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)

Here we report on the progress we have made in elucidating the mechanisms through which estrogen alters synaptic responses in hypothalamic neurons. We examined the modulation by estrogen of the coupling of various receptor systems to inwardly rectifying and small conductance, Ca(2+)-activated K(+) (SK) channels. We used intracellular sharp-electrode and whole-cell recordings in hypothalamic slices from ovariectomized female guinea pigs. Estrogen rapidly uncouples mu-opioid receptors from G protein-gated inwardly rectifying K(+) (GIRK) channels in beta-endorphin neurons, manifest by a reduction in the potency of mu-opioid receptor agonists to hyperpolarize these cells. This effect is blocked by inhibitors of protein kinase A and protein kinase C. Estrogen also uncouples gamma-aminobutyric acid (GABA)(B) receptors from the same population of GIRK channels coupled to mu-opioid receptors. At 24 h after steroid administration, the GABA(B)/GIRK channel uncoupling observed in GABAergic neurons of the preoptic area (POA) is associated with reduced agonist efficacy. Conversely, estrogen enhances the efficacy of alpha(1)-adrenergic receptor agonists to inhibit apamin-sensitive SK currents in these POA GABAergic neurons, and does so in both a rapid and sustained fashion. Finally, we observed a direct, steroid-induced hyperpolarization of both arcuate and POA neurons, among which gonadotropin-releasing hormone (GnRH) neurons are particularly sensitive. These findings indicate a richly complex yet coordinated steroid modulation of K(+) channel activity that serves to control the excitability of hypothalamic neurons involved in regulating the reproductive axis.
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PMID:Estrogen modulation of K(+) channel activity in hypothalamic neurons involved in the control of the reproductive axis. 1196 Jun 20

It was investigated the in vivo effect of glutethimide on the intracellular neuroadaptation characteristic for m-opioid receptor tolerance induced by chronic codeine treatment and reflected by increased levels of adenylyl cyclase (AC) and cAMP-dependent protein kinase (PKA). AC activity was appreciated by cyclic-AMP (cAMP) formation, the levels of adenine and guanine nucleotides in brain extracts being assayed using a high performance liquid chromatographic method. The concomitant chronic administration of codeine and glutethimide resulted in a pronounced and long-lasting energetic depletion of the neurons, consistent with the high risk of overdose, and increase of cAMP's stable metabolite, 5'-AMP. This increase is persistent even after withdrawal and suggests an interference with the adenylyl cyclase system involved in the development of tolerance of opioid receptor and in relapse and provides a possible explanation of addiction and fast increase of doses observed in humans abusing this combination.
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PMID:Influence of glutethimide on rat brain mononucleotides by sub-chronic codeine treatment. 1206 75

Responses to opioid agonists vary, depending on past opioid exposure and the physiological state. The intracellular signaling pathway mediated by cAMP and protein kinase A (PKA) has been linked to regulation of opioid receptor responsiveness. The role of the cAMP-PKA pathway in regulating opioid receptor gene expression is incompletely defined. Mu-opioid receptor (MuOR) and orphanin FQ/nociceptin receptor (ORL(1)) transcripts were measured after activating this pathway in human neuroblastoma cells. Human SH-SY5Y neuroblastoma cells were maintained in continuous monolayer culture. Cells were incubated with combinations of agents which activate the cAMP-PKA signal transduction pathway, including forskolin and choleratoxin (CTX). MuOR and ORL(1) transcript levels were measured by hybridization to specific probes. Activation of the cAMP-PKA signal transduction pathway with forskolin in the presence of phosphodiesterase inhibitors was associated with a time-dependent decrease in the level of MuOR mRNA; partial recovery was observed with prolonged incubations. Forskolin effects were mimicked by CTX, but not by dideoxyforskolin. The PKA inhibitor H89 blunted the actions of forskolin. However, forskolin responses persisted despite coincubation with protein synthesis inhibitors. ORL(1) transcript levels did not significantly change, but vasoactive intestinal polypeptide (VIP) transcripts exhibited substantial increases, in the presence of forskolin or CTX. These observations support a role for cAMP in regulating MuOR responsiveness through actions at the level of receptor gene expression. ORL(1) transcript levels are not effected, suggesting that the cAMP-PKA pathway has differential effects on the expression of mRNA for different, but biochemically closely related, opioid receptor subtypes.
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PMID:Orphanin FQ/nociceptin and mu-opioid receptor mRNA levels in human SH-SY5Y neuroblastoma cells: effects of activating the cAMP-PKA signal transduction pathway. 1210 67

