Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of dopamine (DA) on the binding of [3H]phorbol 12,13-dibutyrate ([3H]PdBu) in cultured rat striatal cells was examined. DA maximally increased specific [3H]PdBu binding by 70 +/- 10%, an increase comparable to that observed with norepinephrine (NE). This finding suggests that DA activates protein kinase C in cultured striatal cells, because increases in [3H]PdBu binding reflect translocation of protein kinase C. Half-maximal stimulation was observed with 10(-6) M DA. The peak response was observed at 2-3 min after addition of 10(-4) M DA, but [3H]PdBu binding was still increased above basal at 30 min. DA was not acting via an adrenergic receptor. Prazosin (10(-6) M) blocked the response to NE, suggesting mediation by an alpha 1-adrenergic receptor, but had little effect on the response to DA. Conversely, the D1 receptor antagonist SCH-23390 (10(-6) M) blocked the response to DA, but only partially inhibited the response to NE. Morphine (10(-6) M) inhibited the response to DA by 46 +/- 14%, but did not affect significantly the response to NE. The DA effect on [3H]PdBu binding is apparently independent of the increase in cyclic AMP seen on D1 receptor activation. Forskolin, apomorphine, and the D1 agonist SKF-38393 all increased cyclic AMP in striatal cells, but were less effective than DA in stimulating [3H]PdBu binding. The D2 agonist quinpirole was ineffective in stimulating either cyclic AMP or [3H]PdBu binding.
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PMID:Dopamine stimulates [3H]phorbol 12,13-dibutyrate binding in cultured striatal cells. 131 74

The effects of morphine on DNA synthesis by external granular layer (EGL) neuroblasts was examined in whole-mount organotypic cultures isolated from 10-day-old rat cerebella using bromodeoxyuridine (BrdU). After 24 h in vitro, explants were treated for 24 h with 10 nM, 1 or 100 microM morphine, morphine plus 30 nM, 3 or 300 microM of the opiate antagonist naloxone, respectively, or those concentrations of naloxone alone. BrdU was added during the last 4 h of drug treatment. EGL neuroblasts were unambiguously identified by size and morphology, location and by protein kinase C II immunocytochemistry. The proportion of EGL neuroblasts incorporating BrdU was significantly reduced in the presence of 1 microM morphine, while 100 microM morphine had little additional effect. The concentration of morphine predicted to cause a half-maximal reduction in BrdU labeling index was 22.5 nM. Morphine's ability to reduce BrdU incorporation by EGL neuroblasts was concentration dependent and was prevented by concomitant treatment with naloxone, implicating the involvement of opioid receptors. The results suggest that morphine can directly regulate the growth of the developing cerebellum by inhibiting neuroblast proliferation within the EGL.
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PMID:Morphine regulates DNA synthesis in rat cerebellar neuroblasts in vitro. 133 49

Morphine administered as a subcutaneous implant was previously reported to inhibit the mitogen-induced initial increases in cytoplasmic free calcium concentrations ([Ca2+]i) in mouse splenocytes. The present studies were initiated to determine whether morphine affects signal transduction subsequent to activation of protein kinase C (PKC) in immune cells. Administration of morphine significantly inhibited the phorbol myristate acetate (PMA)-stimulated increase in interleukin-2 receptor (IL-2R) expression in both CD4+ and CD8+ mouse T cells. In contrast, morphine treatment had no effect on PMA/calcium ionophore (A23187)-induced increase in IL-2 secretion, suggesting a selective inhibition of IL-2R expression. Simultaneous administration of morphine and the opiate antagonist naltrexone blocked the effect of morphine on CD4+ cells. The inhibition of PMA-stimulated IL-2R expression was not reproduced by incubating splenocytes with morphine (10(-8)-10(-5) M). These results suggest that this effect of morphine was mediated through opiate-receptors, but not directly via opiate receptors located on T cells. Moreover, adrenalectomy abolished this effect of morphine in CD4+ but not CD8+ T cells, suggesting that the inhibitory effect of morphine on IL-2R expression in CD4+ T cells may be mediated through a morphine-induced increase in corticosteroid levels. Thus, opiate-induced immunosuppression may involve an inhibition of post-PKC events, especially IL-2R expression, as well as impairment of earlier events in the activation of immune cells such as the increase in [Ca2+]i.
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PMID:Morphine inhibits signal transduction subsequent to activation of protein kinase C in mouse splenocytes. 809 1

