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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neutrophils are relatively insensitive to the anti-inflammatory actions of conventional chemotherapeutic agents, including corticosteroids, emphasizing the requirement for novel pharmacological strategies to control the potentially harmful proinflammatory activities of these cells. In the case of commonly-occurring inflammatory diseases of the airways, the neutrophil is the primary mediator of inflammation in conditions such as chronic obstructive pulmonary disease, cystic fibrosis, acute respiratory distress syndrome, bronchiectasis and non-eosinophilic bronchial asthma. Recent insights into the mechanisms utilized by neutrophils to restore Ca(2+) homeostasis following activation with Ca(2+)-mobilizing, proinflammatory stimuli have facilitated the identification of novel targets for anti-inflammatory chemotherapy in these cells. The most amenable of these from a chemotherapeutic perspective, is the cyclic AMP-dependent protein kinase-modulated endomembrane Ca(2+)-ATPase which promotes clearance of the cation from the cytosol of activated neutrophils. Second generation type 4 phosphodiesterase inhibitors and adenosine receptor agonists operative at the level of subtype A2A adenosine receptors, which are currently undergoing clinical and preclinical assessment respectively, hold promise as pharmacologic modulators during the restoration of Ca(2+) homeostasis. If this promise is realized, it may result in novel chemotherapeutic strategies for the control of hyperacute and chronic inflammatory conditions in which neutrophils are primary offenders. Alternative, potential future targets include the Na(+), Ca(2+)-exchanger and store-operated Ca(2+) channels, which cooperate in the refilling of intracellular Ca(2+) stores.
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PMID:Taming the neutrophil: calcium clearance and influx mechanisms as novel targets for pharmacological control. 1599 82

We found that caffeine significantly inhibited epidermal growth factor (EGF)- and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced cell transformation in the JB6 mouse epidermal cell line. The tumor promoter-induced cell transformation was also blocked by treatment with an adenosine A1 receptor antagonist, 8-phenyltheophylline (8-PTH). Caffeine slightly attenuated activation of EGF-induced activator protein 1 (AP-1) activation, which play important roles in cell transformation, but only at the highest concentration examined (1 mM). Interestingly, pretreatment with caffeine suppressed EGF-induced phosphorylation and activation of Akt and ribosomal p 70 S6 protein kinase (p 70 S 6 K), a target of Akt, without inhibiting phosphatidylinositol 3-kinase (PI 3 K) activation. The inhibition of Akt activation of caffeine was not a result of its adenosine receptor antagonism. Because Akt plays a key role in signal transduction pathways leading to cell proliferation and apoptosis, our results provide novel insight into possible mechanisms of the chemotherapeutic effect of caffeine.
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PMID:Inhibition of epidermal growth factor-induced cell transformation and Akt activation by caffeine. 1604 20

Adenosine is an extracellular nucleoside that is elevated in tissues during hypoxia and ischemia reperfusion and has been implicated in asthma and other lung disorders. There, adenosine is considered an important modulator of physiological functions and inflammation, but its effects on matrix expression and turnover during tissue remodeling are unknown. We examined the effects of adenosine on lung epithelial cells with particular attention to the expression of fibronectin, a matrix glycoprotein highly expressed in injured tissues that has been implicated in wound healing. In A549 lung epithelial cells, we found that adenosine induced expression of fibronectin mRNA and protein in a dose- and time-dependent manner and found that the stimulatory effect of adenosine was inhibited by specific adenosine receptor antagonists. Adenosine stimulation was associated with increased levels of intracellular cAMP and with phosphorylation and DNA binding of the cAMP response element binding protein (CREB), known for its ability to stimulate fibronectin gene transcription. To confirm the latter, A549 cells were transfected with a DNA construct containing the human fibronectin promoter connected to a luciferase reporter gene. Adenosine stimulated transcription of the gene, and this effect was blocked by inhibitors of protein kinase activation. Finally, we tested primary lung fibroblasts and primary alveolar epithelial type II cells and found increased fibronectin expression in response to adenosine. Overall, our observations suggest that adenosine might modulate tissue remodeling by stimulating fibronectin expression in lung epithelial cells through induction of purinergic receptor-mediated signals that target CREB phosphorylation and stimulate fibronectin gene transcription.
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PMID:Adenosine induces fibronectin expression in lung epithelial cells: implications for airway remodeling. 1618 71

