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)

The endogenous nucleoside adenosine is thought to play a role in the pathophysiology of asthma by stimulating mast cells. We previously showed that the human mast cell line HMC-1 expresses A2A and A2B receptors, and that both receptors activate adenylate cyclase via Gs-protein but that only A2B receptors are also coupled to phospholipase C via Gq proteins. Stimulation of A2B but not A2A receptors induced production of interleukin-8 (IL-8) from HMC-1 cells. The mechanism by which adenosine promotes IL-8 synthesis has not been defined. In this study, we tested the hypothesis that mitogen-activated protein kinase (MAPK) signaling pathways are involved in this process. Stimulation of HMC-1 with the stable adenosine analog NECA (5'-N-ethylcarboxamidoadenosine) activated p21(ras) and both p42 and p44 isoforms of extracellular signal-regulated kinase (ERK). NECA (10 microM) induced a 1.9 +/- 0. 06-fold increase in ERK activity, whereas 10 microM of the selective A2A agonist CGS 21680 (4-((N-ethyl-5'-carbamoyladenos-2-yl)-aminoethyl)-phenylpropionic acid) had no effect. NECA, in parallel with the activation of ERK, also stimulated the p46 isoform of c-Jun N-terminal kinase (MEK) and p38 MAPK. Furthermore, the selective MAPK/ERK kinase 1 inhibitor PD 98059 (2'-amino-3'-methoxyflavone), and p38 MAPK inhibitors SB 202190 (4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)1H-imidazole) and SB 203580 (4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H- imidaz ole) blocked A2B receptor-mediated production of IL-8. These results indicate that extracellular adenosine can regulate ERK, c-Jun N-terminal kinase, and p38 MAPK signaling cascades and that activation of ERK and p38 MAPK pathways are essential steps in adenosine A2B receptor-dependent stimulation of IL-8 production in HMC-1.
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PMID:Role of p38 mitogen-activated protein kinase and extracellular signal-regulated protein kinase kinase in adenosine A2B receptor-mediated interleukin-8 production in human mast cells. 1010 Oct 31

Brain-derived neurotrophic factor contributes profoundly to modulate activity-dependent synaptic plasticity in adult brain areas such as the hippocampus, but the mechanisms underlying this important role still remain unclear. Recently, we have shown that two serine/threonine kinases, calcium/calmodulin-dependent protein kinase-2 and casein kinase-2, are capable of mediating brain-derived neurotrophic factor responses in adult rat hippocampus. In the present study, using hippocampal slices from adult rat, we show that phospholipase C-regulated calcium signals couple the brain-derived neurotrophic factor receptor to two distinct pathways: a pathway in which calcium/calmodulin-dependent protein kinase-2 stimulates a signalling module involving the p38 subfamily of mitogen-activated protein kinases and its downstream target, usually named mitogen-activated protein kinase-activated protein kinase-2; and a pathway in which the extracellular signal-regulated kinase subfamily of mitogen-activated protein kinases activates casein kinase-2. Our results suggest that: (i) extracellular signal-regulated kinase is activated by B-Raf in response to a calcium-sensitive adenylate cyclase; and (ii) extracellular signal-regulated kinase activates casein kinase-2 via a protein phosphatase(s) that may be of the PP1 and/or PP2A type. Interestingly, we also show that neurotrophin-induced activation of the two signalling cascades promotes a sustained activation of mitogen-activated protein kinase-activated protein kinase-2 and casein kinase-2 in slices. Considering the ability of these two kinases to be persistently activated, and that most of the protein kinases which lie in these pathways are believed to be important for multiple events underlying neuronal plasticity, it is suggested that the mechanisms described here might contribute both to rapid synaptic changes through local effects and to long-lasting synaptic responses through new gene transcription in the hippocampus.
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PMID:Identification of two persistently activated neurotrophin-regulated pathways in rat hippocampus. 1067 Apr 37

