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

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

1 Endothelial cells of human umbilical vein were isolated and cultured in vitro. 2 In these cells there was a concentration-dependent release of prostacyclin and activation of adenylate cyclase by human calcitonin gene-related peptide (hCGRP). The concentration of hCGRP for half-maximum activation of adenylate cyclase (Kact) by hCGRP was 190 nM. 3 Bradykinin induced a ten fold greater release of prostacyclin than CGRP, but did not activate adenylate cyclase. 4 hCGRP may exert its potent vasodilator properties by stimulating release of vasorelaxant substances, including prostacyclin from endothelial cells.
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PMID:Human calcitonin gene-related peptide activates adenylate cyclase and releases prostacyclin from human umbilical vein endothelial cells. 332 63

Bradykinin receptors on normal lung membranes seem to be coupled to adenylate cyclase. Stimulation of the enzyme from sensitized lung membranes by adrenaline and vasoactive intestinal peptide was markedly reduced, whereas the ability of bradykinin and histamine to activate the sensitized adenylate cyclase was unaffected. Additional experiments are necessary in order to delineate the precise molecular events associated with activation of each of the two presently known bradykinin receptor types.
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PMID:Activation by bradykinin and vasoactive intestinal peptide of adenylate cyclase from immunologically sensitized lung membranes. 381 96

Bradykinin-stimulated increases in renal prostaglandin (PG) synthesis are thought to result in subsequent increases in cAMP content. This study assesses the relationship between bradykinin-stimulated increases in PGE2 and cAMP syntheses in renal inner medullary slices. Bradykinin-mediated increases in cAMP (2 min) preceded those in PGE2 (5 min) synthesis. Forskolin, an activator of adenylate cyclase, increased cAMP, while 2',5'-dideoxyadenosine, an adenylate cyclase inhibitor, reduced cAMP. However, neither agent altered bradykinin-stimulated PGE2 synthesis. Aspirin decreased basal and abolished bradykinin-stimulated PGE2 production, but did not alter bradykinin-induced increases in cAMP content. Maximal stimulatory concentrations of 1-methyl-3-isobutylxanthine, a cyclic nucleotide phosphodiesterase inhibitor, and bradykinin were additive in their capacity to increase inner medullary cAMP content. These results suggest that 1-methyl-3-isobutylxanthine and bradykinin increase cAMP by separate mechanisms and that bradykinin increases inner medullary cAMP by a direct effect on the production of that cyclic nucleotide. Bradykinin-mediated increases in cAMP and PGE2 syntheses by renal medullary slices are independent effects of this renally acting hormone.
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PMID:Independent effects of bradykinin on adenosine 3',5'-monophosphate and prostaglandin E2 metabolism by rabbit renal medulla. 619 96

1. The release of calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) from the dorsal horn of the rat spinal cord in vitro in response to dorsal root stimulation was measured by radioimmunoassay. 2. Stimulation of the dorsal roots (3 or 4 roots on each side) at 10 Hz for 5 min evoked a mean release (R1) of 134.3 +/- 17.5 (n = 10) fmol CGRP-LI; the release (R2) evoked by a second stimulation period 30 min later under control conditions was 77 +/- 10% (n = 10) of R1. Test compounds were applied to the preparation following release R1, and their effect calculated from the value of R2/R1. 3. Bradykinin (0.01-10 microM) had no significant effect on the basal release of CGRP-LI, but at 0.1-10 microM it increased 2-3 fold the release evoked by dorsal root stimulation. 4. This effect of bradykinin was prevented by indomethacin (10 microM), or by the B2-receptor antagonist, Hoe140 (1-10 microM). In the presence of Hoe140, bradykinin significantly reduced R2/R1; the explanation for this is not clear. 5. The B1-receptor agonist, Des-Arg9-bradykinin (10 microM), did not affect CGRP-LI release nor was the effect of bradykinin blocked by the B1-receptor antagonist, Des-Arg9-Leu8-bradykinin (10 microM). 6. Various prostaglandins were found to mimic the effect of bradykinin on CGRP-LI release. Their approximate order of potency was prostaglandin D2 (PGD2) = PGE1 > PGF2 alpha = PGE2; PGI2 was ineffective at 10 microM.7. Forskolin (30 muM) and 3-isobutyl l-methylxanthine (IBMX; 10 fM) also increased the evoked release of CGRP-LI.8. It is concluded that bradykinin acts on B2-receptors in the spinal cord, causing the formation ofprostanoids, which in turn cause an enhancement of neuropeptide release from primary afferent nerve terminals in the dorsal horn. This effect may be secondary to activation of adenylate cyclase. Because B2-receptors are mainly associated with primary afferent nerve terminals, it is likely that prostanoid production is also a function of these structures. Whether this action of bradykinin has any physiological function in nociceptive transmission remains unclear..
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PMID:Effect of bradykinin and prostaglandins on the release of calcitonin gene-related peptide-like immunoreactivity from the rat spinal cord in vitro. 767 28

