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)

The antihypertrophic action of angiotensin-converting enzyme inhibitors in the heart results partly from local potentiation of bradykinin. We have demonstrated that the antihypertrophic action of bradykinin is mediated by the release of nitric oxide from endothelium and elevation of cardiomyocyte cGMP. Whether other paracrine factors derived from the coronary endothelium, such as prostacyclin (PGI2), may act to prevent hypertrophy has not been explored. In the vasculature, activation by PGI2 of IP and EP1 prostanoid receptors elicits vasodilatation (via cAMP-dependent signaling) and vasoconstriction, respectively. The present objective was to determine whether IP prostanoid receptor activation has antihypertrophic actions in adult rat cardiomyocytes (ARCM). The selective IP agonist cicaprost (1 microM) virtually abolished the increase in [3H]phenylalanine incorporation (a marker of hypertrophy) induced either by endothelin-1 (ET-1; 60 nM, n = 10, P < 0.005) or by angiotensin II (1 microM, n = 6, P < 0.005). Cicaprost also inhibited ET-1 induction of c-fos mRNA expression, an additional marker of hypertrophy in ARCM (n = 5, P < 0.005). In the absence of hypertrophic stimuli, cicaprost alone did not significantly influence either marker. The antihypertrophic actions of cicaprost were mimicked by the dual IP/EP1 agonist iloprost (1 microM) in the presence of the EP1 antagonist AH-6809 (3 microM). Furthermore, cicaprost modestly but significantly increased cardiomyocyte cAMP content by 13 +/- 6% (P < 0.05, n = 4), and the antihypertrophic effect of cicaprost was lost in the presence of the cAMP-dependent protein kinase inhibitor H-89 (1 microM, n = 5, P < 0.05). However, ET-1 also induced increases in the activity of the intracellular growth signals ERK1 (by 3-fold) and ERK2 (by 5-fold) in ARCM, and these were not inhibited by cicaprost (P < 0.01, n = 5). Activation of IP receptors thus represents a novel approach to prevention of hypertrophy, and this effect is linked to cAMP-dependent signaling.
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PMID:Activation of IP prostanoid receptors prevents cardiomyocyte hypertrophy via cAMP-dependent signaling. 1507 55

Prostaglandin E(2) (PGE(2)) can have pro- or anti-inflammatory effects, depending on engagement of different PGE(2) receptor (EP) subtypes. The role of EPs in regulating autoimmune inflammation was studied in the murine arthritis/lupus model induced by pristane. Peritoneal macrophages were isolated (biomagnetic beads) from BALB/c, DBA/1, or C57BL/6 mice treated with pristane (intraperitoneally, 3 months earlier) or thioglycolate (3 days earlier) or with untreated controls. EPs, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) mRNA expression was examined by reverse transcriptase-polymerase chain reaction (RT-PCR). Cells were cultured unstimulated or stimulated with lipopolysaccharide (LPS) or LPS + interferon-gamma in combination with EP subtype-specific agonists. Tumor necrosis factor alpha (TNF-alpha) and interleukin (IL)-6 production was tested by enzyme-linked immunosorbent assay (culture supernatant) and flow cytometry. TNF-alpha mRNA levels also were examined. High levels of EPs (EP4/2>EP1>EP3), iNOS, and COX-2 mRNA were expressed in peritoneal macrophages from pristane-treated but not untreated or thioglycolate-treated mice (RT-PCR). TNF-alpha production was inhibited 50-70% at 2-24 h by EP4/2 agonists, whereas IL-6 was enhanced up to approximately 220%. TNF-alpha inhibition is mediated partly via the protein kinase A pathway and partly via IL-6. Intracellular TNF-alpha staining was inhibited 20% by EP4/2 agonists. TNF-alpha mRNA levels were inhibited 50-70% at 2-24 h, indicating that TNF-alpha inhibition was partly at the level of transcription. EP1/3 agonists had little effect. Synovial cells from mice with pristane-induced arthritis (DBA/1) also expressed EP2/4, and the EP2/4 agonist inhibited TNF-alpha production. PGE(2) can modulate inflammatory reactions via the EP2/4 receptor through its regulation of TNF-alpha and IL-6. Modification of EP signaling may be a new therapeutic strategy in inflammatory/autoimmune diseases.
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PMID:Prostaglandin E2 receptors EP2 and EP4 are up-regulated in peritoneal macrophages and joints of pristane-treated mice and modulate TNF-alpha and IL-6 production. 1507 56

