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)

Vasoactive intestinal peptide (VIP) is a neuropeptide synthesized by immune cells that can modulate several immune aspects, including the function of cells involved in the inflammatory response, such as macrophages and monocytes. The production and release of cytokines by activated phagocytes are important events in the pathogenesis of ischemia-reperfusion injury. There is abundant evidence that the proinflammatory cytokine TNF-alpha is an important mediator of shock and organ failure complicating Gram-negative sepsis. VIP has been shown to attenuate the deleterious consequences of this pathologic phenomenon. In this study we have investigated the effects of VIP and the structurally related neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP38) on the production of TNF-alpha by endotoxin-activated murine peritoneal macrophages. Both neuropeptides rapidly and specifically inhibit the LPS-stimulated production of TNF-alpha, exerting their action through the binding to VPAC1 receptor and the subsequent activation of the adenylate cyclase system. VIP and PACAP regulate the production of TNF-alpha at a transcriptional level. In vitro results were correlated with an inhibition of both TNF-alpha expression and release in endotoxemic mice in vivo. The immunomodulatory role of VIP in vivo is supported by the up-regulation of VIP release in serum and peritoneal fluid by LPS and proinflammatory cytokines such as TNF-alpha, IL-1beta, and IL-6. These findings support the idea that under toxicity conditions associated with high LPS doses, VIP and PACAP could act as protective mediators that regulate the excessive release of TNF-alpha to reduce inflammation or shock.
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PMID:Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit endotoxin-induced TNF-alpha production by macrophages: in vitro and in vivo studies. 997 16

Crude myocardial sarcolemmal membrane fractions were prepared from rat hearts subjected to total global ischemia with and without normoxic reperfusion, or global anoxic (N2) perfusion with and without normoxic reperfusion. The direct effects on beta-adrenoceptor number, G-protein levels and stimulation of the adenylate cyclase (AC) complex were assessed. In terms of AC activation, ischemia led to a marked increase (4-fold) in sensitivity to terbutaline (beta2-agonist) and phorbol ester (tetradecanoyl phorbol acetate = TPA) stimulation, whereas the dobutamine (beta1) responsiveness and Gpp(NH)p activation through G(s)alpha/G(i2)alpha remained unaltered. However, forskolin-elicited holoenzyme activity fell markedly during normoxic reperfusion. Ischemia did not change the beta1-adrenoceptor number, while beta2-receptor population increased by approximately 45%. Western blots of myocardial G(s)A and G(i2)alpha contents revealed that ischemia selectively diminished G(i2)alpha levels only by some 50-70%. Contrastingly, anoxia selectively increased the AC sensitivity (2-fold) to beta1-adrenergic stimulation. As subsequent to ischemia, anoxia also increased the sensitivity to TPA stimulation, however, only 2-fold. Gpp(NH)p activation was unchanged, while forskolin-enhanced activity gradually declined, also during ensuing normoxic reperfusion. Anoxia brought about a 75% enhancement in beta1-receptor number, while beta2-receptors remained unaffected. However, altered receptor number normalized on termination of normoxic reperfusion. Finally, anoxia led to a 50-60% decimation of myocardial G(i2)alpha levels, while G(s)alpha was only marginally reduced. Despite the fact that the ischemia and anoxia effectuated a similar deterioration of physiological heart parameters, myocardial contents of energy rich phosphate moieties and loss of G(i2)alpha, ischemia rendered the most profound increase in responsiveness of the sarcolemmal AC system.
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PMID:Enhanced responsiveness of the myocardial beta-adrenoceptor-adenylate cyclase system in the perfused rat heart (I). 1019 81

Pituitary adenylate cyclase-activating polypeptides and PAC1-R are expressed during early embryogenesis and PACAP's neurotrophic action supports a role in neuronal development. In the adult brain PACAP functions as a neuroprotective factor that attenuates the neuronal damage resulting from various insults. The tumor suppressor gene p53 and the new zinc finger protein Zac regulate apoptosis and cell cycle arrest through unrelated pathways and both genes are up-regulated under cerebral ischemia. We report here that p53 and Zac induce expression of the PAC1-R gene. By this mechanism p53 and Zac could fine-tune the balance between death promoting and protective signals and may thus fulfil a dual role in ischemia.
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PMID:Induction of the PAC1-R (PACAP-type I receptor) gene by p53 and Zac. 1036 51

