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)

Calmodulin plays an important role in cellular proliferation as part of a signal transduction pathway activated by phospholipase C. Drugs that block the ability of calmodulin to bind to and activate its target enzymes inhibit the growth of a wide variety of malignant cells. To identify more potent and selective inhibitors of this potential target for new drug development, we studied two recently synthesized compounds, KS-501 and KS-502, for their activity against calmodulin-sensitive enzymes and for their ability to block the growth of parental and multidrug-resistant leukemic cells. KS-501 and KS-502 inhibited the activation of a calmodulin-sensitive cyclic nucleotide phosphodiesterase. The mechanism of enzyme inhibition was through interfering with calmodulin activation rather than through a direct effect on the enzyme. KS-501 was more potent than KS-502 and was studied in greater detail. This compound inhibited the activation of calmodulin kinase I and II, but had less effect against cyclic adenosine 3',5'-monophosphate (cyclic AMP)-sensitive kinase. KS-501 was also more effective than KS-502 in inhibiting the growth of sensitive L1210 leukemic lymphocytes. Both compounds were less effective inhibitors of multidrug-resistant L1210 leukemia than of the parental line. These studies identify a new class of calmodulin inhibitor, with selectivity for calmodulin-dependent kinases over cyclic AMP-dependent protein kinase. Since the total synthesis of the KS-compounds has been accomplished, it should now be possible to develop derivatives with greater activity and selectivity.
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PMID:Effects of KS-501, KS-502 and their enantiomers on calmodulin-sensitive enzyme activity and cellular proliferation. 760 47

One of the developmental pathways used by the social amoeba Dictyostelium discoideum produces dormant spores. As with any temporary resistant stage, these spores must be able to germinate rapidly in response to positive environmental stimuli. One such stimulus is the autoactivator, an endogenous, diffusible molecule that is secreted by spores. Previous work has shown that three phases of germination, autoactivation, spore swelling and amoebal emergence, require the activity of the Ca(2+)-dependent, regulatory protein calmodulin, implicating Ca2+ as an essential cation during germination. In this study we used a pharmacological approach coupled with the direct measurement of Ca2+ levels in germinating spore populations by atomic adsorption to examine Ca(2+)-dependent signal transduction during spore activation and germination in D. discoideum. Inhibitors of both phospholipase C and internal Ca2+ release inhibited autoactivation while exogenously added Ins(1,4,5)P3, acted synergistically with the autoactivator. The antagonists specifically affected spore activation as mediated by the autoactivator, since neither had any effect on heat-activated spores. In contrast, La3+, an inhibitor of Ca2+ uptake, had little or no effect on either autoactivation or the swelling of autoactivated spores. However, an inhibition of Ca2+ influx by La3+ inhibited both the swelling of heat-activated spores and amoebal emergence following each period of autoactivation or heat activation. Ca2+ levels change in the spore population during germination. During activation and swelling, Ca2+ efflux occurs from the spores. Both of the activating stimuli used here, the autoactivator and heat, caused this Ca2+ efflux. The efflux is reversed during emergence when there is a net Ca2+ uptake by the spores and cells from the medium. Together these data provide the first evidence that autoactivation is mediated by Ca(2+)-dependent signal transduction, leading to Ca2+ efflux, and that the late event of germination, amoebal emergence, requires Ca2+ uptake to proceed. The data also suggest that the responses of the spore to the each of autoactivator and heat, i.e. Ca2+ movements and germination, are mediated by different mechanisms.
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PMID:The role of Ca2+ during spore germination in Dictyostelium: autoactivation is mediated by the mobilization of Ca2+ while amoebal emergence requires entry of external Ca2+. 765 15

The aim of this study was to investigate the effect of a calmodulin antagonist, calmidazolium, on the muscarinic receptor-mediated increase in inositol 1,4,5-trisphosphate [I(1,4,5)P3] in SH-SY5Y cells. Exposure to 10 microM calmidazolium suppressed the initial I(1,4,5)P3 peak increase (IC50 1 microM) whereas the steady-state was less affected. Furthermore, calmidazolium displayed non-competitive antagonistic properties of [3H]quinuclidinyl benzylate binding to intact SH-SY5Y cells and to membranes from these cells. These effects were also obtained with another calmodulin inhibitor, trifluoperazine (10 microM). These results demonstrate that novel finding that the calmodulin inhibitors calmidazolium and trifluoperazine act as non-competitive muscarinic antagonists in SH-SY5Y cells and inhibit muscarinic receptor-stimulated phospholipase C activation in these cells.
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PMID:Calmidazolium inhibits muscarinic receptor-mediated PLC activation in SH-SY5Y cells. 766 98

