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:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have developed the coexpression system of both delta-opioid receptor (DOR1) and M2-muscarinic receptor (M2) which mediate agonist-evoked currents due to common post-receptor mechanisms including Gi1 and phospholipase C (PLC) activation in Xenopus oocytes reconstituted with Gi1 alpha. The DOR1-currents by 100 nM D-Ser2-leu-enkephalin-Thr6 (DSLET) were selectively desensitized by 10 nM phorbol 12-myristate 13-acetate (PMA). The PMA-desensitization of DSLET-currents was abolished in the presence of calphostin C, a protein kinase C inhibitor, or reversed by an intracellular injection of calcineurin, a protein phosphatase 2B. When a higher concentration (3 microM) of DSLET was used, DSLET-currents were rapidly desensitized by repeated challenges of DSLET itself. However, repeated challenges of 10 microM ACh caused no influence on such DSLET- or M2-currents. The desensitization of DSLET-currents was selectively reversed by protein kinase C inhibitors. Similar results were also obtained with various delta-opioid agonists. These results suggest that protein kinase C is involved in the homologous desensitization of delta-opioid receptors.
...
PMID:Protein kinase C involvement in homologous desensitization of delta-opioid receptor coupled to Gi1-phospholipase C activation in Xenopus oocytes. 747

1. Acute homologous desensitization of mu-opioid receptor-induced currents was pharmacologically characterized in locus coeruleus (LC) neurones by use of intracellular and whole cell recording in superfused brain slices. 2. Following desensitization of opioid receptors by perfusion with a high concentration of [Met5] enkephalin (ME) for 5 min, there was a reduction in the maximum response and a rightward shift of the concentration-response curves for ME, [D-Ala2, N-MePhe4, Gly-ol]enkephalin (DAMGO) and normorphine. 3. By simultaneously fitting the operational model to the paired pre- and post-desensitization concentration-response data for each agonist, estimates of the level of desensitization were obtained. The values obtained for the three agonists (between 88% and 96%) were similar and did not vary according to the efficacy of the agonist used. 4. Use of whole cell patch recording techniques caused a slow rundown in the amplitude of ME currents (approx. 40% reduction over 60 min) but did not greatly affect the expression of acute desensitization of opioid currents. 5. When included in the patch recording solution, the phosphatase inhibitors, microcystin (50 nM-4 microM) and okadaic acid (1 microM) had no effect on the induction of desensitization or the normal ability of opioid or alpha 2-adrenoceptors to produce currents. Microcystin decreased the rate of recovery of the ME (300 nM) currents following desensitization; however, okadaic acid had little effect on the rate of recovery from desensitization. 6. Strong calcium buffering with BAPTA (10-20 mM) had no effect on desensitization or the recovery from desensitization. 6. Strong calcium buffering with BAPTA (10-20 mM) had no effect on desensitization or the recovery from desensitization.7 These results suggest that acute homologous desensitization of micro-opioid receptors in LC neurones entails a rapid loss of responsiveness that involves a majority of the receptor population. The mechanism by which desensitization is reversed may involve a non-calcium-dependent protein phosphatase but the processess that cause desensitization remain unclear.
...
PMID:Characterization of acute homologous desensitization of mu-opioid receptor-induced currents in locus coeruleus neurones. 758 22

Regulation of gene expression is one of the mechanisms by which neuronal activity elicits long-term changes in neuronal phenotype and function. Although activity-dependent induction of immediate-early genes has been extensively studied, much less is known about the late-response genes. We have investigated the activity-dependent regulation of delta-opioid receptor (DOR) mRNA levels in NG108-15 cells. Transsynaptic activation was mimicked by depolarization with 55 mM KCl or veratridine. Both treatments lead to a time-dependent increase of DOR mRNA levels. Ca2+ entry through L-type voltage-dependent Ca2+ channels activated by depolarization appears to be involved, because L-type channel blockers reduced the induction of DOR expression. Ca2+ binding to calmodulin is the next step in the signal transduction pathway, because a calmodulin antagonist, W7, reduced the effect of veratridine. A selective inhibitor of calmodulin kinases (KN-62) and cyclosporin, an inhibitor of calcineurin, also antagonized the depolarization-induced increase in DOR mRNA levels, which indicates that both calcium/calmodulin-dependent enzymes are involved in the activity-dependent induction of DOR gene expression. Induction of DOR gene expression by an activity-dependent increase in intracellular Ca2+ concentration may serve as a feedback regulatory mechanism because activation of DOR leads to hyperpolarization and lower excitability of neurons.
...
PMID:Ca2+/calmodulin-dependent transcriptional activation of delta-opioid receptor gene expression induced by membrane depolarization in NG108-15 cells. 942 52