1. Unlike some interfaces between the blood and the nervous system (e.g., nerve perineurium), the brain endothelium forming the blood-brain barrier can be modulated by a range of inflammatory mediators. The mechanisms underlying this modulation are reviewed, and the implications for therapy of the brain discussed. 2. Methods for measuring blood-brain barrier permeability in situ include the use of radiolabeled tracers in parenchymal vessels and measurements of transendothelial resistance and rate of loss of fluorescent dye in single pial microvessels. In vitro studies on culture models provide details of the signal transduction mechanisms involved. 3. Routes for penetration of polar solutes across the brain endothelium include the paracellular tight junctional pathway (usually very tight) and vesicular mechanisms. Inflammatory mediators have been reported to influence both pathways, but the clearest evidence is for modulation of tight junctions. 4. In addition to the brain endothelium, cell types involved in inflammatory reactions include several closely associated cells including pericytes, astrocytes, smooth muscle, microglia, mast cells, and neurons. In situ it is often difficult to identify the site of action of a vasoactive agent. In vitro models of brain endothelium are experimentally simpler but may also lack important features generated in situ by cell:cell interaction (e.g. induction, signaling). 5. Many inflammatory agents increase both endothelial permeability and vessel diameter, together contributing to significant leak across the blood-brain barrier and cerebral edema. This review concentrates on changes in endothelial permeability by focusing on studies in which changes in vessel diameter are minimized. 6. Bradykinin (Bk) increases blood-brain barrier permeability by acting on B2 receptors. The downstream events reported include elevation of [Ca2+]i, activation of phospholipase A2, release of arachidonic acid, and production of free radicals, with evidence that IL-1 beta potentiates the actions of Bk in ischemia. 7. Serotonin (5HT) has been reported to increase blood-brain barrier permeability in some but not all studies. Where barrier opening was seen, there was evidence for activation of 5-HT2 receptors and a calcium-dependent permeability increase. 8. Histamine is one of the few central nervous system neurotransmitters found to cause consistent blood-brain barrier opening. The earlier literature was unclear, but studies of pial vessels and cultured endothelium reveal increased permeability mediated by H2 receptors and elevation of [Ca2+]i and an H1 receptor-mediated reduction in permeability coupled to an elevation of cAMP. 9. Brain endothelial cells express nucleotide receptors for ATP, UTP, and ADP, with activation causing increased blood-brain barrier permeability. The effects are mediated predominantly via a P2U (P2Y2) G-protein-coupled receptor causing an elevation of [Ca2+]i; a P2Y1 receptor acting via inhibition of adenyl cyclase has been reported in some in vitro preparations. 10. Arachidonic acid is elevated in some neural pathologies and causes gross opening of the blood-brain barrier to large molecules including proteins. There is evidence that arachidonic acid acts via generation of free radicals in the course of its metabolism by cyclooxygenase and lipoxygenase pathways. 11. The mechanisms described reveal a range of interrelated pathways by which influences from the brain side or the blood side can modulate blood-brain barrier permeability. Knowledge of the mechanisms is already being exploited for deliberate opening of the blood-brain barrier for drug delivery to the brain, and the pathways capable of reducing permeability hold promise for therapeutic treatment of inflammation and cerebral edema.
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PMID:Inflammatory mediators and modulation of blood-brain barrier permeability. 1069 6

