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)

alpha(2A)-Adrenergic receptor-mediated Ca(2+) signaling and integrin alpha(IIb)beta(3) exposure were investigated in human platelets under conditions where indirect, thromboxane- or ADP-mediated effects were absent. The alpha(2)-adrenergic receptor agonists, UK14304 and epinephrine (EPI), were unable to raise cytosolic levels of inositol 1,4,5-trisphosphate (InsP(3)) or Ca(2+) but potentiated the [Ca(2+)](i) rises evoked by other agonists that act through stimulation of phospholipase C (thrombin or platelet-activating factor) or stimulation of Ca(2+)-induced Ca(2+) release (CICR) in the absence of InsP(3) generation (thimerosal or thapsigargin). In addition, alpha(2)-adrenergic stimulation resulted in a 20% lowering in the cytosolic cAMP level. In platelets treated with G(salpha)-stimulating prostaglandin E(1), EPI increased the Ca(2+) signal evoked by either phospholipase C- or CICR-stimulating agonists mainly through modulation of the cAMP level. The stimulating effects of UK14304 and EPI on platelet Ca(2+) responses, and also on integrin alpha(IIb)beta(3) exposure and platelet aggregation, were abolished by pharmacological stimulation of cAMP-dependent protein kinase, and these effects were mimicked by inhibition of this activity. In permeabilized platelets, UK14304 and EPI potentiated InsP(3)-induced, CICR-mediated mobilization of Ca(2+) from internal stores in a similar way as did inhibition of cAMP-dependent protein kinase. In summary, a G(ialpha)-mediated decrease in cAMP level appears to play a major role in the platelet-activating effects of alpha(2A)-adrenergic receptor stimulation. Thus, in platelets, unlike other cell types, occupation of the G(ialpha)-coupled alpha(2A)-adrenergic receptors does not result in phospholipase C activation but rather in modulation of the Ca(2+) response by relieving cAMP-mediated suppression of InsP(3)-dependent CICR.
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PMID:alpha(2A)-adrenergic receptor stimulation potentiates calcium release in platelets by modulating cAMP levels. 1063 73

Lung surfactant is synthesized in the alveolar type II cell. Its lipids and hydrophobic proteins (SP-B and SP-C) are stored in lamellar bodies and secreted by regulated exocytosis. In contrast, the hydrophilic proteins (SP-A and SP-D) appear to be secreted independently of lamellar bodies. Regulation of surfactant secretion is mediated by at least three distinct signaling mechanisms: activation of adenylate cyclase with formation of cAMP and activation of cAMP-dependent protein kinase; activation of protein kinase C; and a Ca(2+)-regulated mechanism that likely results in the activation of Ca(2+)-calmodulin-dependent protein kinase. These signaling mechanisms are activated by a variety of agonists, some of which may have a physiological role. ATP is one such agent and it activates all three signaling mechanisms. There is increasing information on the identity of several of the signaling proteins involved in surfactant secretion although others remain to be established. In particular the identity of the phospholipase C, protein kinase C and phospholipase D isomers expressed in the type II cell and/or involved in surfactant secretion has been established. Distal steps in the secretory pathway beyond protein kinase activation as well as the physiological regulation of surfactant secretion, are major issues that need to be addressed.
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PMID:Regulation of surfactant secretion. 1136 48

An anti-leptin receptor polyclonal antibody (receptor antibody), as well as leptin, stimulated the release of free fatty acids from isolated mouse fat pads in a time-dependent manner. Following a 90-min incubation, maximal lipolysis was observed at 6 microg/ml receptor antibody and 0.1 nM leptin. The receptor antibody did not show any additive effect to the stimulation of lipolysis induced by leptin, suggesting that they exert their actions through a similar mechanism involving the leptin receptor. N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89), quin 2-AM, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), and neomycin sulfate (neomycin) all potently inhibited the stimulation of lipolysis by the receptor antibody and leptin. Short-term incubation of the fat pads with the receptor antibody or leptin showed a transient increase in the cellular content of cAMP and myo-inositol 1,4,5-trisphosphate (IP3) in similar concentrations to the free fatty acid release. Quin 2-AM and W-7 also inhibited the increase in cAMP content, suggesting that a Ca(2)+/calmodulin-dependent process may be involved in a part of the mechanism in which the receptor antibody and leptin exert their effects. The increase in cellular IP3 content via phosphoinositide-specific phospholipase C (PLC) sensitive to neomycin appears to be a primary step to initiate intracellular events. Both the receptor antibody and leptin may stimulate the lipolysis through mechanisms involving a transient increase in the cellular IP3 content followed by cAMP production, which leads to the activation of cAMP-dependent protein kinase.
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PMID:Anti-leptin receptor antibody mimics the stimulation of lipolysis induced by leptin in isolated mouse fat pads. 1159 Feb 24