Prostaglandins (PG) are key mediators of diverse functions in the skin and several reports suggest that PG mediate post-inflammatory pigmentary changes through modulation of melanocyte dendricity and melanin synthesis. The proteinase-activated receptor 2 (PAR-2) is important for skin pigmentation because activation of keratinocyte PAR-2 stimulates uptake of melanosomes through phagocytosis in a Rho-dependent manner. In this report, we show that activation of keratinocyte PAR-2 stimulates release of PGE(2) and PGF(2alpha) and that PGE(2) and PGF(2alpha) act as paracrine factors that stimulate melanocyte dendricity. We characterized the expression of the EP and FP receptors in human melanocytes and show that human melanocytes express EP1 and EP3, and the FP receptor, but not EP2 and EP4. Treatment of melanocytes with EP1 and EP3 receptor agonists resulted in increased melanocyte dendricity, indicating that both EP1 and EP3 receptor signaling contribute to PGE(2)-mediated melanocyte dendricity. Certain EP3 receptor subtypes have been shown to increase adenosine 3',5'-cyclic monophosphate (cAMP) through coupling to Gs, whereas EP1 is known to couple to Gq to activate phospholipase C with elevation in Ca(2+). The cAMP/protein kinase A system is known to modulate melanocyte dendrite formation through modulation of Rac and Rho activity. Neither PGF(2alpha) or PGE(2) elevated cAMP in human melanocytes showing that dendricity observed in response to PGE(2) and PGF(2alpha) is cAMP-independent. Our data suggest that PAR-2 mediates cutaneous pigmentation both through increased uptake of melanosomes by keratinocytes, as well as by release of PGE(2) and PGF(2alpha) that stimulate melanocyte dendricity through EP1, EP3, and FP receptors.
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PMID:Proteinase-activated receptor-2 stimulates prostaglandin production in keratinocytes: analysis of prostaglandin receptors on human melanocytes and effects of PGE2 and PGF2alpha on melanocyte dendricity. 1514 Feb 25

We reported recently that interleukin (IL)-1beta exposure resulted in a prolonged increase in MUC5AC mucin production in normal, well differentiated, human tracheobronchial epithelial (NHTBE) cell cultures, without significantly increasing MUC5AC mRNA (Am J Physiol 286:L320-L330, 2004). The goal of the present study was to elucidate the signaling pathways involved in IL-1beta-induced MUC5AC production. We found that IL-1beta increased cyclooxygenase-2 (COX-2) mRNA expression and prostaglandin (PG) E(2) production and that the COX-2 inhibitor celecoxib suppressed IL-1beta-induced MUC5AC production. Addition of exogenous PGE(2) to NHTBE cultures also increased MUC5AC production and IL-1beta-induced Muc5ac hypersecretion in tracheas from wild-type but not from COX-2-/- mice. NHTBE cells expressed all four E-prostanoid (EP) receptor subtypes and misoprostol, an EP2 and EP4 agonist, increased MUC5AC production, whereas sulprostone, an EP1 and EP3 agonist, did not. Furthermore, specific protein kinase A (PKA) inhibitors blocked IL-1beta and PGE(2)-induced MUC5AC production. However, neither inhibition of epidermal growth factor receptor (EGFR) activation with the tyrosine kinase inhibitor 4-(3-chloroanilino)-6,7-dimethoxyquinazoline HCl (AG-1478) or EGFR blocking antibody nor inhibition of extracellular signal-regulated kinase/P-38 mitogen activated protein kinases with specific inhibitors blocked IL-1beta stimulation of MUC5AC mucin production. We also observed that tumor necrosis factor (TNF)-alpha, platelet activating factor (PAF), and lipopolysaccharide (LPS) induced COX-2 and increased MUC5AC production that was blocked by celecoxib, suggesting a common signaling pathway of inflammatory mediator-induced MUC5AC production in NHTBE cells. We conclude that the induction of MUC5AC by IL-1beta, TNF-alpha, PAF, and LPS involves COX-2- generated PGE(2), activation of EP2 and/or EP4 receptor(s), and cAMP-PKA-mediated signaling.
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PMID:Interleukin-1beta-induced mucin production in human airway epithelium is mediated by cyclooxygenase-2, prostaglandin E2 receptors, and cyclic AMP-protein kinase A signaling. 1526 25