Recent molecular evidence points to transient and/or stage-specific expression of delta- and kappa-opioid receptors by thymic and peripheral T lymphocytes. Since medical treatments or stress commonly increase opioid levels, it is important to understand the mechanisms by which opioids affect T lymphocyte functions. We therefore created and studied a T cell line expressing the cloned delta-opioid receptor (DOR1). DOR1 ligation by a specific DOR1 agonist, deltorphin, augmented IL-2 secretion by synergizing with signals from TCR-CD3 and CD28. Reporter gene constructs were used to map this effect of deltorphin to the AP-1- and NF-AT/AP-1-binding sites of the IL-2 promoter. Although DOR1 signaling increased [Ca2+]i, deltorphin enhanced transcriptional activity of the NF-AT/AP-1-binding site via a mechanism independent of calcineurin and distinct from the effects of elevated [Ca2+]i. Deltorphin also increased accumulation of AP-1 transcription factor complexes, suggesting that DOR1 augments IL-2 secretion by increasing the AP-1 component of the NF-AT/AP-1 transcription factor. These results advance the molecular understanding of opioid effects on lymphocytes, and in addition, demonstrate regulation of IL-2 synthesis and secretion by the novel mechanism of receptor-mediated AP-1 induction.
...
PMID:Delta-opioid receptors expressed by Jurkat T cells enhance IL-2 secretion by increasing AP-1 complexes and activity of the NF-AT/AP-1-binding promoter element. 954 83

cDNAs encoding KEPI, a novel protein kinase C (PKC)-potentiated inhibitory protein for type 1 Ser/Thr protein phosphatase (PP1), were identified. They were found among morphine-regulated brain mRNAs identified using subtracted differential display techniques. Full-length rat, mouse, and human cDNA and genomic sequences were elucidated with library screening and data base searching. Rat, mouse, and human KEPI cDNAs encode 164-165 amino acid proteins with calculated isoelectric points of 5.2. Each species' amino acid sequence contains consensus sequences for phosphorylation by PKC (KVT(72)VK), protein kinase A (RKLS(154)), and casein kinase II (S(43)SRE, S(120)EEE). Multiple KEPI N-terminal myristoylation consensus sites provide potential regions for membrane anchoring. Subcellular fractionation and Western analyses revealed that most KEPI immunoreactivity was associated with P2 and P3 membrane-enriched fractions and little in cytosolic fractions. 2.6-kb KEPI mRNAs were detected in brain, especially in the cerebral cortex and hippocampus, and in heart and skeletal muscle. Brain KEPI mRNA was up-regulated by both acute and chronic morphine treatments. The human KEPI gene contains four exons extending over more than 100 kb of genomic sequence on 6q24-q25, near the mu opiate receptor gene. These sequences displayed sufficient homology with the porcine PP1 inhibitor CPI-17 that we asked whether KEPI could share the ability of CPI-17 to modulate PP1 activity in a PKC-dependent fashion. Recombinant mouse KEPI is phosphorylated by PKC with a K(m) of 2.6 microm and a t(1/2) of 20 min. Phospho-KEPI inhibits PP1alpha with an IC(50) of 2.7 nm, a potency more than 600-fold greater than that displayed by unphosphorylated KEPI. Neither phospho- nor dephospho-KEPI inhibits protein phosphatase 2A. Up-regulation of KEPI expression by morphine, an agonist at PKC-regulating G-protein-coupled mu receptors, provides a novel signaling paradigm in which the half-lives of serine/threonine phosphorylation events can be influenced by activities at G(i)/G(o)-coupled receptors that modulate KEPI expression, KEPI phosphorylation, and KEPI regulation of PP1 activity.
...
PMID:KEPI, a PKC-dependent protein phosphatase 1 inhibitor regulated by morphine. 1181 71