The effect of the antidiarrheal drug loperamide, a mu-opiate agonist, on ACTH secretion and biosynthesis, cAMP generation and phosphoinositide turnover was studied in rat anterior pituitary cell cultures. The cAMP-dependent protein kinase A pathway was stimulated with both corticotropin-releasing hormone (CRH; 2-5 nM) and the membrane-permeable Bu(2)cAMP (0.5-2.5 mM). The protein kinase C pathway was stimulated with 1 microM arginine vasopressin (AVP) and 1-10 nM phorbol 12-myristate 13-acetate (PMA). After 3.5 h, loperamide (10 microM) had no effect on basal ACTH levels but significantly suppressed CRH-induced ACTH release, in a dose-dependent manner, to 60 +/- 4% of control (100%) (p < 0.0001). After 24 h, basal proopiomelanocortin mRNA was significantly decreased to 50% of control by loperamide (p < 0.05). The suppressive effect of loperamide on CRH-induced ACTH secretion was not reversible by naloxone (0.1-1,000 microM). Morphine (0.01-10 microM) had no effect on basal and CRH-induced ACTH secretion. Loperamide did not influence basal and CRH-induced adenylate cyclase activity in anterior pituitary cell membrane preparations, but it significantly blunted Bu(2)cAMP-induced ACTH secretion in cell culture from 100 +/- 4 to 77 +/- 4% (p < 0.05). In Ca(2+)-depleted medium (Ca2+ < 0.1 mM), loperamide had no suppressive effect on CRH-induced ACTH secretion. AVP-induced ACTH secretion was significantly suppressed by loperamide from 100 +/- 5 to 74 +/- 3% (p < 0.0001), while basal and AVP-induced inositol 1-phosphate generation and PMA-induced ACTH secretion were not affected by loperamide.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Loperamide inhibits corticotrophic cell function by a naloxone-insensitive mechanism in the rat in vitro. 823 60

Morphine, the opioid-agonist, and the antagonists naloxone and levallorphan exerted direct effects on spontaneously-contracting cultures of cardiac myocytes from neonatal rats. Naloxone and levallorphan induced an increase in the amplitude of systolic cell motion (ASM) and in the size of [Ca2+]i-transients, measured as indo-1 fluorescence ratio (IFR), whereas morphine caused an increase in IFR with no change in ASM. Both morphine and naloxone caused a transient increase in 45Ca2+ influx into the cardiomyocytes. Analysis of the relationship between changes in ASM and IFR indicated dual action of the drugs: (a) An increase in [Ca2+]i-transients elicited by morphine and the antagonists, apparently resulting from a transient increase of Ca2+ influx. (b) Altered myofibril responsiveness to Ca2+; the agonists decreased it, and the antagonists increased it. Intracellular pHi measurements in cardiomyocytes loaded with the fluorescent indicator BCECF revealed that morphine caused acidosis and the antagonists caused alkalosis. These pH changes were inhibited by pertussis-toxin, protein kinase inhibitor K323a, phorbol-ester and ethylisopropyl-amiloride, indicating pathways mediated by GTP-binding proteins and altered activities of protein kinase C and Na+/H+ exchanger. Preincubation with pertussis toxin prior to the addition of morphine prevented the decrease in the myofibril responsiveness to Ca2+ as well as the decrease in pHi but did not affect the increase in [Ca2+]i-transients and the increase in the rate of Ca2+ influx. As a result, addition of morphine after preincubation with pertussis toxin caused a positive inotropic effect. Our results indicate that morphine acts by two different pathways distinguishable by their sensitivity to pertussis toxin (1), increased Ca2+ influx leading to increased Ca(2+)-transients and (2) decreased intracellular pH leading to reduced myofibril responsiveness to Ca2+.
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PMID:Opioid effects on contractility, Ca(2+)-transients and intracellular pH in cultured cardiac myocytes. 837 18