Recent studies suggest that the inducible isoform of cyclooxygenase, COX-2, promotes motor neuron loss in rodent models of ALS. We investigated the effects of PGE2, a principal downstream prostaglandin product of COX-2 activity, on motor neuron survival in an organotypic culture model of ALS. We find that PGE2 paradoxically protects motor neurons at physiological concentrations in this model. PGE2 exerts its downstream effects by signaling through a class of four distinct G-protein-coupled E-prostanoid receptors (EP1-EP4) that have divergent effects on cAMP. EP2 and EP3 are dominantly expressed in ventral spinal cord in neurons and astrocytes, and activation of these receptor subtypes individually or in combination also rescued motor neurons. The EP2 receptor is positively coupled to cAMP, and its neuroprotection was mimicked by application of forskolin and blocked by inhibition of PKA, suggesting that its protective effect is mediated by downstream effects of cAMP. Conversely, the EP3 receptor is negatively coupled to cAMP, and its neuroprotective effect was blocked by pertussis toxin, suggesting that its protective effect is dependent on Gi-coupled heterotrimeric signaling. Taken together, these data demonstrate an unexpected neuroprotective effect mediated by PGE2, in which activation of its EP2 and EP3 receptors protected motor neurons from chronic glutamate toxicity.
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PMID:PGE2 receptors rescue motor neurons in a model of amyotrophic lateral sclerosis. 1529 76

Cerebrospinal fluid prostaglandin E2 (PGE2) and tumor necrosis factor-alpha (TNF-alpha) levels are elevated in patients with Alzheimer's disease (AD), which suggests that they are involved in neurodegeneration. We previously reported that TNF-alpha derived from human macrophages, in response to beta-amyloid or amyloidogenic C-terminal peptide, is a main mediator of inflammatory neurotoxicity. In a continuation of this work, the present study investigated the direct effect of PGE2, one of the major prostaglandins produced in the brain, on cell viability in SH-SY5Y neuronal cells treated with TNF-alpha. PGE2 did not promote neurotoxicity, but rather had a strong protective effect against TNF-alpha by ameliorating TNF-alpha-induced apoptosis and also by rescuing the intracellular level of beta-catenin, a key transducer of the Wnt signaling pathway. PGE2-mediated stabilization of beta-catenin was accompanied by T-cell factor/lymphoid enhancer factor (Tcf/Lef)-mediated transcriptional activation, which was followed by an increase in the cyclinD1 level. Pharmacological studies provided further evidence supporting the notion that PGE2-mediated neuroprotection against TNF-alpha involves the stimulation of Tcf/Lef signaling through EP1-, EP2-, and EP4-mediated increases of beta-catenin in SH-SY5Y cells. In addition, this PGE2 effect appears to be dependent on the activation of protein kinase A, phosphatidylinositol 3-kinase, phospholipase C, and to a lesser extent protein kinase C. Thus, the molecular mechanism governing the inhibitory effect of PGE2 against TNF-alpha may involve the activation and cross talk of multiple signal transduction and play an important role in regulating the survival of neurons during the neurotoxic inflammatory response associated with neurodegenerative diseases including AD.
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PMID:Mechanisms involved in prostaglandin E2-mediated neuroprotection against TNF-alpha: possible involvement of multiple signal transduction and beta-catenin/T-cell factor. 1534 93

