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

---

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

We studied the acute tolerance liability of peripheral opioid analgesia in mice. The analgesia was assessed by the inhibition of bradykinin (BK)-induced nociceptive action by using a newly developed flexor reflex paradigm. Morphine [intraplantarly (i.pl.)] given ipsilaterally to BK showed a dose-dependent reduction of the BK (2 pmol) responses, whereas the administration of 10 nmol of morphine into the contralateral side failed to show any significant analgesic effects. Furthermore, DAMGO ([D-Ala(2),MePhe(4), Gly-ol(5)]-enkephalin), a mu-opioid receptor (MOR) agonist, and U-69593, a kappa-opioid receptor (KOR) agonist, but not DSLET ([D-Ser(2)]Leu-enkephalin-Thr(6)), a delta-opioid receptor agonist, showed similar analgesia on the BK responses. The morphine- or U-69593 [(5alpha,7alpha, 8beta)-(+)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec -8yl] benzeneacetamide]-induced analgesia was markedly attenuated by the intrathecal injection of each antisense oligodeoxynucleotide for the MOR or KOR, respectively, suggesting that these peripheral analgesia are mediated through MORs and KORs located on nociceptor endings, respectively. As BK response was completely recovered to the control level 4 h after morphine (3 nmol i.pl.) or U-69593 (10 nmol i.pl.) administration, these compounds were challenged again to see the inhibition of BK responses. Although morphine analgesia by the second challenge was markedly attenuated, U-69593 analgesia was not. The attenuated morphine analgesia was completely reversed by the pretreatment of calphostin C, Go6976, or HBDDE, a protein kinase C inhibitor, but not by KT-5720, a protein kinase A inhibitor. These results suggest that selective acute tolerance of peripheral morphine analgesia, but not U-69593 analgesia, through MORs and KORs located on polymodal nociceptors, respectively, in the bradykinin-nociception test in mice was mediated through protein kinase C activation.
...
PMID:Protein kinase C-mediated acute tolerance to peripheral mu-opioid analgesia in the bradykinin-nociception test in mice. 1077 42

The present study extends our previous finding that the endothelium-independent relaxation in porcine coronary artery rings is enhanced after short-term (20 min) exposure to a physiological concentration (1 nM) of 17beta-estradiol and demonstrates that this effect may be attributable to activation of the cyclic AMP pathway. Isometric tension was recorded in isolated rings of porcine coronary arteries. Relaxation by levcromakalim and sodium nitroprusside, but not bradykinin and calcium ionophore A23187, were significantly potentiated following 20 min treatment with 1 nM 17beta-estradiol. This enhancing effect was insensitive to the transcriptional and translational inhibitors, actinomycin D and cycloheximide respectively and absent following repeated washing of the rings prior to construction of relaxation-response curves. The potentiating actions of 1 nM 17beta-estradiol on endothelium-independent relaxation were mimicked by the cyclic AMP analogue 8-Bromo-cyclic AMP and the protein kinase A activator Sp-cyclic AMPS but not by the cyclic GMP analogue 8-Bromo-cyclic GMP. The modulatory effect of 17beta-estradiol was increased in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine. The cyclic AMP-dependent protein kinase A inhibitor Rp-cyclic AMPS, but not the cyclic GMP antagonist Rp-8-Bromo-cyclic GMPS, effectively inhibited the enhancing effects 1 M 17beta-estradiol had on the relaxation responses of levcromakalim and sodium nitroprusside. These data support our earlier findings that physiologically relevant concentrations of 17beta-estradiol can acutely modify vasorelaxation in vitro. Furthermore, we report that this short-term effect of 17beta-estradiol on vasorelaxation appears to be mediated via non-genomic pathways and involves the cyclic AMP cascade.
...
PMID:Enhanced relaxation of porcine coronary arteries after acute exposure to a physiological level of 17beta-estradiol involves non-genomic mechanisms and the cyclic AMP cascade. 1078 Sep 81

Caveolin-3 (cav-3) is a key structural component of caveolar membrane in skeletal muscle. Cav-3-enriched light membrane (CELM) fractions obtained from C2C12 myotubes contain phospholipase D1 (PLD1) and its major regulators, RhoA and protein kinase Calpha (PKCalpha). All these proteins were found bound to cav-3. An in vivo assay of PLD activity, which allows to localize the reaction product in CELMs, indicated that the enzyme associated to this membrane microdomain was active. Moreover, bradykinin (BK), thrombin and phorbol 12-myristate 13-acetate induced rapid stimulation of PLD activity in CELMs. The cav-3-PLD1 complex was not affected by BK treatment, whereas the agonist induced a marked increase of RhoA association with cav-3. Furthermore, BK-induced PLD activation in CELMs was dependent, at least in part, on PKCalpha.
...
PMID:Receptor-activated phospholipase D is present in caveolin-3-enriched light membranes of C2C12 myotubes. 1080 49