Previously, we have shown that alpha-2C and alpha-1A adrenergic receptors (AR) stimulate prostacyclin (PGI2) synthesis through a pertussis toxin-sensitive guanine nucleotide-binding protein (G protein) in vascular smooth muscle cells (VSMC). The purpose of this study was to assess the role of Ca++ in PGI2 production elicited by alpha-AR activation and to investigate the modulation of the Ca++ channel by G proteins coupled to these alpha-AR in VSMC. PGI2 was measured as immunoreactive 6-keto-PGF1 alpha by radioimmunoassay and cytosolic calcium ([Ca++]i) by spectrofluorometry using fura-2. Norepinephrine, methoxamine and UK-14304 enhanced 6-keto-PGF1 alpha production and [Ca++]i, which was inhibited by depletion of extracellular Ca++ and by Ca++ channel antagonists (verapamil, nifedipine and PN 200-110). Moreover, the Ca++ channel activator Bay K 8644 increased 6-keto-PGF1 alpha production in a nifedipine-sensitive manner, indicating the involvement of dihydropyridine-sensitive Ca++ channels in VSMC. Pertussis toxin inhibited AR agonist-induced 6-keto-PGF1 alpha production and the increase in [Ca++]i. Alpha AR agonists increase Ca++ influx in the presence of guanosine 5'-0-(2- thiodiphosphate) (GTP-gamma-S), and this effect was blocked in the presence of guanine 5'-O-(2-thiodiphosphate) (GDP-beta-S) and antiserum against Gi alpha 1-2 protein in reversibly permeabilized cells with beta-escin. VSMC of rabbit aortae contain a G protein(s) that was recognized by Gi alpha 1-2 but not Gi alpha 3 or G0 antibodies at 1:200 dilution. The calmodulin inhibitor W-7 blocked AR agonist and Bay K 8644-stimulated 6-keto-PGF1 alpha production. The phospholipase A2 inhibitors 7,7-dimethyleicosadienoic acid and oleoyloxyethyl phosphocholine but not phospholipase C inhibitor U-73122 reduced 6-keto-PGF1 alpha production in VSMC. These data suggest that a pertussis toxin-sensitive G protein, probably Gi alpha 1-2, coupled to alpha AR regulates Ca++ influx, which, in turn, by interacting with calmodulin, increases phospholipase A2 activity to release arachidonic acid for PGI2 synthesis in VSMC of rabbit aortae.
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PMID:Alpha adrenergic receptor subtypes involved in prostaglandin synthesis are coupled to Ca++ channels through a pertussis toxin-sensitive guanine nucleotide-binding protein. 768 1

Acetylcholine (ACh) caused a dose-dependent contraction of gallbladder muscle cells in either a normal (1.9 mM) Ca2+, zero-Ca2+ or 4 mM Sr2+ medium, with a maximal contraction about 21 +/- 1% at 10(-6) M. Pirenzepine, methoctramine and p-fluoro-hexahydro-sila-difenidol (the M1, M2 and M3 antagonist, respectively) alone had no inhibitory effect on ACh-induced contraction in normal Ca2+ medium, which was blocked by the combination of methoctramine and p-F-HHSiD. In the 4 mM Sr2+ medium, methoctramine dose dependently inhibited ACh-induced contraction and shifted the ACh dose-response curve to the right. The contraction induced by ACh was further blocked by 10(-4) M propranolol (phosphatidic acid phosphohydrolase inhibitor that prevents the production of diacylglycerol from phospholipase D activation), 10(-5) M H-7 and chelerythrine (the protein kinase C inhibitors) by 64%, 75% and 77%, respectively. In contrast, in the zero-Ca2+ medium, p-fluoro-hexahydro-sila-difenidol dose-dependently inhibited ACh-induced contraction and shifted the ACh dose-response curve to the right. The action of ACh was further blocked by 10(-6) M U-73122 (phospholipase C inhibitor) and 10(-5) M CGS 9343B (calmodulin antagonist) by 95% and 77%, respectively. In conclusion, ACh contracts the gallbladder muscle by stimulating the M2 and M3 muscarinic receptors. The M2 receptors are linked to Ca2+ influx, activation of phospholipase D and protein kinase C-dependent pathway, whereas the M3 receptors are preferentially associated with the activation of phospholipase C, intracellular Ca2+ release and calmodulin-dependent pathway.
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PMID:Distinct muscarinic receptors and signal transduction pathways in gallbladder muscle. 775 67