Bradykinin receptors have been identified in human gingival fibroblasts; the primary signal transduction pathways and their dependence on calcium have been characterized. Binding data revealed a calcium-independent binding of bradykinin to the cell membrane with a receptor density of 25,000 receptors per cell and a Kd of 1.6 nM. The bradykinin receptor-mediated activation of phospholipase C (PLC) resulted in an extensive and rapid stimulation of phosphoinositide metabolism. Using radioreceptor assay techniques, in the absence of LiCl, the inositol 1,4,5-trisphosphate (Ins 1,4,5P3) generation was found to be transient, with maximal levels attained within 15 s. An EC50 of 12 nM was observed for the accumulation of total inositol polyphosphates. The activation of phospholipase A2 (PLA2), and the subsequent release of arachidonic acid and the primary metabolite prostaglandin E2, also was found to be time- and concentration-dependent. Stimulation of tyrosine kinase activity by bradykinin was concentration-dependent and resulted in the phosphorylation of three substrates of unknown identity. Bradykinin stimulation did not activate adenylate cyclase as there occurred no increase in the generation of cyclic AMP. The mobilization of intracellular calcium stores followed closely the Ins 1,4,5 P3 kinetics and had an EC50 of 11 nM. Chelation of extracellular calcium reduced significantly the duration of the calcium response, while only minimally lowering the rapid, maximal increase in intracellular free calcium concentration ([Ca2+]i). A sustained elevation of [Ca2+]i was found to be essential in PLC and PLA2 signaling, as well as in tyrosine kinase activation, suggesting a major role for membrane calcium channels in bradykinin stimulation of cellular responses in these cells. Bradykinin was found to inhibit dramatically epidermal growth factor-induced DNA synthesis in confluent cells, although to a much lesser degree in subconfluent cells. This pattern was similar to the observed maximal specific increase in bradykinin binding with confluency. Together these results demonstrate the presence of bradykinin receptors in human gingival fibroblasts; these receptors are coupled to signal transduction mechanisms involving the PLC, PLA2, and tyrosine kinase effector systems, all of which require extracellular calcium to achieve maximal activation.
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PMID:Bradykinin receptors and signal transduction pathways in human fibroblasts: integral role for extracellular calcium. 768 36

Bradykinin and phorbol 12-myristate 13-acetate stimulate adenylate cyclase activity in serum-depleted cultured airway smooth muscle via a protein kinase C (PKC)-dependent pathway. The probable target is the type II adenylate cyclase, which can integrate coincident signals from both PKC and Gs. Therefore, activation of Gs (by cholera-toxin pre-treatment) amplified the bradykinin-stimulated cyclic AMP signal and concurrently attenuated the partial activation of extracellular-signal-regulated kinase-2 (ERK-2) by bradykinin. We have previously demonstrated that, in order to induce full activation of ERK-2 with bradykinin, it is necessary to obliterate PKC-stimulated cyclic AMP formation. We concluded that the cyclic AMP signal limits the magnitude of ERK-2 activation [Pyne, Moughal, Stevens, Tolan and Pyne (1994) Biochem. J. 304, 611-616]. The present study indicates that the bradykinin-stimulated ERK-2 pathway is entirely cyclic AMP-sensitive, and suggests that coincident signal detection by adenylate cyclase may be an important physiological route for the modulation of early mitogenic signalling. Furthermore, the direct inhibition of adenylate cyclase activity enables bradykinin to induce DNA synthesis, indicating that the PKC-dependent activation of adenylate cyclase limits entry of cells into the cell cycle. These studies suggest that the mitogenicity of an agonist may be governed, in part, by its ability to stimulate an inhibitory cyclic AMP signal pathway in the cell. The activation of adenylate cyclase by PKC appears to be downstream of phospholipase D. However, in cells that were maintained in growth serum (i.e. were not growth-arrested), bradykinin was unable to elicit a PKC-stimulated cyclic AMP response. The lesion in the signal-response coupling was not at the level of either the receptor or phospholipase D, which remain functionally operative and suggests modification occurs at either PKC or adenylate cyclase itself. These studies are discussed with respect to the cell signal regulation of mitogenesis in airway smooth muscle.
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PMID:Adenylate cyclase, cyclic AMP and extracellular-signal-regulated kinase-2 in airway smooth muscle: modulation by protein kinase C and growth serum. 770 66