The cellular and molecular mechanisms governing bradykinin B1 and B2 receptor expression and function are poorly understood. We investigated the regulation of both B1 and B2 receptors in human embryonic lung fibroblasts (HEL 299) by the proinflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and interleukin 1beta (IL-1beta). TNF-alpha and IL-1beta both induced a rapid and transient increase in B1 and B2 receptor mRNA expression that was maximal by 2 h, accompanied by an increase in B1 and B2 receptor protein, as measured by radioligand binding assay with [(3)H]des-Arg(10)-kallidin, and [(3)H]bradykinin, respectively. The induced B1 receptors were functionally coupled, because the B1 agonist, des-Arg(10)-kallidin, induced an increase in arachidonic acid release in TNF-alpha-stimulated cells but not in control cells. The induction of B1 and the up-regulation of B2 receptors by TNF-alpha was partly mediated through activation of p38 mitogen-activated protein kinase and that of B2 receptor by protein kinase A. TNF-alpha and IL-1beta regulation of both B1 and B2 receptors was inhibited by dexamethasone. When compared with vehicle-treated cells, dexamethasone increased the rate of decline of both B1 and B2 receptor mRNAs. Nuclear run-on experiments demonstrate that the induction of B1 and the up-regulation of B2 receptors as well as the inhibitory effect of dexamethasone are entirely mediated through post-transcriptional mechanisms.
...
PMID:Post-transcriptional regulation of bradykinin B1 and B2 receptor gene expression in human lung fibroblasts by tumor necrosis factor-alpha: modulation by dexamethasone. 1082 82

Activation of the bradykinin B2 receptor in endothelial cells initiates a complex array of cellular responses mediated by diverse signaling pathways, including stimulation of the mitogen-activated protein (MAP) kinase cascade and activation of the endothelial isoform of nitric-oxide synthase (eNOS). Several protein kinases have been implicated in eNOS regulation, but the role of MAP kinases remains less well understood. We explored the interactions between eNOS and components of the MAP kinase pathway in bovine aortic endothelial cells (BAEC). Using co-immunoprecipitation experiments, we isolated eNOS in a complex with the MAP kinases extracellular signal-regulated kinases 1 and 2 (ERK1/2) as well as the protein kinases Raf-1 and Akt. Within minutes of adding bradykinin to BAEC, the eNOS-Raf-1-ERK-Akt heteromeric complex dissociated, and it subsequently reassociated following more prolonged agonist stimulation. Bradykinin treatment of BAEC led to the activation of ERK, associated with an increase in phosphorylation of eNOS; phosphorylation of eNOS by ERK in vitro significantly reduced eNOS enzyme activity. Evidence for the direct phosphorylation of eNOS by MAP kinase in BAEC came from "back-phosphorylation" experiments using [gamma-(32)P]ATP and ERK in vitro to phosphorylate eNOS isolated from cells previously treated with bradykinin or the MAP kinase inhibitor PD98059. The ERK-catalyzed in vitro (32)P phosphorylation of eNOS isolated from BAEC treated with bradykinin was significantly attenuated compared with untreated cells, indicating that bradykinin treatment led to the phosphorylation of ERK-sensitive sites in cells. Conversely, eNOS isolated from endothelial cells pretreated with the MAP kinase inhibitor PD98059 showed increased ERK-promoted phosphorylation in vitro. Taken together, our results suggest that bradykinin-induced activation of ERK leads to eNOS phosphorylation and enzyme inhibition, a process influenced by the reversible associations of members of the MAP kinase pathway with eNOS.
...
PMID:Bradykinin-regulated interactions of the mitogen-activated protein kinase pathway with the endothelial nitric-oxide synthase. 1089 67