Diverse and distinct hormonal stimuli arriving at the cardiomyocyte engage specific surface receptors to initiate hydrolysis of inositol phospholipids by phospholipase C whereby information flows from changes in intracellular levels of inositol 1,4,5-trisphosphate and inositol 1,3,4,5-tetrakisphosphate, 1,2-diacylglycerol and Ca2+ to the specific phosphorylation of cellular proteins by various protein kinases such as the protein kinase C family, Ca(2+)-calmodulin-dependent kinase and mitogen activated kinases. The phosphorylation products are potential regulators of the inotropic and chronotropic state, hypertrophic growth and specific gene expression and ischemic preconditioning of the myocardium. This review summarizes the current state of knowledge concerning the phosphatidylinositol cycle and its potential role in mediating various functional responses in myocardium. The multiplicity of receptor types, G-proteins, phospholipases C and protein kinases raises fundamental questions about the mechanisms that assure the precision and timing of the myocardial response to hormonal stimuli.
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PMID:Signal transduction by the phosphatidylinositol cycle in myocardium. 776 Mar 91

Receptor-mediated activation of heterotrimeric guanine nucleotide-binding proteins (G proteins) results in the dissociation of alpha from beta gamma subunits, thereby allowing both to regulate effectors. Little is known about the regions of effectors required for recognition of G beta gamma. A peptide encoding residues 956 to 982 of adenylyl cyclase 2 specifically blocked G beta gamma stimulation of adenylyl cyclase 2, phospholipase C-beta 3, potassium channels, and beta-adrenergic receptor kinase as well as inhibition of calmodulin-stimulated adenylyl cyclases, but had no effect on interactions between G beta gamma and G alpha o. Substitutions in this peptide identified a functionally important motif, Gln-X-X-Glu-Arg, that is also conserved in regions of potassium channels and beta-adrenergic receptor kinases that participate in G beta gamma interactions. Thus, the region defined by residues 956 to 982 of adenylyl cyclase 2 may contain determinants important for receiving signals from G beta gamma.
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PMID:A region of adenylyl cyclase 2 critical for regulation by G protein beta gamma subunits. 776 32

Adenylyl cyclase exists as a family of closely related subtypes which differ in their tissue distribution and regulatory properties. Submicromolar rises in [Ca2+]i produced via activation of phospholipase C (PLC) or Ca2+ channel opening, provide a mechanism by which Ca2+/calmodulin (CaM) or protein kinase C (PKC)-sensitive isoforms of adenylyl cyclase can be regulated. In this study we have examined, in detail, the muscarinic (M3) regulation of adenylyl cyclase in SH-SY5Y cells and report a role for both [Ca2+]e and [Ca2+]i. Carbachol (1 mM) and potassium (100 mM) caused a time (T1/2 = 3 and 4 min, respectively) and dose (EC50 = 6.95 microM and 34.7 mM respectively) related increase in cAMP formation. This amounted to an approximate two-fold increase over basal levels. Carbachol and potassium also caused a biphasic increase in [Ca2+]i with basal, peak and plateau values of 118.4 nM, 697.6 nM, 253.0 nM and 104.0 nM, 351.6 nM, 181.5 nM, respectively. Calcium channel blockade with nickel (2.5 mM) abolished potassium-stimulated cAMP formation and rises in [Ca2+]i. However, carbachol-stimulated cAMP formation was significantly decreased only at the later time points, where rises in [Ca2+]i were also essentially abolished. Further evidence for a role for [Ca2+]e and [Ca2+]i is provided by the stimulation of cAMP formation by carbachol in the absence of added Ca2+, followed by a further increase on its re-addition. Carbachol- and potassium-stimulated cAMP formation were inhibited by the CaM antagonist trifluoperazine (100 microM). The mu-opiate agonists, morphine and fentanyl also inhibited carbachol-stimulated cAMP formation. In addition, cAMP formation in SH-SY5Y cell membranes was significantly increased in the presence of Ca2+ (1.46 microM), CaM (200 nM) and forskolin (1 microM). PKC inhibition with Ro 31 8220 did not affect carbachol-stimulated cAMP formation. Taken collectively, these data suggest that SH-SY5Y cells express type 1, and possibly type 8 isoforms of adenylyl cyclase, which can be regulated by intra- and extracellular Ca2+.
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PMID:Adenylyl cyclase in SH-SY5Y human neuroblastoma cells is regulated by intra- and extracellular calcium. 778 4

