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)

Bradykinin (BK) receptor and P2-purinergic receptor are known to be coupled to phospholipase C (PLC) in PC12 cells. To study the interaction between these two PLC-linked receptors, the presence of both receptors on individual cells was demonstrated by sequential Ca2+ spikes caused by BK and ATP in a single fura-2-loaded cell. BK- and ATP-induced catecholamine (CA) secretions were desensitized within 5 min. However, in the sequential experiment, the BK-induced homologous desensitization of CA secretion did not block the ATP-induced secretion, and vice versa. Each agonist-induced an increase in inositol 1,4,5-trisphosphate (IP3) production and intracellular free Ca2+ concentration also led to homologous desensitization. However, there was no heterologous desensitization between the two agonists. When the cells were treated with both BK and ATP simultaneously, the amounts of CA secretion, IP3 production, internal Ca2+ mobilization, and Ca2+ influx were all additive. We also found that both IP3-induced Ca2+ release from intracellular Ca2+ stores and Ca2+ influx from extracellular space were able to release [3H]norepinephrine, and the secretion induced by both agonists was exactly additive in the absence or presence of extracellular Ca2+. The data suggest that the CA secretions caused by BK or ATP may have separate secretory pathways even though they activate identical second messenger pathways.
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PMID:Signal flows from two phospholipase C-linked receptors are independent in PC12 cells. 786 Nov 36

P2Y purinergic receptors previously have been shown to couple either to activation of phospholipase C through a pertussis toxin-insensitive mechanism or to inhibition of adenylyl cyclase through pertussis toxin-sensitive members of the G1 family of G proteins. These and other pharmacological data strongly suggest that multiple P2Y purinergic receptors exist. Webb et al. [FEBS Lett. 324:219-225 (1993)] cloned a cDNA that, when expressed in frog oocytes, displayed the general pharmacological characteristics of a P2Y purinergic receptor but whose second messenger linkage was not resolved. We have now cloned the meleagrid (turkey) homologue of the previously cloned chick P2Y purinergic receptor and have stably expressed it in a heterologous human cell line (1321N1 astrocytoma cells) to establish its signaling properties. The purinergic receptor agonist 2-methylthio-ATP (2MeSATP) stimulated a marked activation of phospholipase C in 1321N1 cells stably expressing the meleagrid receptor. The order of potency of a series of analogues of ATP and ADP for stimulation of phospholipase C by the receptor expressed in 1321N1 cells [2MeSATP = 2-methylthio-ADP > adenosine 5'-O-(2-thio)diphosphate > ADP > 2-chloro-ATP = adenosine 5'-O-(3-thio)triphosphate > or = ATP > adenylyl-imidodiphosphate > UTP] was similar to that observed for P2Y purinergic receptors in turkey erythrocytes and many other tissues and was markedly different from those of the P2U and P2X purinergic receptor subtypes. Stimulation of inositol lipid hydrolysis by P2Y purinergic agonists was not affected by preincubation of cells with pertussis toxin. In contrast to its marked effects on phospholipase C activity, 2MeSATP caused only a small and variable inhibition of cAMP accumulation. Ribonuclease protection analysis of turkey tissues showed that this P2Y purinergic receptor is most highly expressed in blood and brain. Taken together, these results indicate that a phospholipase-C-activating P2Y purinergic receptor has been cloned and stably expressed in 1321N1 astrocytoma cells.
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PMID:Expression of a cloned P2Y purinergic receptor that couples to phospholipase C. 805 61

Extracellular ATP increases inositol phosphates, cytosolic Ca2+ concentration ([Ca2+]i), arachidonic acid (AA) release, and iodide efflux in FRTL-5 cells. To examine the sequence of events in P2-purinergic receptor activation by ATP, a phospholipase C (PLC) inhibitor (U-73122) and a phospholipase A2 (PLA2) inhibitor (U-26384), as well as 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'- tetraacetic acid (BAPTA) and downregulation of protein kinase C (PKC) were used. ATP increased inositol trisphosphate (IP3), [Ca2+]i, AA release, and 125I efflux dose dependently. U-73122 inhibited the IP3 and calcium increase but not AA; U-26384 prevented AA release but not the increase in calcium. Both agents inhibited iodide efflux. BAPTA prevented any ATP-induced increase in [Ca2+]i without affecting AA release or 125I efflux. PKC downregulation had no effect on ATP-stimulated AA release, but reduced 125I efflux. We conclude that ATP-induced iodide efflux involves parallel, not sequential, activation of PLC and PLA2. No increase in [Ca2+]i or PKC activity is required for PLA2 activation. In contrast, an increase in 125I efflux depends on PKC and PLA2 activities, but not an increase in [Ca2+]i.
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PMID:P2-purinergic stimulation of iodide efflux in FRTL-5 rat thyroid cells involves parallel activation of PLC and PLA2. 807 12