Chronic delta-opioid receptor agonist treatment of Chinese hamster ovary (CHO) cells stably expressing the human delta-opioid receptor (hDOR/CHO) leads to increased cAMP formation after the removal of the agonist (adenylyl cyclase superactivation). We have previously found that at the same time, chronic delta-opioid receptor agonist treatment augments phosphorylation of the adenylyl cyclase VI isoenzyme. Since phosphorylation of adenylyl cyclase VI by Raf-1 protein kinase was recently shown, we tested the role of Raf-1 in adenylyl cyclase superactivation in hDOR/CHO cells. We found that pretreatment of the cells with the selective Raf-1 inhibitor GW5074 (3-(3,5-dibromo-4-hydroxybenzylidene-5-iodo-1,3-dihydro-indol-2-one) (10 microM, 30 min) attenuates chronic deltorphin II-mediated increase in forskolin-stimulated cAMP formation by 40% (n = 6, P < 0.05). Better understanding of the molecular mechanism of adenylyl cyclase superactivation should aid in the development of analgesics that act longer and have fewer side effects.
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PMID:Involvement of Raf-1 in chronic delta-opioid receptor agonist-mediated adenylyl cyclase superactivation. 1222 34

The aim of the present study was to investigate whether repeated treatment with the mu-opioid receptor antagonist naloxone could affect G-protein activation induced by a selective mu-opioid receptor agonist [D-Ala(2),N-MePhe(4),Gly-ol(5)]enkephalin (DAMGO) in mice lacking the protein kinase Cgamma isoform monitoring guanosine-5'-o-(3-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) binding. Repeated s.c. administration of naloxone for 7 days resulted in a significant enhancement of the increased [(35)S]GTPgammaS binding by DAMGO to membranes of the spinal cord obtained from mice lacking the protein kinase Cgamma isoform. Furthermore, immunoreactivities of membrane-located protein kinase Cgamma and phosphorylated-protein kinase C in the spinal cord of ICR mice were not altered by repeated naloxone treatment. The present data provide direct evidence that protein kinase Cgamma is not involved in the development of the up-regulation of mu-opioid receptor functions to activate G-proteins in the mouse spinal cord by repeated naloxone treatment.
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PMID:Up-regulation of mu-opioid receptor-mediated G-protein activation in protein kinase Cgamma knockout mice following repeated naloxone treatment. 1256 63

Adenylyl cyclase (AC) superactivation is thought to play an important role in opioid tolerance, dependence, and withdrawal. In the present study, we investigated the involvement of protein kinases in chronic delta-opioid agonist-mediated AC superactivation in Chinese hamster ovary (CHO) cells stably expressing the human delta-opioid receptor (hDOR/CHO). Maximal forskolin-stimulated cAMP formation in hDOR/CHO cells increased by 472 +/- 91, 399 +/- 2, and 433 +/- 73% after chronic treatment with the delta-opioid agonists (+)-4-[(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxy-benzyl]-N,N-diethyl benzamide (SNC 80), [d-Pen2,d-Pen5]-enkephalin, and deltorphin II, respectively. Concurrently, chronic SNC 80 (1 micro M, 4-h) treatment augmented 32P incorporation into a 200-kDa protein immunoreactive with the ACV/VI antibody by 300 +/- 60% in hDOR/CHO cell lysates. The calmodulin antagonist calmidazolium significantly attenuated chronic deltorphin II-mediated AC superactivation. Tyrosine kinase (genistein) and protein kinase C (chelerythrine) inhibitors individually had minimal effect on chronic delta-opioid agonist-mediated AC superactivation. Conversely, simultaneous treatment with both genistein and chelerythrine significantly attenuated AC superactivation. Because we showed previously that the Raf-1 inhibitor 3-(3,5-dibromo-4-hydroxybenzylidene-5-iodo-1,3-dihydro-indol-2-one (GW5074) attenuates AC superactivation, we hypothesize that parallel calmidazolium-, chelerythrine-, and genistein-sensitive pathways converge at Raf-1 to mediate AC superactivation by phosphorylating AC VI in hDOR/CHO cells.
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PMID:Converging protein kinase pathways mediate adenylyl cyclase superactivation upon chronic delta-opioid agonist treatment. 1266 Mar 10