Morphine is mainly used to relieve pain in the terminal stage of cancer patients. We found that morphine has inhibitory effects on growth of various human cancer cell lines, with IC50 from 2.7 to 8.8 mM, and BALB/3T3 cells, with IC50 of 1.5 mM. Although the IC50 values were relatively high, we decided to study the mechanisms of anti-carcinogenic effects of morphine. Morphine inhibited activation of protein kinase C induced by teleocidin, one of the 12-O-tetradecanoylphorbol-13-acetate (TPA)-type tumour promoters (IC50, 1 mM). Based on our previous evidence that tumour necrosis factor-alpha (TNF-alpha) acts as an endogenous tumour promoter on BALB/3T3 cells initiated with 3-methylcholanthrene, we found that morphine dose-dependently inhibited TnF-alpha release from KATO III cells (IC50, 5.6 mM) and also from BALB/3T3 cells (IC50, 1.3 mM) induced by okadaic acid, one of the non-TPA type tumour promoters. Moreover, morphine inhibited expression of TNF-alpha mRNA in BALB/3T3 cells (IC50, 1.6 mM), but not expression of early response genes. Morphine may improve condition of cancer patients by suppression of tumour growth and reduction of amounts of an endogenous tumor promoter, TNF-alpha, in tissues. The high dosage of morphine required to induce anticarcinogenic effects is also discussed.
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PMID:Anti-cancer effects of morphine through inhibition of tumour necrosis factor-alpha release and mRNA expression. 896 46

Recent studies have reported that protection from ischemic preconditioning (PC) is blocked by the opioid receptor antagonist naloxone (NAL). We tested whether an opioid agonist could mimic PC in the rabbit heart, whether that protection involved protein kinase C (PKC) activation, and whether opioid receptors act in concert with other PKC-coupled receptors. Rabbit hearts were subjected to 30 min coronary occlusions and were reperfused for either 3 (in situ) or 2 (in vitro) h. Infarct size was determined by staining with triphenyltetrazolium chloride. In untreated in situ hearts 38.5+/-1.6% of the risk zone infarcted. PC with 5 min ischemia/10 min reperfusion significantly limited infarction to 12.7+/-2.9% (p < 0.01). NAL infusion did not modify infarction (39.6+/-1.6%) in non-PC hearts, but blocked the effect of one cycle of PC (34.4+/-3.6% infarction). NAL, however, could not block cardioprotection when PC was amplified with 3 cycles of ischemia/reperfusion (9.9+/-1.4% infarction, p < 0.01 vs. control). Morphine could also mimic ischemic preconditioning, but only at a dose much higher than would be used clinically (3 mg/kg). In isolated hearts pretreatment with morphine (0.3 microM) significantly limited infarction to 9.3+/-1.2% (p < 0.01 vs. 32.0+/-3.1% in controls). This cardioprotective effect of morphine could be blocked by either the PKC inhibitor chelerythrine (30.4+/-2.6% infarction) or NAL (34.0+/-2.6% infarction). Neither chelerythrine nor NAL by itself modified infarction in non-PC hearts. NAL could not block protection from one cycle of PC in isolated hearts indicating that an intact innervation may be required for endogenous opioid production. Thus, opioid receptors, like other PKC-coupled receptors, participate in the triggering of PC in the rabbit heart.
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PMID:Opioid receptor contributes to ischemic preconditioning through protein kinase C activation in rabbits. 977 79