A number of metabolites produced during abdominal ischemia can stimulate and/or sensitize visceral afferents. The precise mechanisms whereby these metabolites act are uncertain. Other studies have shown that the adenylate cyclase-cAMP system may be involved in the activation of sensory neurons. Therefore, we hypothesized that cAMP contributes to the activation of ischemically sensitive abdominal visceral afferents. Single-unit activity of abdominal visceral C fibers was recorded from the right thoracic sympathetic chain in anesthetized cats before and during 7 min of abdominal ischemia. Forty-six percent of ischemically sensitive C fibers responded to intra-arterial injection of 8-bromo-cAMP (0.35-1. 0 mg/kg), an analog of cAMP, with responses during ischemia increasing from 0.50 +/- 0.06 to 0.84 +/- 0.08 impulses/s (P < 0.05, n = 11 C fibers). Conversely, an inhibitor of adenylate cyclase, 2', 5'-dideoxyadenosine (DDA; 0.1 mg/kg iv), attenuated ischemia-induced increase in activity of afferents from 0.66 +/- 0.10 to 0.34 +/- 0. 09 impulses/s (P < 0.05; n = 8). Furthermore, whereas exogenous PGE(2) (3-4 microg/kg ia) augmented the ischemia-induced increase in activity of afferents (P < 0.05, n = 10), treatment with DDA (0.1 mg/kg iv) substantially reduced the increase in discharge activity of afferents during ischemia, which was augmented by PGE(2) (1.45 +/- 0.24 vs. 0.70 +/- 0.09 impulses/s, -DDA vs. +DDA; P < 0.05) in six fibers. A time control group (n = 4), however, demonstrated similar increases in the activity of afferents with repeated administration of PGE(2). These data suggest that cAMP contributes to the activation of abdominal visceral afferents during ischemia, particularly to the action of PGs on activation and/or sensitization of these endings.
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PMID:Role of cAMP in activation of ischemically sensitive abdominal visceral afferents. 1071 Mar 53

Adenosine regulates many physiological functions through specific cell membrane receptors. On the basis of pharmacological studies and molecular cloning, four different adenosine receptors have been identified and classified as A(1), A(2A), A(2B), and A(3). These adenosine receptors are members of the G-protein-coupled receptor family. While adenosine A(1) and A(2A) receptor subtypes have been pharmacologically characterized through the use of selective ligands, the A(3) adenosine receptor subtype is presently under study in order to better understand its physio-pathological functions. Activation of adenosine A(3) receptors has been shown to stimulate phospholipase C and D and to inhibit adenylate cyclase. Activation of A(3) adenosine receptors also causes the release of inflammatory mediators such as histamine from mast cells. These mediators are responsible for processes such as inflammation and hypotension. It has also been suggested that the A(3) receptor plays an important role in brain ischemia, immunosuppression, and bronchospasm in several animal models. Based on these results, highly selective A(3) adenosine receptor agonists and/or antagonists have been indicated as potential drugs for the treatment of asthma and inflammation, while highly selective agonists have been shown to possess cardioprotective effects. The updated material related to this field of research has been rationalized and arranged in order to offer an overview of the topic.
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PMID:A(3) adenosine receptor ligands: history and perspectives. 1072 24

We determined the effects of 17beta-estradiol, the most effective estrogen, acutely administered, on the heart/ventricular myocyte with or without treatment with isoproterenol (Iso). At 0.1 to 1 nM, 17beta-estradiol, which itself had no effect, reduced the heart rate and developed pressures in the isolated perfused heart treated with 10(-7) M Iso. One nanomolar 17beta-estradiol also inhibited the cyclic AMP (cAMP) production in Iso-treated ventricular myocytes. At 10 nM to 1 microM, 17beta-estradiol itself reduced the heart rate and incidence of ischemia/reperfusion-induced arrhythmias, with the exception of diastolic pressure. The effects of 17beta-estradiol on heart rate, systolic and mean pressures, and arrhythmias were significantly enhanced in the heart/ventricular myocyte treated with Iso. Tamoxifen, an estrogen receptor antagonist, did not antagonize the effect of 17beta-estradiol on the Ca(2+) current in ventricular myocytes treated with Iso, nor did it alter the effect of the hormone on the cAMP production augmented by Iso and forskolin. The effects of 17beta-estradiol on Ca(2+) current in the presence or absence of tamoxifen and/or Iso were similar in male rats, which do not possess the estrogen receptor, and female rats, which have the estrogen receptor. In conclusion, we have shown for the first time that estrogen at physiological concentrations modulates negatively the stimulatory actions of Iso on the heart rate and cardiac contractility. The effects may result from activation of an unknown membrane receptor and the adenylate cyclase/cAMP pathway, which enhances Ca(2+) influx across the L-type Ca(2+) channel.
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PMID:Enhanced responses to 17beta-estradiol in rat hearts treated with isoproterenol: involvement of a cyclic AMP-dependent pathway. 1077 33

