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:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanism by which kappa-opioid receptor (kappaor) modulated apoptosis was investigated in CNE2 human epithelial tumor cells. Induction of these cells to undergo apoptosis with staurosporine was associated with a massive increase in intracellular cAMP level. The inhibition of the increase in cAMP partially inhibited apoptosis as evidenced by a reduction of PARP and caspase-3 cleavage. Accordingly, a low but significant level of apoptosis is induced in these cells by the elevation of cAMP through the addition of forskolin and isobutylmethylxanthine. The existence of a cAMP-dependent and a cAMP-independent apoptotic pathway is therefore suggested. Receptor binding studies, RT-PCR experiments and Western blot analysis demonstrated the presence of type 1 kappaor in the CNE2 cells. Stimulation of kappaor in these cells resulted in the production of inositol (1,4,5)-trisphosphate, reduction of cAMP level and a marked enhancement of staurosporine-induced apoptosis. The potentiation of apoptosis by kappaor was prevented by inhibition of phospholipase C but was slightly enhanced by the presence of the active cAMP analogues, 8-CPT-cAMP and dibutyryl-cAMP. These data demonstrate for the first time that the phospholipase C pathway activated by type 1 kappaor expressed by cancer cells is involved in the potentiation of apoptosis.
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PMID:kappa-Opioid receptor potentiates apoptosis via a phospholipase C pathway in the CNE2 human epithelial tumor cell line. 1111 38

In SH-SY5Y cells, activation of delta-opioid receptors with [D-Pen(2,5)]-enkephalin (DPDPE; 1 microM) did not alter the intracellular free Ca(2+) concentration [Ca(2+)](i). However, when DPDPE was applied during concomitant Gq-coupled m3 muscarinic receptor stimulation by carbachol or oxotremorine-M, it produced an elevation of [Ca(2+)](i). The DPDPE-evoked increase in [Ca(2+)](i) was abolished when the carbachol-sensitive intracellular Ca(2+) store was emptied. There was a marked difference between the concentration-response relationship for the elevation of [Ca(2+)](i) by carbachol (EC(50) 13 microM, Hill slope 1) and the concentration-response relationship for carbachol's permissive action in revealing the delta-opioid receptor-mediated elevation of [Ca(2+)] (EC(50) 0.7 mM; Hill slope 1.8). Sequestration of free G protein beta gamma dimers by transient transfection of cells with a beta gamma binding protein (residues 495-689 of the C terminal tail of G protein-coupled receptor kinase 2) reduced the ability of delta opioid receptor activation to elevate [Ca(2+)](i). However, DPDPE did not elevate either basal or oxotremorine-M-evoked inositol phosphate production indicating that delta-opioid receptor activation did not stimulate phospholipase C. Furthermore, delta-opioid receptor activation did not result in the reversal of muscarinic receptor desensitization, membrane hyperpolarization or stimulation of sphingosine kinase. There was no coincident signalling between the delta-opioid receptor and the lysophosphatidic acid receptor which couples to elevation of [Ca(2+)](i) in SH-SY5Y cells by a PLC-independent mechanism. In SH-SY5Y cells the coincident signalling between the endogenously expressed delta-opioid and m3 muscarinic receptors appears to occur in the receptor activation-Ca(2+) release signalling pathway at a step after the activation of phospholipase C.
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PMID:Coincident signalling between the Gi/Go-coupled delta-opioid receptor and the Gq-coupled m3 muscarinic receptor at the level of intracellular free calcium in SH-SY5Y cells. 1125 87