Adenosine and nitric oxide (NO) are important local mediators of vasodilatation. The aim of this study was to elucidate the mechanisms underlying adenosine receptor-mediated NO release from the endothelium. In studies on freshly excised rat aorta, second-messenger systems were pharmacologically modulated by appropriate antagonists while a NO-sensitive electrode was used to measure adenosine-evoked NO release from the endothelium. We showed that A1-mediated NO release requires extracellular Ca2+, phospholipase A2 (PLA2) and ATP-sensitive K+ (KATP) channel activation whereas A2A-mediated NO release requires extracellular Ca2+ and Ca2+-activated K+ (KCa) channels. Since our previous study showed that A1- and A2A-receptor-mediated NO release requires activation of adenylate cyclase (AC), we propose the following novel pathways. The K+ efflux resulting from A1-receptor-coupled KATP-channel activation facilitates Ca2+ influx which may cause some stimulation of endothelial NO synthase (eNOS). However, the increase in [Ca2+]i also stimulates PLA2 to liberate arachidonic acid and stimulate cyclooxygenase to generate prostacyclin (PGI2). PGI2 acts on its endothelial receptors to increase cAMP, so activating protein kinase A (PKA) to phosphorylate and activate eNOS resulting in NO release. By contrast, the K+ efflux resulting from A2A-coupled KCa channels facilitates Ca2+ influx, thereby activating eNOS and NO release. This process may be facilitated by phosphorylation of eNOS by PKA via the action of A2A-receptor-mediated stimulation of AC increasing cAMP. These pathways may be important in mediating vasodilatation during exercise and systemic hypoxia when adenosine acting in an endothelium- and NO-dependent manner has been shown to be important.
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PMID:The cellular mechanisms by which adenosine evokes release of nitric oxide from rat aortic endothelium. 1623 64

Adenosine produces a wide variety of physiological effects through the activation of specific adenosine receptors (A(1), A(2A), A(2B), A(3)). Adenosine, acting particularly at the A(2A) adenosine receptor (A(2A)AR), is a potent endogenous anti-inflammatory agent and sensor of inflammatory tissue damage. The complete healing of wounds is the final step in a highly regulated response to injury. Recent studies on epidermal wounds have identified the A(2A)AR as the main adenosine receptor responsible for altering the kinetics of wound closure. We hypothesized that A(2A)AR promotes wound healing in bronchial epithelial cells (BECs). To test this hypothesis, the human BEC line BEAS-2B and bovine BECs (BBECs) were used. Real-time RT-PCR of RNA from unstimulated BEAS-2B cells revealed transcriptional expression of A(1), A(2A), A(2B) and A(3) receptors. Western blot analysis of lysates from BEAS-2B cells and BBECs detected a single band at 44.7 kDa in both the BECs, indicating the presence of A(2A)AR. In a wound healing model, we found that adenosine stimulated wound repair in cultured BBECs in a concentration-dependent manner, with an optimal closure rate observed between 4 and 6 h. Similarly, the A(2A)AR agonist 5'-(N-cyclopropyl)carboxamidoadenosine (CPCA) augmented wound closure, with a maximal closure rate occurring between 4 and 6 h. Inhibition of A(2A)AR with ZM-241385, a known A(2A)AR antagonist, impeded wound healing. In addition, ZM-241385 also attenuated adenosine-mediated wound repair. Kinase studies revealed that adenosine-stimulated airway repair activates PKA by ligating A(2A)AR. Collectively, the data suggest that the A(2A)AR is involved in BEC adenosine-stimulated wound healing and may prove useful in understanding purinergic-mediated actions on airway epithelial repair.
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PMID:Adenosine A2A receptors promote adenosine-stimulated wound healing in bronchial epithelial cells. 1636 56