U46619, a thromboxane A2 mimetic, but not ADP, caused activation of p38 mitogen activated protein (MAP) kinase in aspirin-treated platelets. In nonaspirinated human platelets ADP activated p38 MAP kinase in both a time-and concentration-dependent manner, suggesting that ADP-induced p38 MAP kinase activation requires generation of thromboxane A2. However, neither a thromboxane A2/prostaglandin H2 receptor antagonist SQ29548 and a thromboxane synthase inhibitor, furegrelate, either alone or together, nor indomethacin blocked ADP-induced p38 kinase activation in nonaspirinated platelets. Other cycloxygenase products, PGE2, PGD2, and PGF2alpha, failed to activate p38 kinase in aspirin-treated platelets. Hence, ADP must be generating an agonist, other than thromboxane A2, via an aspirin-sensitive pathway, which is capable of activating p38 kinase. AR-C66096, a P2TAC (platelet ADP receptor coupled to inhibition of adenylate cyclase) antagonist, did not inhibit ADP-induced p38 MAP kinase activation. The P2X receptor selective agonist, alpha, beta-methylene ATP, failed to activate p38 MAP kinase. On the other hand, the P2Y1 receptor selective antagonist, adenosine-2'-phosphate-5'-phosphate inhibited ADP-induced p38 kinase activation in a concentration-dependent manner, indicating that the P2Y1 receptor alone mediates ADP-induced generation of the p38 kinase-activating factor. These results demonstrate that ADP causes the generation of a factor in human platelets, which can activate p38 kinase, and that this response is mediated by the P2Y1 receptor. Neither the P2TAC receptor nor the P2X1 receptor has any significant role in this response.
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PMID:The P2Y1 receptor mediates ADP-induced p38 kinase-activating factor generation in human platelets. 1075 52

This study examined the immunomodulatory effects of hydrogen peroxide (H(2)O(2)) in B6C3F1 mouse splenic lymphocytes. H(2)O(2) produced a marked and dose-related inhibition of both lipopolysaccharide (LPS)-induced B-cell proliferation and concanavalin A (Con A)-induced T-cell proliferation. Unexpectedly, little effect was observed with H(2)O(2) on the antibody-forming cell (AFC) response to the polyclonal B-cell activator, LPS. It was also observed that H(2)O(2) did not have any detectable effect on forskolin-stimulated adenylate cyclase, indicating that cyclic AMP (cAMP) is not a mediator of H(2)O(2)-induced suppression of the immune response. Rather, LPS-induced activation of protein kinase C (PKC) was completely inhibited when cells were pretreated with H(2)O(2) for 18 h, although PKC activity was increased approximately twofold following treatment with H(2)O(2) for 10 min. In addition, H(2)O(2) pretreatment blocked the phosphorylation of two stress-activated mitogen-activated protein kinases (MAPKs), c-Jun N-terminal kinase (JNK) and p38 by LPS in a concentration-dependent fashion. Therefore, these data suggest that H(2)O(2) suppresses immune response through the desensitization of PKC, which subsequently results in inhibition of JNK and p38.
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PMID:Hydrogen peroxide inhibits the immune response to lipopolysaccharide by attenuating signaling through c-Jun N-terminal kinase and p38 associated with protein kinase C. 1093 14

Receptor activity modifying protein-3 (RAMP-3) has been shown to complex with the calcitonin receptor-like receptor, establishing a functional receptor for adrenomedullin (AM). AM exhibits potent antiproliferative and antimigratory effects on rat mesangial cells (RMCs). In this study we investigated the effect of platelet-derived growth factor (PDGF) on RAMP-3 expression in RMCs. We show here that PDGF-BB stimulates RAMP-3 mRNA expression in a concentration-dependent manner. Pretreatment with actinomycin-D and alpha-amanitin demonstrates that this effect is independent of new RNA synthesis. Furthermore, PDGF increased the half-life of RAMP-3 mRNA from 66.5 to 331.6 min. Using selective inhibitors, our results also indicate that the increase in RAMP-3 mRNA is mitogen-activated protein kinase (MAPK) kinase (MEK)/MAPK and p38 MAPK dependent. PDGF also caused a corresponding elevation in membrane-associated RAMP-3 protein. Associated with this increase, PDGF pretreatment led to a significantly higher AM-mediated adenylate cyclase activity, suggesting a functional consequence for the PDGF-induced increase in RAMP-3 expression. Taken together, these data identify PDGF-dependent regulation of RAMP-3 expression as a possible mechanism for modulating the responsiveness of the mesangial cell to AM.
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PMID:Novel regulation of adrenomedullin receptor by PDGF: role of receptor activity modifying protein-3. 1199 47