Receptor subtypes and intracellular signaling events involved in bradykinin-evoked contraction of colonic circular muscle are unknown. We studied the roles of inositol trisphosphate (IP3) and cyclic AMP generation and the selectivity for B1 and B2 receptors in guinea pig colon. Bradykinin induced concentration-dependent contraction of circular muscle strips with an EC50 of 2 x 10(-8) M that was inhibited by the B2 antagonist D-Argo-(Hyp3,Thi5,8,D-Phe7)-bradykinin but not the B1 antagonist des-Arg9-[Leu8]bradykinin. The B1 agonist des-Arg9-bradykinin did not evoke contraction or relaxation. Bradykinin induced concentration-dependent shortening of isolated myocytes from circular muscle with an EC50 of 2 x 10(-11) M that was inhibited by the B2 but not the B1 antagonist, confirming the myogenic nature of the bradykinin receptors. Persistence of myocyte contraction in a calcium-free medium with EGTA confirmed the lack of dependence on extracellular calcium. In colon muscle tissue, bradykinin evoked concentration-dependent IP3 generation with an EC50 of 10(-7) M and a maximal level of 58 +/- 17 pmol/mg of protein at 10(-4) M that was inhibited by the B2 but not the B1 antagonist. Bradykinin, acting on B2 receptors, inhibited cyclic AMP formation after forskolin (10(-5) M) with an EC50 of 3 x 10(-8) M and maximal inhibition of 48% at 10(-5) M. In conclusion, bradykinin induces colon muscle contraction via myogenic non-B1 receptors, which are likely of the B2 subtype, with phosphoinositide turnover activation and adenylate cyclase inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Bradykinin acting on B2 receptors contracts colon circular muscle cells by IP3 generation and adenylate cyclase inhibition. 771 87

1. Bradykinin and related kinins possess two different types of action (consisting of relaxation and contraction) in the isolated rat duodenum via their specific receptors. However, the mechanisms of these actions have not been fully elucidated. The present study was undertaken to investigate the effects of the agents affecting cyclic nucleotide metabolism on bradykinin-induced relaxations and on bradykinin- and des-Arg9-bradykinin-induced contractions. 2. Des-Arg9-bradykinin, B1 receptor agonist, and high concentrations of bradykinin elicited dose-dependent contractile responses in the rat duodenum, while low concentrations of bradykinin caused a dose-dependent relaxation in this tissue. 3. Nicotinic acid, an inhibitor of adenylate cyclase, inhibited the relaxation of rat duodenum induced by bradykinin at low concentrations in a non-competitive manner. However, the inhibitory efficacy of nicotinic acid against bradykinin was limited by 39.9% and this inhibition was not further increased by higher concentrations of nicotinic acid up to 10(-3) M. 4. Imidazole, an activator of cyclic nucleotide phosphodiesterase, caused a slight inhibition of the relaxant responses to low concentrations of bradykinin and of the contractile responses to des-Arg9-bradykinin and high concentrations of bradykinin in isolated rat duodenum. These inhibitions were also limited in efficacies and not increased by higher concentrations of imidazole. 5. Methylene blue, an agent that inhibits soluble guanylate cyclase, suppressed the contractions of rat duodenum induced by des-Arg9-bradykinin and high concentrations of bradykinin in a non-competitive manner. Again, these inhibitions were limited and further increase in the inhibitory efficacy was not observed in spite of increasing the methylene blue concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of the agents affecting cyclic nucleotide metabolism on the bradykinin- and des-Arg9-bradykinin-induced relaxations and contractions in isolated rat duodenum. 789 50