In this study we show that expression of active Cdc42Hs and Rac1 GTPases, two Rho family members, leads to the reorganization of the vimentin intermediate filament (IF) network, showing a perinuclear collapse. Cdc42Hs displays a stronger effect than Rac1 as 90% versus 75% of GTPase-expressing cells show vimentin collapse. Similar vimentin IF modifications were observed when endogenous Cdc42Hs was activated by bradykinin treatment, endogenous Rac1 by platelet-derived growth factor/epidermal growth factor, or both endogenous proteins upon expression of active RhoG. This reorganization of the vimentin IF network is not associated with any significant increase in soluble vimentin. Using effector loop mutants of Cdc42Hs and Rac1, we show that the vimentin collapse is mostly independent of CRIB (Cdc42Hs or Rac-interacting binding)-mediated pathways such as JNK or PAK activation but is associated with actin reorganization. This does not result from F-actin depolymerization, because cytochalasin D treatment or Scar-WA expression have merely no effect on vimentin organization. Finally, we show that genistein treatment of Cdc42 and Rac1-expressing cells strongly reduces vimentin collapse, whereas staurosporin, wortmannin, LY-294002, R(p)-cAMP, or RII, the regulatory subunit of protein kinase A, remain ineffective. Moreover, we detected an increase in cellular tyrosine phosphorylation content after Cdc42Hs and Rac1 expression without modification of the vimentin phosphorylation status. These data indicate that Cdc42Hs and Rac1 GTPases control vimentin IF organization involving tyrosine phosphorylation events.
...
PMID:Cdc42Hs and Rac1 GTPases induce the collapse of the vimentin intermediate filament network. 1090 Jan 95

While the expression and/or activity of endothelial nitric oxide synthase (eNOS) has been characterized in spontaneously hypertensive (SHR) and normotensive Wistar Kyoto rat (WKY) hearts, in coronary endothelial cells (ECs) from both strains, the effect of NO on intracellular calcium concentration ([Ca(2+)](i)) is still unknown. Coronary microvascular ECs were isolated from SHR and WKY and characterized. Immunocytochemistry and Western blot analysis showed that eNOS was similarly expressed in ECs from both strains. Measuring [Ca(2+)](i) by imaging analysis of fura-2-loaded cells, we demonstrated that alpha-thrombin (3-180 U l(-1)) induced a superimposable dose-dependent calcium transient in ECs from both strains. In WKY ECs, S-nitroso-N-acetyl-DL-penicillamine (SNAP) dose-dependently (10 - 100 microM) and 0.1 microM atrial natriuretic factor (ANF) reduced the maximum and the decay time of alpha-thrombin-induced calcium transient. The inhibitory effects of SNAP and ANF were prevented by blocking cyclic GMP-dependent protein kinase. Non selective eNOS inhibitors prolonged the decay time of alpha-thrombin-induced calcium transient, while the selective inducible NOS inhibitor 1400 W was ineffective. SNAP (100 microM) and 0.1 microM ANF increased cyclic GMP content up to 22.9 and 42.3 fold respectively. In SHR ECs, alpha-thrombin-induced calcium transient was not modified by SNAP, ANF or eNOS inhibition. SNAP (100 microM) and 0.1 microM ANF increased cyclic GMP content up to 9. 3 and 51 fold respectively. In WKY ECs, SNAP dose-dependently (10 - 100 microM) reduced also bradykinin-induced calcium transient, while in SHR ECs was ineffective. We concluded that in SHR ECs, the cyclic GMP-dependent regulation of calcium transient is lost.
...
PMID:Lack of nitric oxide- and guanosine 3':5'-cyclic monophosphate-dependent regulation of alpha-thrombin-induced calcium transient in endothelial cells of spontaneously hypertensive rat hearts. 1092 46

The metalloendopeptidase EC (EP24.15) is a neuropeptide-metabolizing enzyme expressed predominantly in brain, pituitary, and testis, and is implicated in several physiological processes and diseases. Multiple putative phosphorylation sites in the primary sequence led us to investigate whether phosphorylation effects the specificity and/or the kinetics of substrate cleavage. Only protein kinase A (PKA) treatment resulted in serine phosphorylation with a stoichiometry of 1.11 +/- 0.12 mol of phosphate/mol of recombinant rat EP24.15. Mutation analysis of each putative PKA site, in vitro phosphorylation, and phosphopeptide mapping indicated serine 644 as the phosphorylation site. Phosphorylation effects on catalytic activity were assessed using physiological (GnRH, GnRH(1-9), bradykinin, and neurotensin) and fluorimetric (MCA-PLGPDL-Dnp and orthoaminobenzoyl-GGFLRRV-Dnp-edn) substrates. The most dramatic change upon PKA phosphorylation was a substrate-specific, 7-fold increase in both K(m) and k(cat) for GnRH. In both rat PC12 and mouse AtT-20 cells, EP24.15 was serine-phosphorylated, and EP24.15 phosphate incorporation was enhanced by forskolin treatment, and attenuated by H89, consistent with PKA-mediated phosphorylation. Cloning of the full-length mouse EP24.15 cDNA revealed 96.7% amino acid identity to the rat sequence, and conservation at serine 644, consistent with its putative functional role. Therefore, PKA phosphorylation is suggested to play a regulatory role in EP24.15 enzyme activity.
...
PMID:The neuropeptide processing enzyme EC 3.4.24.15 is modulated by protein kinase A phosphorylation. 1096 67