The periaqueductal gray (PAG) is the main target site of the opioid-induced analgesia. The present study was designed to examine the roles of protein kinase A (PKA) and C (PKC) in the opioid-induced modulation of the currents activated by an inhibitory neurotransmitter, gamma-aminobutyric acid (GABA). The PAG neurons were acutely isolated and voltage-clamped under the nystatin-perforated patch-clamp mode. The GABA-activated current was sensitively blocked by a GABA(A) receptor antagonist, bicuculline, and selectively carried by chloride ions. The GABA(A) receptor-activated Cl(-) current was potentiated by a mu-opioid receptor agonist, [D-Ala(2),N-MePhe(4),Gly(5)-ol]-enkephalin acetate (DAMGO). The GABA response was also potentiated by phorbol-12-myristate-13-acetate (PMA). Pretreatment with PMA occluded the DAMGO potentiation. However, both chelerythrine and 2-[1-(3-dimethylaminopropyl)indol-3-yl]-3-(indol-3-yl) maleimide (GF109203X) also potentiated the GABA response. Pretreatment with chelerythrine or GF109203X also occluded the DAMGO potentiation. Meanwhile, the GABA response was potentiated by N-(2-[p-bromocinnamylamino]-ethyl)-5-isoquinolinesulfonamide (H-89), while not altered by forskolin. Pretreatment with H-89 occluded the potentiation effect of DAMGO on the GABA response. In addition, the DAMGO effect was completely blocked by pretreatment with forskolin. From the result, it can be suggested that activation of mu-opioid receptor potentiates the GABA(A) response through the mediation of PKA inhibition, and that PKC is not directly involved in the action mechanism of DAMGO.
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PMID:Roles of protein kinase A and C in the opioid potentiation of the GABAA response in rat periaqueductal gray neuron. 1266 43

Previously, several important cis-elements and trans-factors have been shown to play a functional role in the proximal promoter of mouse mu-opioid receptor (MOR) gene. In this study, we defined another functional element located the in -450 to -400 bp (translational start site designated as +1) region of the proximal promoter, which is also essential for the full promoter activity. It is designated as the morAP-2-like element for its sequence homologous to the consensus AP-2 element. Surprisingly, electrophoretic mobility shift analysis (EMSA) revealed that Sp1 and Sp3, but not AP-2 proteins, were specifically bound to the morAP-2-like element. Mutation of the morAP-2-like element, resulting in a loss of Sp binding, led to an approximately 35% decrease in activity, further confirming the positive role of the morAP-2-like element in MOR gene expression. Dephosphorylation of Sp proteins with alkaline phosphatase also decreased Sp binding to the morAP-2-like element in EMSA, suggesting phosphorylation of Sp is essential for its binding to this element. However, direct or indirect activation of PKA, a classical G-protein coupled signaling pathway, resulted in no significant change of Sp binding to the morAP-2-like element, nor of the promoter activity the SH-SY5Y cells, MOR expressing cells, suggesting that phosphorylation of Sp does not involve PKA. These results suggest that the binding of different phosphorylated forms of Sp proteins to the morAP-2-like element may contribute to the fine tuning of MOR expression in different cells.
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PMID:Role of an AP-2-like element in transcriptional regulation of mouse mu-opioid receptor gene. 1267 Jul 13