The sterol 4,4-dimethyl-5-cholesta-8,14,24-trien-3-ol (follicular fluid meiosis-activating sterol [FF-MAS]) isolated from human follicular fluid induces resumption of meiosis in mouse oocytes cultured in vitro. The purpose of this study was to examine the hypothesis that differential signal transduction mechanisms exist for FF-MAS-induced and spontaneous in vitro resumption of meiosis in mouse oocytes. Mouse oocytes were dissected from ovaries originating from mice primed with FSH 48 h before oocyte collection. Mechanically denuded germinal vesicle (GV) oocytes were in vitro matured in medium supplemented with hypoxanthine and FF-MAS or allowed to mature spontaneously; both groups were exposed to individual compounds known to inhibit specific targets in the cell. After 20-22 h of in vitro maturation, resumption of meiosis was assessed as the frequency of oocytes in GV breakdown (GVBD) stage. Pertussis toxin (2.5 microg/ml) did not influence resumption of meiosis in either group. Dibutyryl cyclic GMP (320 microM) inhibited FF-MAS-induced GVBD, but not spontaneous GVBD, whereas the subtype 5 phosphodiesterase-inhibitor zaprinast (50 microM) inhibited GVBD in both groups. Microinjection of the catalytic subunit of cAMP-dependent protein kinase into oocytes inhibited spontaneous GVBD, but not FF-MAS-induced GVBD. An inhibitor of cytoplasmic polyadenylation, cordycepin (80 microM), inhibited or retarded spontaneous GVBD to a further extent than it did FF-MAS-induced GVBD. Spontaneous GVBD was more sensitive to the histone H1 kinase-inhibitor olomoucine (250 microM) than was FF-MAS-induced GVBD. Addition of the mitogen-activated protein kinase (MAPK)-inhibitor PD 98059 (50 microM), phospholipase C-inhibitor U-73122 (10 microM), p21(ras)-inhibitor lovastatine (250 microM), and the src-like kinase inhibitor PP2 (20 microg/ml) inhibited FF-MAS-induced GVBD, but not spontaneous GVBD. Both MAPKs, extracellular regulated kinase (ERK) 1 and ERK2, were phosphorylated under FF-MAS-induced meiotic resumption, in contrast to spontaneous meiotic resumption, in which ERK1 and ERK2 phosphorylation occurred 2 h after GVBD. In the present study, we show that FF-MAS acts through an MAPK-dependent pathway, and we suggest that src-like kinase, p21(ras), and phosphoinositide signaling lie upstream of MAPK in the FF-MAS-activated signaling pathway. Clearly, striking pathway differences are present between spontaneous versus FF-MAS-induced meiotic resumption.
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PMID:Resumption of meiosis induced by meiosis-activating sterol has a different signal transduction pathway than spontaneous resumption of meiosis in denuded mouse oocytes cultured in vitro. 1171 37

Although the presence of intracellular angiotensin II (Ang II) and of Ang II-binding sites has been reported, their roles in cell function have not been fully clarified. The purpose of the present study was to test the hypothesis that intracellular Ang II modifies voltage-operated Ca(2+) channels in vascular smooth muscle. Ca(2+) channel currents were recorded in guinea pig mesenteric arterial myocytes with the whole-cell patch-clamp method. Intracellular dialysis of Ang II increased the amplitudes of Ca(2+) channel current (133 +/- 9% of the control with 10 nmol/L Ang II, n=16). Concomitant dialysis of the Ang II type 1 receptor antagonist, CV-11974 (1 micromol/L, n=11), but not the bath application of this drug, suppressed this Ang II action. In contrast, the dialysis of the Ang II type 2 receptor antagonist, PD123319 (1 micromol/L, n=5), failed to affect the Ang II action. Dialysis of either a phospholipase C inhibitor (U-73122, 10 micromol/L, n=5) or protein kinase C inhibitors (calphostin C, 100 nmol/L, n=5; protein kinase C inhibitor peptide-[19-36], 1 micromol/L, n=5) suppressed the Ang II action. Dialysis of KT5720 (100 nmol/L, n=5), an inhibitor of cAMP-dependent protein kinase, did not affect the Ang II action. Intracellular dialysis of angiotensin I (10 nmol/L) enhanced Ca(2+) channel currents (13 3 +/- 8%, n=6), which were sensitive to intracellular enalaprilat (1 micromol/L, n=5) or CV-11974 (n=5). These results suggest that intracellular Ang II has a stimulating action on voltage-operated Ca(2+) channels in vascular smooth muscle, possibly through intracellular binding sites similar to the Ang II type 1 receptor, which are associated with phospholipase C and protein kinase C.
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PMID:Intracellular angiotensin II stimulates voltage-operated Ca(2+) channels in arterial myocytes. 1188 93