The present study was designed to investigate whether the phospholipase C gamma (PLC gamma)/phosphoinositide 3-kinase (PI3-Kinase) pathway could participate in the expression of the supraspinal antinociception induced by intracerebroventricular (i.c.v.) administration of mu-opioid receptor agonist in the mouse. The i.c.v. pretreatment with PI3-Kinase inhibitors, wortmannin and LY294002, and a specific antibody to PLC gamma 1 significantly attenuated the antinociception produced by either i.c.v. or systemic (s.c.) injection of a prototype of mu-agonist morphine. The s.c. injection of morphine produced a marked increase in the level of membrane-bound PLC gamma 1 isoform as compared to that from the saline-treated mice. This up-regulation of PLC gamma 1 by morphine was significantly inhibited by i.c.v. pretreatment with LY294002, indicating that morphine can activate PLC gamma 1 through the stimulation of PI3-Kinase. Pretreatment with a specific IP3 receptor inhibitor xestospongin C suppressed the morphine-induced antinociception in a dose-dependent manner. Recent studies have demonstrated that PI3-Kinase can be activated by G beta gamma, but not by G alpha subunit. In the present study, i.c.v. pretreatment with specific antibodies to G12 alpha and G beta gamma significantly suppressed the antinociception induced by morphine, whereas the specific antibody to Gq/11 alpha did not affect the antinociception induced by morphine. The present findings suggest that the supraspinal antinociception induced by mu-opioid receptor agonist may be mediated, at least in part, by the activation of PLC gamma through the stimulation of PI3-Kinase modulated by G beta gamma subunit.
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PMID:[The involvement of phosphoinositide 3-kinase (PI3-Kinase) and phospholipase C gamma (PLC gamma) pathway in the morphine-induced supraspinal antinociception in the mouse]. 1140 Mar 24

To investigate the role of G-protein beta gamma subunits in delta-opioid signal transduction, we have transfected Chinese hamster ovary (CHO) cells stably expressing the human delta-opioid receptor (hDOR/CHO cells) with the G(alpha)-subunit of transducin-1 (hDOR/T1/CHO). Inhibition of forskolin-stimulated adenylyl cyclase and phospholipase C beta (PLC beta) activation was measured in each of these cell lines. Because PLC beta(3) activation in CHO cells has been shown to be mediated by free G(beta gamma) subunits derived from G(alpha i/o), the action of transducin was confirmed by measuring a significant attenuation of (+)-4-[(alpha R)-alpha-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80)-mediated maximal inositol-1,4,5-trisphosphate formation in transducin-expressing cells of 59 +/- 12% compared with control cells. The acute inhibition of cAMP formation was unchanged between control and transducin-expressing cells. We show that cells stably expressing the human delta-opioid receptor exhibited a pertussis toxin-sensitive cAMP overshoot in response to chronic application of SNC80. After 4 h of pretreatment and washout with 100 nM SNC80, maximal forskolin-stimulated cAMP formation in hDOR/CHO cells increased by 229 +/- 37% compared with buffer-treated cells. Expression of transducin in hDOR/CHO cells diminished this response: hDOR/T1/CHO cells showed no significant change in maximal forskolin-stimulated cAMP formation after pretreatment and washout. These data indicate that the expression of alpha-transducin scavenges free G(beta gamma) subunits and, furthermore, that free G(beta gamma) subunits play a role in opioid-mediated PLC beta activation and adenylyl cyclase superactivation, but not acute inhibition of forskolin-stimulated cAMP formation in hDOR/CHO cells.
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PMID:Expression of alpha-transducin in Chinese hamster ovary cells stably transfected with the human delta-opioid receptor attenuates chronic opioid agonist-induced adenylyl cyclase superactivation. 1164 36

We have investigated the mechanisms regulating the expression of the mu-opioid receptor, using P19 mouse embryonal carcinoma cells, which normally lack this receptor, but which can be induced to express it in aggregated cells by retinoic acid treatment. The expression level of mu-opioid receptor mRNA was found to be closely correlated with aggregation status, and more specifically by cell to cell interaction requiring neural cell adhesion molecules (NCAM). We showed that NCAM activates the mu-opioid receptor gene through a pathway involving phospholipase C-arachidonic acid-calcium channel-calcium/calmodulin kinase II. A similar pathway was previously shown to promote neurite outgrowth, however, with distinct specificity, including the role of calcium channels. Activation of L-type calcium channels elevated mu-opioid receptor expression, while N-type-channel activity had the opposite effect. The effect of anti-NCAM-antibody treatment was not due to retardation of general neural development and was specific to the mu-opioid receptor gene. Our results indicate that the P19 system is an useful model to study the expression of the mu-opioid receptor gene.
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PMID:mu-Opioid receptor gene expression: the role of NCAM. 1173 27