Incubation of human distal bronchi from 48 patients for 15 h with 10(-7) M fenoterol induced sensitization characterized by an increase in maximal contraction to endothelin-1 (ET-1) and acetylcholine (ACh). Incubation of human bronchi with 10(-6), 3 x 10(-6), and 10(-5) M forskolin (an adenyl cyclase activator) reproduced sensitization to ET-1 and ACh. The sensitizing effect of fenoterol was inhibited by coincubation with gliotoxine (a nuclear factor-kappaB inhibitor), dexamethasone, indomethacin (a cyclooxygenase inhibitor), GR-32191 (a TP prostanoid receptor antagonist), MK-476 (a cysteinyl leukotriene type 1 receptor antagonist), SR-140333 + SR-48968 + SR-142801 (neurokinin types 1, 2, and 3 tachykinin receptor antagonists) with or without HOE-140 (a bradykinin B(2) receptor antagonist), SB-203580 (an inhibitor of the 38-kDa mitogen-activated protein kinase, p38(MAPK)), or calphostin C (a protein kinase C blocker). Our results suggest that chronic exposure to fenoterol induces proinflammatory effects mediated by nuclear factor-kappaB and pathways involving leukotrienes, prostanoids, bradykinin, tachykinins, protein kinase C, and p38(MAPK), leading to the regulation of smooth muscle contraction to ET-1 and ACh.
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PMID:In vitro sensitization of human bronchus by beta2-adrenergic agonists. 1237 56

Corticotropin-releasing factor receptor type 2beta, expressed in the rodent cardiovascular system, is a member of the G protein-coupled receptor family. This receptor is coupled positively to adenylate cyclase and is bound preferentially by the urocortin (Ucn)-related peptides (Uncs): Ucn, Ucn II, and Ucn III. In the present study, we investigated the effects of Ucns on IL-6 levels in A7r5 aortic smooth muscle cells. In this cell line, both Ucn and Ucn II induced accumulation of intracellular cAMP via corticotropin-releasing factor receptor type 2beta and also caused a significant increase in IL-6 output levels. The adenylate cyclase inhibitor, MDL-12330A, inhibited this Ucn- or Ucn II-induced increase in IL-6 levels. Although H89 (10 micro M), a protein kinase A inhibitor, had no effect on the increase in IL-6 concentration, bisindolylmaleimide I (10 nM), a protein kinase C inhibitor, was found to significantly inhibit IL-6 output levels. Blockade of Ucn- or Ucn II-induced increases in IL-6 levels by SB203580 (100 nM), a p38 MAPK inhibitor, suggested that the p38 MAPK pathway was involved in this regulation. The cAMP-mediated increase in IL-6 levels was suppressed synergistically by both bisindolylmaleimide I and SB203580. These findings demonstrate that both protein kinase C and p38 MAPK signaling cascades are involved downstream of the Ucns-cAMP pathway in A7r5 aortic smooth muscle cells.
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PMID:Urocortin-related peptides increase interleukin-6 output via cyclic adenosine 5'-monophosphate-dependent pathways in A7r5 aortic smooth muscle cells. 1274 80

Four corticotropin-releasing factor (CRF)-related peptides have been found in mammals and are known as CRF, urocortin, urocortin II, and urocortin III (also known as stresscopin). The three urocortins have considerably higher affinities for CRF receptor type 2 (CRF R2) than CRF, and urocortin II and urocortin III are highly selective for CRF R2. In the present study, the authors examined the hypothesis that urocortin II or urocortin III, in addition to urocortin, produces vasodilation as a candidate for natural ligands of CRF R2beta in rat thoracic aorta. Involvement of protein kinases on urocortin-induced vasodilation was also explored. The vasodilative effects of urocortin II and urocortin III were more potent than that of CRF, but less potent than that of urocortin. Urocortin II-induced vasodilation was significantly attenuated by a CRF R2-selective antagonist, antisauvagine-30. Both SQ22536, an adenylate cyclase inhibitor, and Rp-8-Br-cAMPS, a protein kinase A (PKA) inhibitor, were found to attenuate the urocortin II-induced vasodilation. SB203580, a p38 mitogen-activated protein (MAP) kinase inhibitor, also inhibited the effects of urocortin and urocortin II on vasodilation. Thus, urocortins contribute to vasodilation via p38 MAP kinase as well as PKA pathways.
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PMID:Vasodilative effects of urocortin II via protein kinase A and a mitogen-activated protein kinase in rat thoracic aorta. 1450 43