The effects of indomethacin (IDM) and aspirin (ASA) on ACh (10 microM) -stimulated exocytotic events were studied in guinea pig antral mucous cells by using video optical microscopy. IDM or ASA, which inhibits cyclooxygenase (COX), decreased the frequency of ACh-stimulated exocytotic events by 30% or 60%, respectively. The extent of inhibition induced by ASA (60%) decreased by 30% when IDM or arachidonic acid (AA, the substrate of COX) was added. IDM, unlike ASA, appears to induce the accumulation of AA, which enhances the frequency of ACh-stimulated exocytotic events in ASA-treated cells. ONO-8713 (100 microM; an inhibitor of the EP1-EP4 prostaglandin receptors) and N-[2-((p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide, HCl (H-89, 20 microM; an inhibitor of PKA) also decreased the frequency of ACh-stimulated exocytotic events by 60%. However, the supplementation of PGE(2) (1 microM) prevented the IDM-induced decrease in the frequency of ACh-stimulated exocytotic events. SC-560 (an inhibitor of COX-1) decreased the frequency of ACh-stimulated exocytotic events by 30%, but NS-398 (an inhibitor of COX-2) did not. Moreover, IDM decreased the frequency of exocytotic events stimulated by ionomycin, suggesting that COX-1 activity is stimulated by an increase in intracellular Ca(2+) concentration ([Ca(2+)](i)). ACh and ionomycin increased PGE(2) release in antral mucosal cells. In conclusion, in ACh-stimulated antral mucous cells, an increase in [Ca(2+)](i) activates Ca(2+)-regulated exocytotic events and PGE(2) release mediated by COX-1. The released PGE(2) induces the accumulation of cAMP, which enhances the Ca(2+)-regulated exocytosis. The autocrine mechanism mediated by PGE(2) maintains the high-level mucin release from antral mucous cells during ACh stimulation.
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PMID:Inhibition of ACh-stimulated exocytosis by NSAIDs in guinea pig antral mucous cells: autocrine regulation of mucin secretion by PGE2. 1534 68

Prostaglandin E2 (PGE2) and prostaglandin I2 (PGI2) are major inflammatory mediators that play important roles in pain sensation and hyperalgesia. The role of their receptors (EP and IP, respectively) in inflammation has been well documented, although the EP receptor subtypes involved in this process and the underlying cellular mechanisms remain to be elucidated. The capsaicin receptor TRPV1 is a nonselective cation channel expressed in sensory neurons and activated by various noxious stimuli. TRPV1 has been reported to be critical for inflammatory pain mediated through PKA- and PKC-dependent pathways. PGE2 or PGI2increased or sensitized TRPV1 responses through EP1 or IP receptors, respectively predominantly in a PKC-dependent manner in both HEK293 cells expressing TRPV1 and mouse DRG neurons. In the presence of PGE2 or PGI2, the temperature threshold for TRPV1 activation was reduced below 35 degrees C, so that temperatures near body temperature are sufficient to activate TRPV1. A PKA-dependent pathway was also involved in the potentiation of TRPV1 through EP4 and IP receptors upon exposure to PGE2 and PGI2, respectively. Both PGE2-induced thermal hyperalgesia and inflammatory nociceptive responses were diminished in TRPV1-deficient mice and EP1-deficient mice. IP receptor involvement was also demonstrated using TRPV1-deficient mice and IP-deficient mice. Thus, the potentiation or sensitization of TRPV1 activity through EP1 or IP activation might be one important mechanism underlying the peripheral nociceptive actions of PGE2 or PGI2.
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PMID:Sensitization of TRPV1 by EP1 and IP reveals peripheral nociceptive mechanism of prostaglandins. 1581 89

