation by ATP, adenosine and its N6-substituted analogues in guinea-pig ileum. 298 36

Although purine nucleosides have been shown to regulate the secretion of several peptide and steroid hormones, effects on pituitary hormone release have not been reported. We show here that in the clonal GH4C1 pituitary cell line maximal concentrations of adenosine (greater than or equal to 50 microM) inhibited PRL and GH secretion by 40%. Adenosine deaminase abolished the inhibitory effect of adenosine but not that of SRIF or (-)N6(R-2-phenylisopropyl)adenosine (PIA), a nonhydrolyzable adenosine analog. Furthermore, this enzyme increased basal secretion by 50%, and analysis of the incubation medium by HPLC demonstrated that the cells secreted biologically effective concentrations of adenosine. These results indicate that adenosine produced in culture tonically inhibits hormone release. In other target cells, adenosine inhibition is mediated by two types of binding sites: an extracellular Ri-site requiring an intact ribose moiety or an intracellular P-site requiring an intact purine ring. Four lines of evidence indicate that in GH4C1 cells, adenosine acts at an Ri-site. PIA, an Ri-site-specific agonist, was a potent inhibitor of hormone release (ED50 = 30 nM). Theophylline, an Ri-site antagonist, competitively inhibited the action of PIA (Ki = 2.4 microM). 3) 2'5'-Dideoxyadenosine, a P-site-specific agonist, did not inhibit PRL release even at a concentration of 1 mM. 4) Dipyridamole, an adenosine uptake inhibitor, did not reduce adenosine inhibition. In addition to its effect on basal secretion, PIA inhibited stimulation of hormone release by vasoactive intestinal peptide and TRH. PIA also reduced vasoactive intestinal peptide-stimulated cAMP accumulation by 75%, consistent with its action to inhibit adenylate cyclase via Ri receptors in other targets. Since PIA inhibition of PRL release and cAMP accumulation was not additive with the effects of SRIF and carbamyl choline, these inhibitors may act via a common rate-limiting step. Our results demonstrate that adenosine activates an Ri-type of adenosine receptor in GH4C1 cells and that the production of adenosine under normal culture conditions causes autocrine inhibition of secretion.
...
PMID:Adenosine inhibits prolactin and growth hormone secretion in a clonal pituitary cell line. 299 34

Human adipocytes are of limited viability (7 +/- 2% release of lactate dehydrogenase/h) and contain active ectophosphatases which are capable of sequentially degrading ATP to adenosine. At densities of 30,000-40,000 cells/ml, human fat cell suspensions accumulated adenosine, inosine, and hypoxanthine, and their concentrations were 38 +/- 8, 120 +/- 10, and 31 +/- 7 nmol/liter after 3 h of incubation. Dipyridamole (10 mumol/liter), an inhibitor of nucleoside transport, caused a 5-7-fold increase in adenosine accumulation which was reduced by 85% on inhibition of ectophosphatases by beta-glycerophosphate and antibodies against ecto-5'-nucleotidase or alpha, beta-methylene 5'-adenosine diphosphate (10 mumol/liter), respectively, indicating that most of the adenosine is produced in the extracellular compartment. Accordingly, the spontaneous accumulation of adenosine was reduced beyond 5 nmol/liter on inhibition of ectophosphatase activities or removal of extracellular AMP by AMP deaminase (4 units/ml). Added adenosine (30 nmol/liter) disappeared until its concentration approached 5 nmol/liter. Isoproterenol (1 mumol/liter) had no effect on adenosine accumulation regardless whether purine production from extracellular sources was minimized or not. In contrast to adenosine, the concentrations of inosine and hypoxanthine displayed only a modest decrease (30-50%) on inhibition of ectophosphatase activities. In addition, isoproterenol caused a 2-3-fold increase in inosine and hypoxanthine production which was concentration-dependent and could be inhibited by propranolol. It is concluded that the adenosine that accumulates in human adipocyte suspensions is almost exclusively derived from adenine nucleotides which are released by leaking cells. By contrast, inosine and hypoxanthine are produced inside the cells, and the release of these latter purines appears to be linked to ATP turnover via adenylate cyclase.
...
PMID:Purine accumulation in human fat cell suspensions. Evidence that human adipocytes release inosine and hypoxanthine rather than adenosine. 337 46

The effects of a series of adenosine derivatives were examined on the catecholamine-stimulated electrically-driven rat left atrium in vitro. All the purines tested reduced the positive inotropic action of isoprenaline, 0.1 microM, with the potency order: L-N6-phenlylisopropyladenosine (L-PIA) greater than 5'-N-ethylcarboxamide adenosine (NECA) greater than D-PIA greater than 2-chloroadenosine greater than adenosine. Dipyridamole did not change the IC50 of adenosine. The adenosine deaminase inhibitor, 2'deoxycoformycin, produced a small but nonsignificant shift to the left of the adenosine concentration-response curve. The cardiac depressant effects of these purines were reversed by theophylline and the IC50 values were unchanged in the presence of atropine or in atria taken from reserpine-treated rats. It is concluded that the purine receptor mediating these effects should not be classified on the A1/A2 system. The relationship between functionally characterized purine receptors and those originally defined as modulating adenylate cyclase is discussed.
...
PMID:Inhibition by purines of the inotropic action of isoprenaline in rat atria. 631 27

Adenosine is an endogenous antiaggregating substance that influences the platelet responses through specific A-type receptors that activate adenylate cyclase increasing the levels of 3',5'-cyclic adenosine monophosphate (cAMP). In this study, we investigated whether adenosine can also influence the levels of 3',5'-cyclic guanosine monophosphate (cGMP) and decrease the aggregating response of human platelets to adenosine-5-diphosphate (ADP) through this nucleotide. In platelet samples from healthy volunteers, we evaluated the effect of adenosine on ADP-induced aggregation and cyclic nucleotide synthesis. Some experiments were repeated in the presence of dipyridamole (inhibitor of adenosine uptake and phosphodiesterase activity), N(G)-monomethyl-L-arginine (L-NMMA, nitric synthase inhibitor), ionomycin (calcium ionophore), and ambroxol (2-amino-3,5-dibromo-N-[trans-4-hydroxycyclohexyl]benzylamine, inhibitor of nitric oxide (NO)-dependent activation of guanylate cyclase). Adenosine decreased the response to ADP in a concentration-dependent way (analysis of variance, ANOVA: P<.0001): cAMP levels increased from 30.0 +/- 2.0 (control) to 46.0 +/- 3.0 pmol/10(9) platelets (in the presence of 15 mumol/l adenosine) and cGMP levels increased from 5.6 +/- 1.0 (control) to 10.9 +/- 2.0 pmol/10(9) platelets (in the presence of 15 mumol/l adenosine). Also, nucleotide levels measured at the end of aggregation were higher in platelet samples exposed to adenosine than in controls. Dipyridamole at 40 mumol/l slightly increased adenosine's effects on both nucleotides. L-NMMA blunted the effect of adenosine on cGMP both in unstimulated samples and in aggregated platelets without any effect on cAMP synthesis. Platelet exposure to L-NMMA and ambroxol partially prevented adenosine's effect on ADP-induced aggregation. In conclusion, adenosine, which enhances intraplatelet cAMP levels, was determined to also cause an increase in cGMP concentrations through a mechanism that involves NO synthesis. This effect plays a direct role in the adenosine-induced antiaggregation.
...
PMID:Adenosine increases human platelet levels of cGMP through nitric oxide: possible role in its antiaggregating effect. 1186 10


1

---