1. omega-CgTx attenuated formalin-evoked biphasic flinches, while PKC inhibitor (STU) attenuated phase 2 and was reversed by PDBu. 2. omega-CgTx and STU suppressed the increase in CSF-glutamate after formalin injection. 3. Morphine completely suppressed both increased flinching and CSF glutamate release. 4. Thus, omega-CgTx (N-type Ca channels) may regulate neurotransmitter release evoked by C fiber activation and the formalin-evoked hyperalgesia may possibly be provoked as a result of PKC activation elicited by both presynaptic neurotransmitter release and activation of NMDA receptors in the spinal neurons.
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PMID:Modulation of formalin-evoked hyperalgesia by intrathecal N-type Ca channel and protein kinase C inhibitor in the rat. 1008 3

Antinociceptive synergism between spinally administered morphine and clonidine decreases to an additive interaction in morphine- and clonidine-tolerant mice. Spinally administered protein kinase C (PKC) inhibitors also decrease the synergism to addition. To determine whether chronic morphine or clonidine treatment alters spinal PKC activity, the present studies measured PKC activity and expression of PKC isoform proteins in spinal cord cytosol and membrane fractions. Mice were treated for 4 days with either placebo pellets, morphine pellets, s.c. saline, or s.c. clonidine. Morphine pellet-implanted mice were tolerant to morphine-induced tail flick antinociception, but not cross-tolerant to clonidine. Clonidine-pretreated mice were tolerant to clonidine, but not cross-tolerant to morphine. Induction of morphine tolerance produced a 2-fold lower Km value for PKC (8.24 +/- 1.67 microM in placebo pellet vs 4.43 +/- 1.24 microM in morphine pellet) in cytosol, but not membrane fractions from spinal cord. Vmax values were not different. No difference in Km or Vmax values was found between proteins from saline- and clonidine-pretreated animals. Immunoreactive cPKCalpha, betaI, and gamma isoforms decreased 14, 26, and 17%, respectively, in cytosol from morphine-tolerant animals. No difference in PKC isoforms was found in the membranes or in fractions from clonidine-tolerant mice. Morphine tolerance, but not clonidine tolerance, enhanced PKC activity while decreasing protein expression.
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PMID:Alteration of spinal protein kinase C expression and kinetics in morphine, but not clonidine, tolerance. 1042 70

Morphine and other micro opioids regulate a number of intracellular signaling pathways, including the one mediated by phospholipase C (PLC). By studying PLC beta3-deficient mice, we have established a strong link between PLC and mu opioid-mediated responses at both the behavioral and cellular levels. Mice lacking PLC beta3, when compared with the wild type, exhibited up to a 10-fold decrease in the ED(50) value for morphine in producing antinociception. The reduced ED(50) value was unlikely a result of changes in opioid receptor number or affinity because no differences were found in whole-brain B(max) and K(d) values for mu, kappa, and delta opioid receptors between wild-type and PLC beta3-null mice. We also found that opioid regulation of voltage-sensitive Ca(2+) channels in primary sensory neurons (dorsal root ganglion) was different between the two genotypes. Consistent with the behavioral findings, the specific mu agonist [D-Ala(2),(Me)Phe(4),Gly(ol)(5)]enkephalin (DAMGO) induced a greater whole-cell current reduction in a greater proportion of neurons isolated from the PLC beta3-null mice than from the wild type. In addition, reconstitution of recombinant PLC protein back into PLC beta3-deficient dorsal root ganglion neurons reduced DAMGO responses to those of wild-type neurons. In neurons of both genotypes, activation of protein kinase C with phorbol esters markedly reduced DAMGO-mediated Ca(2+) current reduction. These data demonstrate that PLC beta3 constitutes a significant pathway involved in negative modulation of mu opioid responses, perhaps via protein kinase C, and suggests the possibility that differences in opioid sensitivity among individuals could be, in part, because of genetic factors.
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PMID:Genetic alteration of phospholipase C beta3 expression modulates behavioral and cellular responses to mu opioids. 1046 17


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