Polymorphonuclear leukocytes are known to play an important role in hypoxia/ischemia and reoxygenation injury. The present study was undertaken to investigate the involvement of protein kinase C, calmodulin, and cyclic adenosine monophosphate in the augmentation of the free-radical generation observed after hypoxia-reoxygenation (H-R). Free-radical generation from the rat polymorphonuclear leukocytes was measured as the arachidonic acid (1-5x10(-5) M)-induced luminol-dependent chemiluminescence response, which was augmented following H-R. The increase in free-radical generation after H-R was completely blocked by the pretreatment of cells with PKC inhibitor H(7), whereas indomethacin (a cyclo-oxygenase inhibitor) or forskolin (an adenylate cyclase activator) failed to modulate the H-R-dependent response. However, W(7)-a calcium/calmodulin (Ca(2+)/CaM) antagonist-partially reduced the augmented free-radical generation observed in the H-R cells. Results obtained thus suggest the possible involvement of protein kinase C and calcium in the augmentation of the free-radical generation response following H-R.
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PMID:Mechanisms involved in the augmentation of arachidonic acid-induced free-radical generation from rat neutrophils following hypoxia-reoxygenation. 1082 84

Ischemic preconditioning (IP) protects the heart against subsequent prolonged ischemia. Whether the beta-adrenoceptor/adenylate cyclase pathway contributes to this cardioprotection is not yet fully known. Using enzyme catalytic cytochemistry we studied the adenylate cyclase activity and its distribution in the preconditioned rat heart. Adenylate cyclase activity was examined in Langendorff-perfused rat hearts subjected to the following conditions: control perfusion; 30 min regional ischemia; 5 min occlusion and 10 min reperfusion (IP); IP followed by ischemia. Ischemia-induced arrhythmias and the effect of ischemic preconditioning on the incidence of arrhythmias were analyzed. At the end of experiment the heart was shortly prefixed with glutaraldehyde. Tissue samples from the left ventricle were incubated in a medium containing the specific substrate AMP-PNP for adenylate cyclase and then routinely processed for electron microscopy. Adenylate cyclase activity was cytochemically demonstrated in the sarcolemma and the junctional sarcoplasmic reticulum (JSR) in control hearts, while it was absent after test ischemia. The highest activity of the precipitate was observed after ischemic preconditioning. In the preconditioned hearts followed by test ischemia, adenylate cyclase activity in the precipitate was preserved in sarcolemma and even more in JSR. Protective effect of ischemic preconditioning was manifested by the suppression of severe arrhythmias. These results indicate the involvement of the adenylate cyclase system in mechanisms underlying ischemic preconditioning.
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PMID:Activation of adenylate cyclase system in the preconditioned rat heart. 1098 92

Preconditioning is a powerful form of (myocardial) protection that follows brief sublethal ischemia. G-protein-coupled receptors constitute the trigger for entrance to the preconditioned state. In conjunction with other receptors, various membrane adenosine receptors play an important role in the transduction of extracellular signals, leading to protection by preconditioning, lasting 1-3 hr. Adenosine A(1)- and A(3)-receptors mediate inhibition of adenylate cyclase via a guanine nucleotide binding inhibitory protein (G(i/o)). A(2)-receptors couple to a comparable stimulatory protein (G(s)). Adenosine receptors are especially abundant in the central nervous system; in lesser numbers, they are found in many tissues, including the heart. A(1)-receptors are located on cardiomyocytes and vascular smooth muscle cells, A(2)-receptors on endothelial and vascular smooth muscle cells, and A(3)-receptors on ventricular myocytes. Ischemic preconditioning by endogenous adenosine takes place through A(1)- and A(3)-receptors. A(2A/B)-receptor activation results in vasodilation. The relevance of cellular mediators, such as 5'-nucleotidase, to generate adenosine for preconditioning is controversial. In contrast, the role of protein kinase C (PKC) is clearly established. Signals from different receptors converge at PKC, reaching a threshold activation of the kinase necessary to induce protection. Tyrosine and mitogen-activated protein kinases may play a role in addition to PKC. The exact products downstream responsible for the memory of preconditioning are elusive. A prime candidate for the end-effector of preconditioning is the K(ATP) channel. Preconditioning with adenosine-receptor agonists offers the possibility for treatment of coronary artery disease, but research in this field is still in its infancy.
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PMID:The role of adenosine in preconditioning. 1100 96


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