Bradykinin activates adenylate cyclase via a pathway that involves the 'up-stream' regulation of phospholipase D (PLD)-catalysed hydrolysis of phosphatidylcholine and activation of protein kinase C (PKC) in airway smooth muscle [Stevens, Pyne, Grady and Pyne (1994) Biochem. J. 297, 233-239]. Coincident signal (Gs alpha and PKC) amplification of the cyclic AMP response can be completely attenuated either by diverting PLD-derived phosphatidate or by inhibiting PKC. In this regard, the coincident signal detector type II adenylate cyclase is expressed as a 110/112 kDa polypeptide in these cells. PKC alpha is not involved in the activation of adenylate cyclase, since a B2-receptor antagonist (NPC567, 10 microM) blocked its bradykinin-stimulated translocation to the membrane and was without effect against both bradykinin-stimulated PLD activity and cyclic AMP formation. Cyclic AMP formation can also be activated by platelet-derived growth factor (PDGF), via a PKC-dependent pathway, although the magnitude of the response is less than that elicited by bradykinin. Nevertheless, these results indicate that multiple receptor types employ PKC to initiate cyclic AMP signals. PDGF (10 ng/ml) elicited the marked sustained activation of extracellular-signal-regulated kinase-2 (ERK-2), whereas bradykinin (1 microM) provoked only modest transient activation of ERK-2. Deoxyadenosine (0.1 mM), a P-site inhibitor of adenylate cyclase, blocked bradykinin-stimulated cyclic AMP formation and converted the activation of ERK-2 into a sustained response. Thus the PKC-stimulated cyclic AMP response can limit the activation of ERK-2 in response to bradykinin. These studies indicate that the integration of distinct signal pathways by adenylate cyclase can determine the kinetics of ERK activation, an enzyme that appears to be important for mitogenic progression.
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PMID:Protein kinase C-dependent cyclic AMP formation in airway smooth muscle: the role of type II adenylate cyclase and the blockade of extracellular-signal-regulated kinase-2 (ERK-2) activation. 799 98

Treatment of cultured tracheal smooth-muscle cells (TSM) with phorbol 12-myristate 13-acetate (PMA) (100 nM) or bradykinin (100 nM) elicited enhanced basal and guanosine 5'-[beta gamma-imido]-triphosphate-stimulated adenylate cyclase activities in subsequently isolated membranes. Combined stimulation of cells was non-additive, indicating that both agents activate adenylate cyclase via similar routes. Both PMA (100 nM) and bradykinin (100 nM) allowed the alpha subunit of Gs to act as a more favourable substrate for its cholera-toxin-catalysed ADP-ribosylation in vitro. PMA was without effect on intracellular cyclic AMP in control cells. However, constitutive activation of Gs by treatment in vivo with cholera toxin (0.5 ng/ml, 18 h) sensitized the cells to PMA stimulation, resulting in a concentration-dependent increase in intracellular cyclic AMP accumulation (EC50 = 7.3 +/- 2.5 nM, n = 5). Bradykinin also elicited a concentration-dependent increase in intracellular cyclic AMP (EC50 = 63.3 +/- 14.5 nM, n = 3). Constitutive activation of Gs resulted in an increased maximal response (10-fold) and potency (EC50 = 6.17 +/- 1.6 nM, n = 3) to bradykinin. This response was not affected by the B2-receptor antagonist, NPC567 [which selectively blocks bradykinin-stimulated phospholipase C (PLC), with minor activity against phospholipase D (PLD) activity]. Des-Arg9-bradykinin (a B1-receptor agonist) was without activity. These results suggest that the receptor sub-type capable of activating PLD may also be stimulatory for cyclic AMP accumulation. Furthermore, pre-treatment of the cells with butan-l-ol (0.3%, v/v), which traps phosphatidate derived from PLD reactions, blocked the bradykinin-stimulated increase in intracellular cyclic AMP. These studies suggest that there may be a causal link between PLD-derived phosphatidate and the positive modulation of adenylate cyclase activity. In support of this, the concentration-dependence for bradykinin-stimulated adenylate cyclase activity was identical with that of bradykinin-stimulated phospholipase D activity (EC50 = 5 nM). Bradykinin, but not PMA, was also capable of eliciting the inhibition of cyclic AMP phosphodiesterase activity in TSM cells (EC50 > 100 nM) via an unidentified mechanism. These studies indicate that cross-regulation between the cyclic AMP pathway and phospholipid-derived second messengers in TSM cells does not occur as a consequence of PLC-catalysed PtdIns(4,5)P2 hydrolysis, but may involve, in part, PLD-catalysed phosphatidylcholine hydrolysis.
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PMID:Bradykinin-dependent activation of adenylate cyclase activity and cyclic AMP accumulation in tracheal smooth muscle occurs via protein kinase C-dependent and -independent pathways. 828 Jan 4


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