Genes encoding numerous proto-oncogenes and cytokines, as well as a number of G-protein coupled receptors, are regulated post-transcriptionally at the level of mRNA stability. A common feature of all of these genes is the presence of A + U-rich elements (AREs) within their 3' untranslated regions. We, and others, have demonstrated previously that mRNAs encoding beta-adrenergic receptors (beta-ARs) are destabilized by agonist stimulation of the beta-AR/Galphas/adenylylcyclase pathway. However, in addition to PK-A, beta-ARs can also activate or inhibit mitogen activated kinase (MAPK) cascades, in a cell-type dependent basis. Recent evidence points to an important role for MAPKs in regulating the turnover of cytokine mRNAs, such as TNFalpha. We hypothesized that activation of MAPK's may also regulate beta-AR mRNA stability. The studies conducted herein demonstrate that generalized stimulation of MAPKs (JNK, p38) with anisomycin resulted in marked stabilization of beta-AR mRNA. Reciprocally, selective inhibition of JNK with SP600125 significantly decreased beta-AR mRNA half-life. Similarly, inhibition of the MEK/ERK pathway with either PD98059 or U0126 decreased beta-AR mRNA stability substantially. However, inhibition of p38 MAPK with SB203580 produced destabilization of beta-AR mRNA only at higher, non pharmacologically selective concentrations. In contrast to their effects on several other ARE containing mRNAs, inhibition of tyrosine kinases by genistein or PI3K by wortmannin, had no detectable effect on beta-AR mRNA stability. In summary, these results demonstrate for the first time that modulation of MAPK pathways can bi-directionally influence beta-AR mRNA stability.
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PMID:Reciprocal regulation of beta-adrenergic receptor mRNA stability by mitogen activated protein kinase activation and inhibition. 1503 Jan 75

Prostaglandins are now recognized to be important regulators for both bone formation and resorption. Among them, prostaglandin E(1) (PGE(1)) has been reported to stimulate cAMP accumulation and to induce alkaline phosphatase (ALP) activity, a marker of differentiation, in osteoblast-like cells. Recently, we have shown that p38 mitogen-activated protein (MAP) kinase pathway regulates ALP activity in response to activation of Gi protein-coupled receptors in mouse osteoblast-like MC3T3-E1 cells (Suzuki et al., Endocrinology 140 (1999) 3177). In the present study, we investigated whether p38 MAP kinase is involved in ALP activation by PGE(1) in MC3T3-E1 osteoblast-like cells. PGE(1) dose-dependently enhanced ALP activities in the concentration range between 1 nM and 1 microM in MC3T3-E1 cells. SB203580, a specific inhibitor of p38 MAP kinase, blocked the increase in ALP activity induced by PGE(1). Further analysis with western blotting suggested that PGE(1) induced an increase in tyrosine (Tyr) phosphorylation of p38 MAP kinase. Both Bt(2)cAMP, a permeable analogue of cAMP, and forskolin, which directly activates adenylate cyclase, also induced an increase in Tyr phosphorylation of p38 MAP kinase. H-89, a potent inhibitor of protein kinase A (PKA), significantly suppressed PGE(1)-induced Tyr phosphorylation of p38 MAP kinase. The results of this study suggest that PGE(1) stimulates p38 MAP kinase through the activation of PKA, resulting in the enhancement of ALP activity.
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PMID:Possible involvement of p38 MAP kinase in prostaglandin E1-induced ALP activity in osteoblast-like cells. 1506 50


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