In this study, membrane depolarization and multiple neurotransmitters (5-HT, acetylcholine, histamine, norepinephrine, epinephrine, glutamate, and ATP) were tested for the ability to elevate the intracellular free Ca2+ concentration ([Ca2+]i) in mouse HT4 neuroblastoma cells. Apart from ATP, none of the treatments gave rise to a detectable Ca2+ response, no matter whether the cells were subjected to temperature-induced neuronal differentiation. Our results provide pharmacological evidence for the co-existence in HT4 cells of both P2X and P2Y receptors, the activation of which by ATP led to Ca2+ influx and Ca2+ release, respectively. The P2Y receptor was found to couple to more than one type of G protein in the signaling pathway, causing the activation of phospholipase C (PLC) and Ca2+ mobilization from intracellular stores. cAMP-dependent protein kinase (PKA) and protein kinase C (PKC) attenuated ATP-evoked [Ca2+]i elevations in different ways. However, no correlation was identified between neuronal differentiation and the ATP-evoked Ca2+ responses in HT4 cells. This work indicates that HT4 cells can serve as a good model to study P2 purinoceptor-associated signaling pathways.
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PMID:Evoked intracellular Ca2+ elevations in HT4 neuroblastoma cells. 1206 Aug 15

Characteristics of pituitary adenylate cyclase-activating polypeptide (PACAP)-induced increase of Ca(2+) entry and catecholamine (CA) release were studied in bovine adrenal medullary chromaffin cells. PACAP induced intracellular free Ca(2+) concentration ([Ca(2+)](i)), showing an initial transient [Ca(2+)](i) rise followed by a sustained rise and CA release, which were not blocked by the blocking agents for nicotinic acetylcholine receptor (nAChR) channel, the voltage-dependent Ca(2+) channel (VOC), or the Na(+) channel. The sarcoendoplasmic Ca(2+)-ATPase inhibitors thapsigargin and cyclopiazonic acid did not affect the PACAP-induced sustained rise of [Ca(2+)](i), but did inhibit the initial [Ca(2+)](i) rise. In cells pretreated with cyclopiazonic acid or membrane-permeable, low-affinity Ca(2+) chelator N',N',N',N'-tetrakis(2-pyridylmethyl)ethylenediamine, PACAP further stimulated the entry of Ca(2+) or Mn(2+), whereas these treatments masked [Ca(2+)](i) dynamics induced by bradykinin. PACAP-induced sustained [Ca(2+)](i) rise and Mn(2+) entry were enhanced by acidic extracellular solution and reduced by alkalinization, whereas thapsigargin-induced Mn(2+) entry was regulated by the opposite. PACAP-induced [Ca(2+)](i) rise and Mn(2+) entry were not affected by blockers of cAMP-dependent protein kinase, phospholipase C, or protein kinase C. All store-operated Ca(2+) channel (SOC) blocking agents tested inhibited thapsigargin-induced Mn(2+) entry. 1(beta-[3-(4-Methoxyphenyl)-propoxy]-4-methoxyphenylethyl)-1H-imidazole hydrochloride (SK&F 96365), (R,S)-(3,4-dihydro-6,7-dimethoxy-isoquinoline-1-yl)-2-phenyl-N,N-di-[2-(2,3,4-trimethoxyphenyl)ethyl]-acetamide, and econazole inhibited PACAP-induced Ca(2+) or Mn(2+) entry, whereas GdCl(3), 7,8-benzoflavone, nor-dihydroguaiaretic acid, 5-nitro-2-(3-phenylpropylamino)benzoic acid, fulfenamic acid, and niflumic acid did not. SK&F 96365 and econazole but not GdCl(3) inhibited PACAP-induced CA release. These results suggest that PACAP activates a novel Ca(2+) entry pathway associated with sustained CA release independent of the nAChR channel, VOC and SOC, activated by acid pH, with different sensitivity to blockers of SOC. This pathway may provide a useful model for the study of receptor-operated Ca(2+) entry.
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PMID:Pituitary adenylate cyclase-activating polypeptide induces a sustained increase in intracellular free Ca(2+) concentration and catechol amine release by activating Ca(2+) influx via receptor-stimulated Ca(2+) entry, independent of store-operated Ca(2+) channels, and voltage-dependent Ca(2+) channels in bovine adrenal medullary chromaffin cells. 1218 54