1 The aim of the present study was to investigate which EP receptor subtypes (EP1-EP4) act predominantly on the modification of the tetrodotoxin-resistant Na+ current (I(NaR)) in acutely isolated neonatal rat nodose ganglion (NG) neurones. 2 Of the four EP receptor agonists ranging from 0.01 to 10 muM, the EP2 receptor agonist (ONO-AE1-259, 0.1-10 microM) and the EP4 receptor agonist (ONO-AE1-329, 1 microM) significantly increased peak I(NaR). The responses were associated with a hyperpolarizing shift in the activation curve. 3 Neither the EP1 receptor agonist ONO-DI-004 nor the EP3 receptor agonist ONO-AE-248 significantly modified the properties of I(NaR). 4 In PGE2 applications ranging from 0.01 to 10 microM, 1 microM PGE2 produced a maximal increase in the peak I(NaR) amplitude. The PGE2 (1 microM)-induced increase in the GV(1/2) baseline (% change in G at baseline V(1/2)) was significantly attenuated by either intracellular application of the PKA inhibitor PKI or extracellular application of the protein kinase C inhibitor staurosporine (1 microM). However, the slope factor k was not significantly altered by PGE2 applications at 0.01-10 microM. In addition, the hyperpolarizing shift of V(1/2) by PGE2 was not significantly altered by either PKI or staurosporine. 5 In other series of experiments, reverse transcription-polymerase chain reaction (RT-PCR) of mRNA from nodose ganglia indicated that all four EP receptors were present. 6 The NG contained many neuronal cell bodies (diameter <30 microm) with intense or moderate EP2, EP3, and EP4 receptor-immunoreactivities. 7 These results suggest that the PGE2-induced modification of I(NaR) is mainly mediated by activation of both EP2 and EP4 receptors.
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PMID:Prostaglandin E2-induced modification of tetrodotoxin-resistant Na+ currents involves activation of both EP2 and EP4 receptors in neonatal rat nodose ganglion neurones. 1582 55

The mechanisms underlying neuropathic pain caused by nerve injury are not well understood. Inflammatory responses in injured nerves are likely to be key contributing factors in the generation and maintenance of neuropathic pain. The pro-inflammatory cytokine interleukin-6 (IL-6) is up-regulated in invading macrophages and has been implicated in the development of neuropathic pain. We previously demonstrated that invading macrophages up-regulate cyclooxygenase 2 (COX2) and prostaglandin E2 (PGE2) receptors EP1 and EP4, suggesting that PGE2 may affect macrophage function via autocrine or paracrine mechanisms. This study was undertaken to determine whether PGE2 is involved in the up-regulation of IL-6 in invading macrophages. Two weeks following partial sciatic nerve ligation, numerous IL-6 immunoreactive (IR) cell profiles were present in injured nerves. Colocalization of IL-6 with the invading macrophage marker ED1 or with COX2 was frequently observed. IL-6-IR, COX2-IR and ED1-IR cells were present only in cultures derived from injured nerve segments. PGE2 and IL-6 release from cultured cells derived from injured nerves was increased significantly compared with uninjured nerves. Non-selective and selective COX2 inhibitors suppressed PGE2 and IL-6 release. Treatment with PGE2 further enhanced IL-6 release in a concentration- and time-dependent manner. A selective EP4 receptor antagonist L-161982 was able to suppress IL-6 release, whereas an EP1 receptor antagonist, SC19220, was ineffective. Moreover, a protein kinase C inhibitor, calphostin C, dramatically suppressed IL-6 release, whereas a protein kinase A inhibitor H-89 and a Ca2+ chelator EGTA failed. Taken together, our data suggest that PGE2 is involved in mediating the up-regulation of IL-6 occurring in invading macrophages. This action is mediated through an EP4 receptor and the protein kinase C signaling pathway.
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PMID:Up-regulation of interleukin-6 induced by prostaglandin E from invading macrophages following nerve injury: an in vivo and in vitro study. 1583 25


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