The aim of this study was to evaluate the effects of serine/threonine protein phosphatase (PP) inhibitors on morphine-induced antinociception in the tail flick test in mice, and on [3H]naloxone binding to the forebrain crude synaptosome fraction. Neither okadaic acid nor cantharidin (1-10000 nM) displaced [3H]naloxone from its specific binding sites, which indicates that they do not interact at the opioid receptor level. The i.c.v. administration of very low doses of okadaic acid (0.001-1 pg/mouse) and cantharidin (0.001-1 ng/mouse), which inhibit PP2A, produced a dose-dependent antagonism of the antinociception induced by morphine (s.c.). However, L-nor-okadaone (0.001 pg/mouse-1 ng/mouse, i.c.v.), an analogue of okadaic acid lacking activity against protein phosphatases, did not affect the antinociceptive effect of morphine. On the other hand, high doses of okadaic acid (10 ng/mouse, i.c.v.) and cantharidin (1 microg/mouse, i.c.v.), which also block PP1, and calyculin-A (0.1 fg/mouse-1 ng/mouse, i.c.v.), which inhibits equally both PP1 and PP2A, did not modify the morphine-induced antinociception. These results suggest that the activation of type 2A serine/threonine protein phosphatases may play a role in the antinociceptive effect of morphine, and that PP1 might counterbalace this activity.
...
PMID:Effects of serine/threonine protein phosphatase inhibitors on morphine-induced antinociception in the tail flick test in mice. 1265 Aug 33

We previously reported that serine/threonine protein phosphatases (PPs) play a role in the antinociception induced by the mu-opioid receptor agonist morphine. In this study we evaluated the possible involvement of PPs on the antinociception induced by agonists of others G protein-coupled receptors in the tail flick test in mice. The subcutaneous administration of clonidine (0.25-4 mg/kg), baclofen (2-32 mg/kg) or U50,488H (2-16 mg/kg) (agonists of alpha(2) adrenoceptors, GABA(B) and kappa-opioid receptors, respectively) produced dose-dependent antinociception. The antinociceptive effects of clonidine and baclofen were antagonized in a dose-dependent way by the protein phosphatase inhibitors okadaic acid (0.001-10 pg/mouse, i.c.v.) and cantharidin (0.001-10 ng/mouse, i.c.v.), and okadaic acid was 1000 times more potent than cantharidin in producing this effect. The effects of these drugs appear to be specifically due to the blockade of PPs, since L-norokadaone (an analogue of okadaic acid that has no effect on PPs) did not modify clonidine- or baclofen-induced antinociception over the wide range of doses used (0.001-1000 pg/mouse, i.c.v.). On the other hand, the antinociception induced by activation of kappa-opioid receptors with U50,488H was not modified by okadaic acid or cantharidin. In conclusion, our data support the idea that serine/threonine PPs are differentially involved in the antinociceptive effects of several agonists of G protein-coupled receptors in mice.
...
PMID:Inhibitors of serine/threonine protein phosphatases antagonize the antinociception induced by agonists of alpha 2 adrenoceptors and GABAB but not kappa-opioid receptors in the tail flick test in mice. 1573 47