Haemorrhagic diatheses due to platelet function defects are a heterogenous and poorly understood group of conditions. We report the investigation of a female with a lifelong history of epistaxes, haemarthroses, menorrhagia and persistent iron-deficiency anaemia. Although platelet numbers and morphology were normal, platelet function was abnormal both in vivo and in vitro. Skin bleeding time was prolonged and aggregation thresholds in platelet-rich plasma to a variety of weak and strong agonists were increased. Platelet granule contents were normal and membrane glycoproteins GpIb and GpIIIa were present in normal amounts. Polyphosphoinositide metabolism and phosphatidic acid generation were diminished in thrombin-stimulated platelets, as was phosphorylation of the 47 kD substrate for protein kinase C and the 20 kD protein myosin light chain kinase, indicating impaired generation of the intracellular second messengers diacylglycerol and inositol trisphosphate due to diminished stimulated phospholipase C activity. Although intracellular free calcium, calmodulin activity and basal cAMP concentrations were normal, washed platelets showed increased cAMP accumulation following stimulation with prostaglandin E1 and forskolin. Platelet membrane lipid analysis revealed a reduction in plasmalogen phosphatidylethanolamine content. It is suggested that the membrane phospholipid abnormalities cause the abnormal platelet reactivity by interfering with signal transduction from platelet receptor, via intermediary G proteins, to phospholipase C and adenylate cylase. The bleeding tendency is likely to be a consequence of the altered stimulus-response coupling.
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PMID:A haemorrhagic platelet disorder associated with altered stimulus-response coupling and abnormal membrane phospholipid composition. 780 35

Cd2+ provokes an immediate production of inositol trisphosphate and the release of Ca2+ from internal stores in human fibroblasts and some other mammalian cells. Ni2+, Co2+, Fe2+, and Mn2+ evoke the release of stored Ca2+, but are less potent than Cd2+ (apparent K0.5 = 40 nM). Zn2+ and Cu2+ competitively inhibit Ca2+ release evoked by Cd2+ without affecting Ca2+ release by hormones such as bradykinin. Zn2+ has the same apparent Ki value (80-90 nM) towards the five agonist metals, which suggests that the metals interact with the same site. Many other divalent cations neither released stored Ca2+ nor affected Cd(2+)-evoked Ca2+ release. The agonist metals appear to activate phospholipase C via a G protein rather than a tyrosine kinase. The production of reactive oxygen species is probably not involved in Ca2+ release by the metals. Cd2+ and other stimuli that raise cytosolic-free Ca2+ induce cyclic (AMP) production, apparently by activating a calmodulin-dependent adenylyl cyclase. We suggest that an orphan receptor mediates the hormonelike responses to Cd2+ and the other agonist metals. The receptor is referred to as an orphan because its physiological stimulus is unknown. Growth of the fibroblasts in high Zn2+ desensitizes them to the five agonist metals without affecting Ca2+ release by bradykinin or histamine. A several hour incubation in culture medium with normal Zn2+ fully restores responsiveness to the five active metals. Growth in high Zn2+ appears to repress the synthesis of the putative orphan receptor because inhibitors of RNA or protein synthesis, or asparagine-linked glycosylation, prevented the restoration of metal responsiveness.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Transmembrane signals and protooncogene induction evoked by carcinogenic metals and prevented by zinc. 784 95


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