Cytokines play significant roles in some cardiovascular disorders, but direct myocardial effects of cytokines remain to be elucidated. In this study, we examined the effects and possible mechanisms of interleukin-2 (IL-2) on contraction and the [Ca2+]i transient of enzymatically isolated ventricular myocytes with spectrofluorometry and video tracking. IL-2 (2.5-200 U/ml) depressed both the contraction and the [Ca2+]i transient in a dose-dependent manner. Pretreatment with the universal opioid receptor antagonist naloxone (10 nM), or a specific kappa opioid receptor antagonist, nor-binaltorphimine (nor-BNI, 10 nM), abolished the inhibitory effect of IL-2 on contraction and the [Ca2+]i transient; the specific delta-opioid receptor antagonist naltrindole (1 microM) had no effect. The effect of IL-2 was also abolished after pretreatment with pertussis toxin (PTX, 5 mg/l), but not by genistein (100 microM). Pretreatment with the phospholipase C inhibitor U73122 (5 microM) significantly inhibited the IL-2-induced depression of contraction and the [Ca2+]i transient. It is concluded that the effects of IL-2 on contraction and the [Ca2+]i transient of ventricular myocytes are mediated via the cardiac kappa opioid receptor, and the postreceptor signal transduction pathway includes a PTX-sensitive G protein and phospholipase C.
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PMID:Opioid receptor-mediated effects of interleukin-2 on the [Ca2+]i transient and contraction in isolated ventricular myocytes of the rat. 1190 31

In this report, we demonstrated that peripheral application of very low dose (amol ranges) of morphine induced flexor response through a substance P (SP) release at the nociceptor endings in mice. The intraplantar (i.pl.) application of morphine produced flexor response in a dose-dependent manner from 0.1 to 1000amol. The mu-opioid receptor (MOP-R) agonist [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO) also produced dose-dependent flexor response in same dose ranges. Morphine-induced flexor responses were markedly inhibited by naloxone and D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr amide (CTOP) both MOP-R antagonists and by intrathecal injection of antisense oligodeoxynucleotide (AS-ODN) for MOP-R which is expected to reduce the receptor expression in sensory nerve endings. Prior incubation with capsaicin, a depletor of SP from polymodal C fibers and [(+)-(2S,3S)-(2-methoxybenzylamino)-2-phenylpiperidine] (CP-99994), a tachykinin 1 receptor antagonist, also blocked the morphine-induced flexor responses. Moreover, pertussis toxin (PTX) which inactivates G(alpha)(i/o); [(1-[6-([(17b)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino)hexyl]-1H-pyrrole-2,5-dione)] (U-73122), an inhibitor of phospholipase C (PLC); ethyleneglycol-bis(beta-aminoethyl ether) N,N,N',N'-tetraacetic acid (EGTA), a Ca(2+) chelating agent; xestospongin C, a membrane-permeable inositol trisphosphate (InsP(3)) receptor antagonist inhibited the morphine-flexor responses. However, thapsigargin, a depletor of intracellular Ca(2+) concentration and diphenhydramine, a histamine (His) H1 receptor antagonist, were unable to block the morphine-induced flexor responses. These results suggest that extremely low doses of morphine can stimulate sensory nerve endings through activation of peripheral MOP-R and its downstream mechanisms include activation of PLC through a SP release from polymodal C fibers.
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PMID:Stimulation of peripheral nociceptor endings by low dose morphine and its signaling mechanism. 1221 27

The mu-opioid agonist DAMGO exerts a dual activity on cAMP production in SK-N-SH neuroblastoma cells. While the classic inhibitory effect was prevented by pretreating the cells with pertussis toxin (PTX), the stimulatory activity was PTX-resistant. The stimulatory effect was abolished by the selective phospholipase C (PLC) blocker U-73122, by the selective protein kinase C (PKC) blocker chelerythrine and by the calcium-channels blockers Ni++, Co++ and Cd++. Hence, it is suggested that the opioid receptor activates PLC (probably through Gq GTP-binding proteins), to mobilize PKC, that positively modulates calcium channels in the plasma membrane; the entry of Ca++ into the cells stimulates calcium-activated adenylyl cyclases to produce cAMP.
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PMID:The mu opioid agonist DAMGO stimulates cAMP production in SK-N-SH cells through a PLC-PKC-Ca++ pathway. 1259 Nov 62