The aim of this study was to examine possible interactions of ERK and calcineurin in cardioprotection afforded by delta-opioid receptor stimulation. Infarction was induced in rat hearts by 20-min coronary occlusion and reperfusion. Tissue ERK level and calcienurin activity were determined by immunoblotting and an assay using a phosphopeptide substrate, respectively. Administration of a delta-opioid receptor agonist, D-Ala2-D-Leu5-enkephalin (DADLE, 1 mg/kg), before ischemia increased the phospho-ERK levels during ischemia and reduced infarct size (as percentage of risk area, %IS/AR) from 47.7 +/- 2.3% to 23.2 +/- 2.5%. This protection was abolished by 10 mg/kg of natrindole hydrochloride (NTI), a delta-opioid receptor antagonist. PD98059, a MEK1/2 inhibitor, abolished both ERK1/2 activation and infarct size limitation by DADLE. Calcineurin inhibitors, cyclosporine-A (5 mg/kg) and FK506 (3.5 mg/kg), reduced %IS/AR (27.4 +/- 4.4% and 29.9 +/- 3.4%, respectively). The protective effects of these calcineurin inhibitors were inhibited by PD98059, and the combination of DADLE with cyclosporine-A or FK506 did not afford further cardioprotection. DADLE significantly suppressed myocardial calcineurin activity, and this effect was inhibited by NTI. Suppression of calcineurin activity by FK506 was associated with modest activation of ERK1/2. These results suggest that suppression of calcineurin and activation of ERK1/2 are interacting mechanisms involved in cardioprotection by delta-opioid receptor activation.
...
PMID:Activation of ERK and suppression of calcineurin are interacting mechanisms of cardioprotection afforded by delta-opioid receptor activation. 1661 6

Pruritus (itch) is an unpleasant sensation inducing the desire to scratch. Chronic pruritus (>6 weeks' duration) is a major and distressing symptom of many diseases of dermatological, systemic, neurological or psychogenic origin. Frequently, the underlying cause of pruritus cannot be identified and causal therapy is not possible. Furthermore, chronic pruritus is frequently refractory to conventional symptomatic therapies. Recent research has revealed new neuronal mechanisms in the skin and brain, suggesting novel therapeutic targets. The efficacy of the corresponding innovative therapies has been proven in recent studies and case series. For example, topical or systemic application of specific agonists such as cannabinoids or calcineurin inhibitors can influence neuroreceptors on sensory nerve fibers of the skin and suppress pruritus. Itch-selective neurons in the dorsal horn of the spinal cord can be targeted to inhibit the transmission of pruritus to the somatosensory cortex. Anticonvulsants, antidepressants and micro-opioid receptor antagonists interfere with the sensation of pruritus in the central nervous system. Chronic pruritus of any origin leads to considerable psychosocial burden and impairs quality of life. Psychoeducational interventions, stress training, training in social competence and relaxation techniques are therefore important elements in the treatment of chronic pruritus. Increasing knowledge of the neurobiology of chronic pruritus offers new therapeutic strategies. Currently, several clinical trials are investigating the efficacy of new substances addressing neuroreceptors and cytokines in the skin and central nervous system. The present review aims to provide an overview of current neurophysiological and neurochemical therapeutic models in chronic pruritus.
...
PMID:Chronic pruritus: targets, mechanisms and future therapies. 1922 35

We previously identified KEPI as a morphine-regulated gene using subtractive hybridization and differential display PCR. Upon phosphorylation by protein kinase C, KEPI becomes a powerful inhibitor of protein phosphatase 1. To gain insights into KEPI functions, we created KEPI knockout (KO) mice on mixed 129S6xC57BL/6 genetic backgrounds. KEPI maps onto mouse chromosome 10 close to the locus that contains the mu-opioid receptor (Oprm1) and provides a major quantitative trait locus for morphine effects. Analysis of single nucleotide polymorphisms in and near the Oprm1 locus identified a doubly-recombinant mouse with C57BL/6 markers within 1 Mb on either side of the KEPI deletion. This strategy minimized the amount of 129S6 DNA surrounding the transgene and documented the C57BL/6 origin of the Oprm1 gene in this founder and its offspring. Recombinant KEPIKO mice displayed (a) normal analgesic responses and normal locomotion after initial morphine treatments, (b) accelerated development of tolerance to analgesic effects of morphine, (c) elevated activity of protein phosphatase 1 in thalamus, (d) attenuated morphine reward as assessed by conditioned place preference. These data support roles for KEPI action in adaptive responses to repeated administration of morphine that include analgesic tolerance and drug reward.
...
PMID:Effect of KEPI (Ppp1r14c) deletion on morphine analgesia and tolerance in mice of different genetic backgrounds: when a knockout is near a relevant quantitative trait locus. 1981 4


1 2 3 Next >>

---