In addition to its role as a CNS neurotransmitter, glutamate has been shown recently to be an important component of the peripheral inflammation response. We demonstrated previously that the group I metabotropic glutamate receptors (mGluRs) mGlu1 and mGlu5 are expressed in the peripheral terminals of sensory neurons and that activation of group I mGluRs in the skin increases thermal sensitivity. In the present study, we provide evidence suggesting that group I mGluRs increase thermal sensitivity by enhancing vanilloid (capsaicin) receptor function. We show that mGlu5 potentiates capsaicin responses in mouse sensory neurons by the phospholipase C pathway but not by activation of protein kinase C. Rather, the effects are mediated by the metabolism of diacylglycerol and the production of prostaglandins via the cyclooxygenase pathway, leading to activation of the cAMP-dependent protein kinase subsequent to prostanoid receptor activation. Behavioral thermal sensitization in mice induced by intraplantar injection of mGlu1/5 agonists was also blocked by inhibitors of protein kinase A and cyclooxygenase, suggesting that a similar signaling pathway operates in vivo. These results demonstrate a novel signaling pathway in sensory neurons and provide a plausible mechanism for the enhancement of thermal sensitivity that occurs with inflammation and after activation of mGluRs on peripheral sensory neuron terminals.
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PMID:Prostaglandin and protein kinase A-dependent modulation of vanilloid receptor function by metabotropic glutamate receptor 5: potential mechanism for thermal hyperalgesia. 1219 66

Natural killer (NK) cells are lymphocytes that are capable of destroying tumor cells and virally infected cells without prior sensitization. Elevation of cyclic 3', 5' adenosine monophosphate (cAMP) levels in NK cells is known to cause dramatic inhibition of NK cytolytic function. However, the effect of lowering cellular levels of cAMP on the cytolytic function of natural killer (NK) cells has not been studied. The current study investigated the effects of inhibiting adenylyl cyclase (AC) or cAMP-dependent protein kinase (PKA) activities on the ability of NK cells to lyse K562 tumor cells, and on the activation of NK-cell phospholipase C (PLC) by tumor targets. Exposure of NK cells to the AC inhibitors MDL-12,330A (MDL) or 2',5',-Dideoxyadenosine (DDA) completely blocked their ability to destroy K562 tumor cells. Further, target-induced stimulation of NK-cell PLC was inhibited by as much as 90% when NK cells were treated with the AC inhibitors. Treatment of NK cells with the PKA inhibitor, H-89, caused essentially complete inhibition of cytotoxic function while decreasing target-induced stimulation of PLC by about 50%. Additionally, exposure to the organotin compound, tributyltin (TBT), which decreases cAMP levels in NK cells (as much as 80%) caused a decrease in cytotoxic function by as much as 90%. These data suggest that decreased levels of cAMP may cause very significant loss of NK cytotoxic function and that this may be mediated by decreased PKA activity. These data coupled with previous work revealing that increased cAMP levels inhibit NK cytotoxic function, suggest that tight regulation of cAMP levels is critical to NK cell function.
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PMID:Decreased adenylyl cyclase and cAMP-dependent protein kinase activities inhibit the cytotoxic function of human natural killer cells. 1294 41

To clarify whether cyclic AMP (cAMP)/cAMP-dependent protein kinase (PKA) activation and Rho-kinase inhibition share a common mechanism to decrease the Ca2+ sensitivity of airway smooth muscle contraction, we examined the effects of 8-bromoadenosine 3',5'-cyclic monophosphate (8-BrcAMP), a stable cAMP analog, and (+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexane carboxamide dihydrochloride, monohydrate (Y-27632), a Rho-kinase inhibitor, on carbachol (CCh)-, guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS)-, 4beta-phorbol 12,13-dibutyrate (PDBu)-, and leukotriene D4 (LTD4)-induced Ca2+ sensitization in alpha-toxin-permeabilized rabbit tracheal and human bronchial smooth muscle. In rabbit trachea, CCh-induced smooth muscle contraction was inhibited by 8-BrcAMP and Y-27632 to a similar extent. However, GTPgammaS-induced smooth muscle contraction was resistant to 8-BrcAMP. In the presence of a saturating concentration of Y-27632, PDBu-induced smooth muscle contraction was completely reversed by 8-BrcAMP. Conversely, PDBu-induced smooth muscle contraction was resistant to Y-27632. In the presence of a saturating concentration of 8-BrcAMP, GTPgammaS-induced Ca2+ sensitization was also reversed by Y-27632. The 8-BrcAMP had no effect on the ATP-triggered contraction of tracheal smooth muscle that had been treated with calyculin A in rigor solutions. The 8-BrcAMP and Y-27632 additively accelerated the relaxation rate of PDBu- and GTPgammaS-treated smooth muscle under myosin light chain kinase-inhibited conditions. In human bronchus, LTD4-induced smooth muscle contraction was inhibited by both 8-BrcAMP and Y-27632. We conclude that cAMP/PKA-induced Ca2+ desensitization contains at least two mechanisms: 1) inhibition of the muscarinic receptor signaling upstream from Rho activation and 2) cAMP/PKA's preferential reversal of PKC-mediated Ca2+ sensitization in airway smooth muscle.
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PMID:8-Bromo-cAMP decreases the Ca2+ sensitivity of airway smooth muscle contraction through a mechanism distinct from inhibition of Rho-kinase. 1512 38


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