Opioid effects on tumor growth have been a controversial topic of discussion. In the present study, morphine inhibited tumor cell proliferation at concentrations of >or=10 micro M. This was primarily caused by inhibition of cell cycle progression from G(1) to S phase. At higher concentrations (>or=500 micro M for 24 h), morphine also caused cell death. In nude mice, morphine significantly reduced the growth of MCF-7 and MDA-MB231 tumors but had no effect on HT-29 tumor growth. In these experiments, morphine plasma concentrations were similar to those found in cancer patients receiving chronic morphine treatment for pain relief (0.9-3.4 micro M). In MCF-7 and MDA-MB231 cells, morphine caused a naloxone (Nx)- and pertussis toxin-sensitive, concentration-dependent increase of GTPase activity, indicating that morphine signals could be transduced by opioid receptors via a G protein. However, the antiproliferative effects of morphine were not antagonized by Nx, pertussis toxin, forskolin, and 8-bromo-cAMP, suggesting that the typical opioid receptor-coupled signaling cascade involving the G(i), adenylyl cyclase, and protein kinase A was not involved. Instead, morphine caused an NH(2)-terminal phosphorylation of p53 at Ser(9) and/or Ser(15) and a stabilization of p53 in MCF-7 cells that express wild-type p53. p53 phosphorylation was not antagonized by Nx and resulted in an increase of p53-dependent proteins including p21, Bax, and the death receptor Fas. Blockade of Fas by Fas-fusion protein or inhibition of caspase 8 resulted in a partial inhibition of morphine-induced apoptosis. In addition, Fas ligand only induced apoptosis when administered together with morphine. However, the sensitivity of the tumor cells toward Fas ligand remained low. HT-29 cells, which express dominant negative p53 and show no increase of GTPase activity when treated with morphine, were less sensitive in vitro and were not affected in vivo. Our results suggest that morphine, alone or in combination with Nx, may reduce the growth of certain tumors, apparently in part through activation of p53.
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PMID:G protein-independent G1 cell cycle block and apoptosis with morphine in adenocarcinoma cells: involvement of p53 phosphorylation. 1270 72

To explore the mechanism by which morphine promotes the incidence of HIV infection, we evaluated the regulatory role of morphine on the interferon-gamma (IFN-gamma) promoter in activated T cells from wild type and mu-opioid receptor knockout mice. Our results show that morphine inhibited anti-CD3/CD28-stimulated IFN-gamma promoter activity in a dose-dependent manner. Chronic morphine treatment of T cells increased intracellular cAMP. To evaluate the role of cAMP in morphine's modulatory function, the effects of dibutyryl cyclic AMP and forskolin were investigated. Both dibutyryl cyclic AMP and forskolin treatment inhibited IFN-gamma promoter activity. Treatment with pertussis toxin, but not with a protein kinase A inhibitor, antagonized morphine's inhibitory effects. Morphine inhibited phosphorylation of ERK1/2 and p38 MAPK; in addition, morphine treatment in the presence of either ERK1/2 or p38 MAPK inhibitor (PD98059 or SB203580) resulted in an additive inhibition of IFN-gamma promoter activity. The transcription factor activator protein-1, NF-kappaB, and nuclear factor of activated T cells (NFAT) were negatively regulated by morphine. Overexpression of NF-kappaB p65 rescued the inhibitory effect of morphine on IFN-gamma promoter activity. However, only when NFATc1 was co-overexpressed with c-fos was the inhibitory effect of morphine on IFN-gamma promoter counteracted. The inhibitory effects of morphine were not observed in T cells obtained from mu-opioid receptor knockout mice, suggesting that morphine modulation of IFN-gamma promoter activity is mediated through the mu-opioid receptor. In summary, our data indicate that morphine modulation of IFN-gamma promoter activity is mediated through two distinct cAMP-dependent pathways, the NF-kappaB signaling pathway and the ERK1/2, p38 MAPK, AP-1/NFAT pathway.
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PMID:Morphine negatively regulates interferon-gamma promoter activity in activated murine T cells through two distinct cyclic AMP-dependent pathways. 1284 91


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