Primary cultures of neonatal rat dorsal root ganglion (DRG) neurons were used to examine the mechanisms underlying both the direct activation and the sensitization of sensory neurons by prostanoids. Prostaglandin E2 (PGE2) elevated cytosolic calcium concentration ([Ca2+]i) in a subpopulation of small (< 19 microm) diameter, capsaicin-sensitive DRG neurons. PGE2 also stimulated substance P (SP) release from DRG cultures. In contrast to bradykinin, PGE2 did not stimulate phosphoinositidase C (PIC) and the PGE2-evoked increase in [Ca2+]i was dependent on extracellular calcium. Pre-treatment with PGE2 potentiated bradykinin-evoked increases in [Ca2+]i in small diameter neurons and increased the number of cells that responded to low concentrations of bradykinin. A similar effect was seen with prostaglandin I2 (PGI2) but not prostaglandin F2alpha (PGF2alpha). PGE2 pretreatment also potentiated bradykinin-evoked release of SP, inducing a leftward shift in the bradykinin concentration-response curve and an increase in the maximum response. PGE2 stimulated adenylyl cyclase activity in DRG cultures, at concentrations and times consistent with those required to observe both the direct and sensitizing effects of the prostanoid on [Ca2+]i responses. Furthermore, the direct and sensitizing effects of PGE2, on both [Ca2+]i responses and SP release, were mimicked by the membrane permeant cAMP analogue dibutyryl cAMP and inhibited by H89, an inhibitor of cAMP-dependent protein kinase A (PKA). These observations are consistent with the hypothesis that both direct activation and sensitization of sensory neurons by prostanoids, such as PGE2, are mediated by PKA-dependent phosphorylation mechanisms.
...
PMID:Prostaglandin E2-induced sensitization of bradykinin-evoked responses in rat dorsal root ganglion neurons is mediated by cAMP-dependent protein kinase A. 1099 8

Bradykinin (BK) is a major kinin with well-documented pharmacological properties including vascular leakage and induction of a variety of cytokines. However, the intracellular signalling mechanisms by which BK induced proinflammatory cytokine production have not been fully elucidated. This study investigated the role of the extracellular signal-regulated protein kinase 1/2 (ERK 1/2) and p38 mitogen-activated protein kinase (p38 MAPK) in the BK-induced interleukin (IL)-6 and IL-8 production by human lung fibroblasts. Lung fibroblasts were stimulated with BK in the presence or in the absence of PD98059, a specific MAPK/ERK kinase-1 inhibitor, or SB203580, a specific p38 MAPK inhibitor, and IL-6 or IL-8 production and their gene expression was examined. BK-induced ERK 1/2 or p38 MAPK phosphorylation was also analysed by Western blot analysis. BK at nanomolar concentrations stimulated lung fibroblasts to produce IL-6 and IL-8 along with increased ERK 1/2 and p38 MAPK phosphorylation. BK-induced IL-6 and IL-8 synthesis was inhibited by a B2-type BK receptor antagonist. Furthermore, PD98059 or SB203580 significantly suppressed BK-induced IL-6 and IL-8 production and their gene expression. These results indicate that bradykinin-induced interleukin-6 and interleukin-8 production are at least partly mediated through the extracellular signal-related protein kinase 1/2 and p38 mitogen-activated protein kinase pathway-dependent activation in human lung fibroblasts, and suggest that bradykinin appears to be involved in the inflammatory reaction leading to acute lung injury through stimulating interleukin-6 and interleukin-8 production by lung fibroblasts.
...
PMID:Bradykinin stimulates IL-6 and IL-8 production by human lung fibroblasts through ERK- and p38 MAPK-dependent mechanisms. 1102 59


<< Previous 1 2 3 4 5 6 7 8 9 10

---