Cystic fibrosis is caused by dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, leading to altered ion transport, chronic infection, and excessive inflammation. Here we investigated regulation of CFTR in airway cell monolayers by adenosine, adenosine receptors, and arachidonic acid. Our studies demonstrate that the A2B adenosine receptor is expressed at high levels relative to the other adenosine receptor subtypes, with a characteristic low-affinity profile for adenosine-stimulated CFTR Cl- currents in both Calu-3 cells and CFBE41o- airway cell monolayers stably transduced with wild-type CFTR. The levels of adenosine found in sputum from patients with cystic fibrosis with moderate to severe lung disease stimulated apical prostaglandin release in Calu-3 and CFBE41o- cells, implicating adenosine regulation of phospholipase A2 (PLA2) activity. A2B adenosine receptor and arachidonic acid stimulation produced CFTR-dependent currents in airway monolayers and increased cAMP levels that were sensitive to cyclooxygenase inhibition. Arachidonic acid demonstrated dual regulation of CFTR, stimulating CFTR and Cl- currents in intact airway monolayers, and potently inhibiting PKA-activated Cl- currents in excised membrane patches. Cl- currents produced by arachidonic acid were sensitive to inhibition of PKA, cyclooxygenase, and 5-lipoxygenase. Together, the results provide a converging mechanism to link regulation of CFTR and airway cell inflammation through adenosine and adenosine receptors.
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PMID:Adenosine regulation of cystic fibrosis transmembrane conductance regulator through prostenoids in airway epithelia. 1639 52

Adenosine, released by cells in an injurious or hypoxic environment, possesses potent anti-inflammatory effects by inhibiting the production of proinflammatory cytokines and superoxide anions (O2-). We hypothesized that adenosine compounds also induced heterologous desensitization of chemokine receptors, which played a critical role in leukocyte trafficking. Our studies using adenosine receptor subtype-specific agonists revealed that pretreatment with adenosine compounds suppressed RANTES-induced chemotaxis and Ca2+ flux through activation of A2a adenosine receptor. Adenosine compounds also desensitized IL-8- and MCP-1-induced chemotaxis, but not that induced by fMLP. Activation of protein kinase A (PKA), a component of the signaling pathway induced by the A2a receptor, was sufficient to desensitize RANTES-induced chemotaxis. Inhibition of PKA reversed the desensitization effects of adenosine compounds, suggesting that PKA was necessary for A2a receptor-mediated heterologous desensitization. In a mouse model, prior activation of A2a receptors blocked RANTES-induced recruitment of leukocytes in an air pouch. Moreover, the A2a receptor-induced cross-desensitization also reduced the susceptibility of monocytes to infection by an R5 strain of HIV-1. Our results suggest that activation of A2a adenosine receptors suppresses chemokine receptor function, and such receptor cross-talk was based on the simple mechanism of PKA-mediated heterologous desensitization, thus contributing to the antiinflammatory activity of adenosine.
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PMID:Adenosine A2a receptors induce heterologous desensitization of chemokine receptors. 1652 19

Blockage of the p53 tumor suppressor has been found to impair nerve growth factor (NGF)-induced neurite outgrowth in PC-12 cells. We report herein that such impairment could be rescued by stimulation of the A(2A) adenosine receptor (A(2A)-R), a G protein-coupled receptor implicated in neuronal plasticity. The A(2A)-R-mediated rescue occurred in the presence of protein kinase C (PKC) inhibitors or protein kinase A (PKA) inhibitors and in a PKA-deficient PC-12 variant. Thus, neither PKA nor PKC was involved. In contrast, expression of a truncated A(2A)-R mutant harboring the seventh transmembrane domain and its C terminus reduced the rescue effect of A(2A)-R. Using the cytoplasmic tail of the A(2A)-R as bait, a novel-A(2A)-R-interacting protein [translin-associated protein X (TRAX)] was identified in a yeast two-hybrid screen. The authenticity of this interaction was verified by pull-down experiments, coimmunoprecipitation, and colocalization of these two molecules in the brain. It is noteworthy that reduction of TRAX using an antisense construct suppressed the rescue effect of A(2A)-R, whereas overexpression of TRAX alone caused the same rescue effect as did A(2A)-R activation. Results of [(3)H]thymidine and bromodeoxyuridine incorporation suggested that A(2A)-R stimulation inhibited cell proliferation in a TRAX-dependent manner. Because the antimitotic activity is crucial for NGF function, the A(2A)-R might exert its rescue effect through a TRAX-mediated antiproliferative signal. This antimitotic activity of the A(2A)-R also enables a mitogenic factor (epidermal growth factor) to induce neurite outgrowth. We demonstrate that the A(2A)-R modulates the differentiation ability of trophic factors through a novel interacting protein, TRAX.
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PMID:Rescue of p53 blockage by the A(2A) adenosine receptor via a novel interacting protein, translin-associated protein X. 1670 26