The purpose of the present study was to investigate whether interleukin-2 (IL-2) changes the activity of sarcoplasmic reticulum (SR) Ca(2+) ATPase, sarcolemmal Ca(2+)ATPase and Na(+)/K(+) ATPase by measuring the Pi liberated from ATP hydrolysis with colorimetrical methods. It was shown that the activity of Ca(2+)ATPase in SR from IL-2-perfused (10, 40, 200, 800 U/ml) rat heart increased dose-dependently. After incubation of the SR with ATP (0.1 approximately 4 mmol/L), the activity of SR Ca(2+)ATPase increased dose-dependently in the control group. In the SR from 200 U/ml IL-2-perfused hearts, the activity of Ca(2+)ATPase was much higher than that in the control group. On the other hand, incubation of the SR with Ca(2+) (1 approximately 40 micromol/L) increased the activity of SR Ca(2+) ATPase in the control group. The activity of SR Ca(2+)ATPase of IL-2-perfused hearts was inhibited as the function to Ca(2+). Pretreatment with specific kappa-opioid receptor antagonist nor-BNI (10 nmol/L) for 5 min attenuated the effect of IL-2 (200 U/ml) on the activity of SR Ca(2+) ATPase. After pretreatment with pertussis toxin (PTX, 5 mg/L) or U73122 (5 micromol/L), IL-2 failed to increase SR Ca(2+)ATPase activity. The activity of SR Ca(2+)ATPase was not changed by incubation of SR isolated from normal hearts with IL-2. Perfusion of rat heart with IL-2 did not affect the activity of sarcolemmal Ca(2+)ATPase and Na(+)/K(+)ATPase. It is concluded that perfusion of rat heart with IL-2 increases the activity of SR Ca(2+)ATPase dose-dependently, which is mainly mediated by cardiac kappa-opioid receptor pathway including a PTX sensitive Gi-protein and phospholipase C. IL-2 increases the activity of SR Ca(2+)ATPase as the function to ATP, but inhibits the activity of SR Ca(2+)ATPase as the function to Ca(2+). IL-2 has no effect on the activity of sarcolemmal Ca(2+)ATPase and Na(+)/K(+)ATPase.
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PMID:[Effect of interleukin-2 on the activity of Ca2+ ATPase and Na+/K+ ATPase of sarcoplasmic reticulum and sarcolemma]. 1259 41

Recent works have documented that the stimulation of the mu-opioid receptor (MOR) can activate phosphoinositide-specific phospholipase C (PI-PLC). Here I demonstrate that PLC beta 3 isoform activated by beta gamma subunit of G-protein (G beta gamma) in the brain may contribute to the negative modulation for supraspinal antinociception induced by morphine in mice. In immunohistochemical studies, phosphoinositide 3-kinase (PI3K) was detected in the membrane of the cell soma and the immunoreactivity of PI3K (PI3K-IR) was almost overlapped with MOR-IR and PLC gamma 1-IR in the periaqueductal gray matter (PAG) that is considered to be one of the most important sites for the expression of MOR-mediated antinociception. Morphine produced a marked increase in the protein level of membrane-bound PLC gamma 1, and this increase induced by morphine was significantly inhibited by intracerebroventricullar (i.c.v.) pretreatment with PI3K inhibitors at the dosage that suppressed the morphine-induced supraspinal antinociception. Furthermore, morphine also caused a robust increase in the number of phosphorylated-PLC gamma 1 (p-PLC gamma 1) expressing cells in the PAG. It is worthwhile to note that MOR-IR was overlapped with p-PLC gamma 1-IR in the same cells that also contained PI3K in this region. Based on these findings, the next experiment was designed to investigate whether a deletion of the PLC gamma 1 gene by i.c.v. pretreatment with antisense oligodeoxynucleotide (AS-ODN) against PLC gamma 1 could affect the antinociception induced by MOR agonists. Pretreatment with AS-ODN against PLC gamma 1 revealed a significant inhibition of supraspinal antinociception induced by MOR-agonists. In addition, the morphine-induced supraspinal antinociception was suppressed by the blockade of the G beta gamma subunit that can directly activate both PI3K and PLC gamma 1. Moreover, mice lacking the gene for inositol 1,4,5-trisphosphate (IP3)-sensitive receptors, which can modulate the release of Ca2+ from the endoplasmic reticulum, exhibited a significant inhibition of the morphine-induced antinociception. Collectively, these findings raise the possibility that the activation of the PLC pathway associated with the stimulation of PI3K and/or G beta gamma is implicated in supraspinal antinociception induced by MOR agonists in mice.
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PMID:[Direct involvement of the supraspinal phosphoinositide 3-kinase/phospholipase C gamma 1 pathway in the mu-opioid receptor agonist-induced supraspinal antinociception in the mouse]. 1288 52


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