Human mast cells express functional A(2A) and A(2B) adenosine receptors. However, only stimulation of A(2B), not A(2A), leads to secretion of interleukin (IL)-4, an important step in adenosine receptor-mediated induction of IgE synthesis by B-cells. In this study, we investigate intracellular pathways that link stimulation of A(2B) receptors to IL-4 up-regulation in HMC-1 mast cells. Both A(2A) and A(2B) receptors couple to G(s) proteins and stimulate adenylate cyclase, but only A(2B) stimulates phospholipase Cbeta through coupling to G(q) proteins leading to activation of protein kinase C and calcium mobilization. Inhibition of phospholipase Cbeta completely blocked A(2B) receptor-dependent IL-4 secretion. The protein kinase C inhibitor 2-{8-[(dimethylamino)-methyl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-3-yl}-3-(1-methyl-1H-indol-3-yl)maleimide (Ro-32-0432) had no effect on A(2B) receptor-mediated IL-4 secretion but inhibited phorbol 12-myristate 13-acetate-stimulated IL-4 secretion. In contrast, chelation of intracellular Ca(2+) inhibited both A(2B) receptor- and ionomycin-dependent IL-4 secretion. This Ca(2+)-sensitive pathway probably includes calcineurin and nuclear factor of activated T cells, because A(2B) receptor-dependent IL-4 secretion was blocked with cyclosporin A or 11R-VIVIT peptide. G(s)-linked pathways also play a role in the A(2B) receptor-dependent stimulation of IL-4 secretion; inhibition of adenylate cyclase or protein kinase A attenuated A(2B) receptor-dependent IL-4 secretion. Although stimulation of adenylate cyclase with forskolin did not increase IL-4 secretion on its own, it potentiated the effect of Pasteurella multocida toxin by 2-fold and ionomycin by 3-fold. Both forskolin and stimulation of A(2B) receptors up-regulated NFATc1 protein levels. We conclude that A(2B) receptors up-regulate IL-4 through G(q) signaling that is potentiated via cross-talk with G(s)-coupled pathways.
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PMID:Cross-talk between G(s)- and G(q)-coupled pathways in regulation of interleukin-4 by A(2B) adenosine receptors in human mast cells. 1670 27

Adenosine is known to modulate the function of neostriatal neurons. Adenosine acting on A(2A) receptors increases the phosphorylation of dopamine- and cAMP-regulated phosphoprotein of M(r) 32 kDa (DARPP-32) at Thr34 (the cAMP-dependent protein kinase [PKA] site) in striatopallidal neurons, and opposes dopamine D2 receptor signaling. In contrast, the role of adenosine A(1) receptors in the regulation of dopamine/DARPP-32 signaling is not clearly understood. Here, we investigated the effect of adenosine A(1) receptors on D(1), D(2) and A(2A) receptor signaling using mouse neostriatal slices. An A(1) receptor agonist, 2-chloro-N(6)-cyclopentyladenosine (100 nM), caused a transient increase, followed by a transient decrease, in DARPP-32 Thr34 phosphorylation. Our data support the following model for the actions of the A(1) receptor agonist. The A(1) receptor-induced early increase in Thr34 phosphorylation was mediated by presynaptic inhibition of dopamine release, and the subsequent removal of tonic inhibition by D(2) receptors of A(2A) receptor/G(olf)/cAMP/PKA signaling. The A(1) receptor-induced late decrease in Thr34 phosphorylation was mediated by a postsynaptic G(i) mechanism, resulting in inhibition of D(1) and A(2A) receptor-coupled G(olf)/cAMP/PKA signaling in direct and indirect pathway neurons, respectively. In conclusion, A(1) receptors play a major modulatory role in dopamine and adenosine receptor signaling.
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PMID:Role of adenosine A1 receptors in the modulation of dopamine D1 and adenosine A2A receptor signaling in the neostriatum. 1675 Aug 92


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