We studied the effect of adenosine on prolactin secretion by the anterior pituitary, and the transduction mechanisms whereby the purine exerts its action. Adenosine inhibited prolactin release in basal and in vasoactive intestinal peptide (VIP)- or TRH-stimulated conditions. Pertussis toxin pretreatment reduced the inhibition of VIP-stimulated prolactin secretion which was induced by adenosine, while it completely abolished the effect of the purine on TRH-evoked prolactin release. In membrane preparations of anterior pituitary cells, adenosine reduced the adenylate cyclase activity stimulated by VIP. Such an inhibition was not blocked by pertussis toxin pretreatment. Furthermore, the purine reduced TRH-stimulated inositol phosphate production in cultured anterior pituitary cells, an effect that was reversed by pretreatment with pertussis toxin. In addition, the nucleoside did not significantly affect the TRH-induced rise in intracellular calcium. In conclusion, our data show that adenosine inhibits prolactin secretion, acting on purinergic receptors coupled to the adenylate cyclase enzyme and phospholipase C. The effect of the nucleoside on adenylate cyclase seems to be achieved either by the involvement of an adenosine receptor coupled to the catalytic subunit of the enzyme via a pertussis toxin-sensitive G protein, or by the activation of a site directly coupled to the catalytic subunit of the adenylate cyclase (the P site). Its effect on phospholipase C seems to be mediated by a purinergic receptor coupled to the intracellular effector via a pertussis toxin-sensitive G protein.
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PMID:Direct effect of adenosine on prolactin secretion at the level of the single rat lactotroph: involvement of pertussis toxin-sensitive and -insensitive transducing mechanisms. 814 40

Outer hair cells (OHC) of the mammalian cochlea are thought to preprocess the sound signal by active movements, which can be induced by electrical or chemical stimulation, e.g. depolarization evoked by high [K+] or increased cytoplasmic [Ca2+]. Extracellular ATP has been found to induce cytoplasmic [Ca2+] increases in OHC but involved mechanisms have not been elucidated. Cytoplasmic [Ca2+] was measured in non-enzymatically isolated single OHC using Fura-2 microspectrometry. Results, using ATP/derivatives and other P2-purinergic receptor (P2R) ligands, as well as Ca(2+)-channel blockers and pertussis toxin, revealed several signal transduction pathways that increase cytoplasmic [Ca2+] in OHC: a P2-purinergic receptor (P2R)--G-protein--effector (phospholipase C or an ion channel) system and a voltage-dependent Ca2+ channel. Agonist potency studies denote a pattern analogous to that found in skeletal muscle, i.e. ATP-alpha-S > ATP = 2-methyl-S-ATP >> ADP > alpha,beta-methylene-ATP, but no activation by ADP beta F or UTP, leaving a choice of P2y or P2zR subtypes. The latter possibility gained strength from calculations showing that up to 8% of ATP may have formed the P2zR agonist ATP4- in the experimental medium. Experiments in Ca(2+)-free medium and with pertussis toxin revealed that the main Ca2+ source was intracellular. Pertussis toxin did not affect [Ca2+] increase induced by carbachol. Acetylcholine, administered a few seconds before ATP, did not affect total cytoplasmic [Ca2+] increases. Induced cytoplasmic [Ca2+] increases were high enough (> 500 nM at 50 microM ATP/derivatives) to hyperpolarize the OHC membrane by opening K(+)-channels and decreased little with time.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:ATP-induced cytoplasmic [Ca2+] increases in isolated cochlear outer hair cells. Involved receptor and channel mechanisms. 815 3

Adenine nucleotides inhibited isoproterenol- and forskolin-stimulated cyclic AMP accumulation in C6-2B rat glioma cells. Inhibition occurred in the presence of a phosphodiesterase inhibitor, and no effect of adenine nucleotides was observed in direct measurements of phosphodiesterase activity in intact cells. Pretreatment of C6-2B glioma cells with pertussis toxin blocked the inhibitory effects of P2Y-purinergic receptor agonists. The pharmacological specificity for a series of ATP and ADP analogs (2-methylthioadenosine 5'-triphosphate > or = 2-methylthioadenosine 5'-diphosphate > adenosine 5'-O-(2-thiodiphosphate) > 2-chloro-adenosine 5'-triphosphate = ADP = adenosine 5'-O-(3-thiotriphosphate) > ATP > UTP) was similar to that expected of a P2Y-purinergic receptor; the P2X-purinergic receptor agonists, alpha,beta-methyleneadenosine 5'-triphosphate and beta,gamma-methylene-adenosine 5'-triphosphate, had no effect. Because activation of phospholipase C occurs in response to P2-purinergic receptor activation in many target tissues, the effects of P2Y-receptor agonists on inositol phosphate accumulation were measured in C6-2B cells. No evidence for P2Y-purinergic receptor-mediated regulation of inositol lipid metabolism was observed under conditions where muscarinic cholinergic receptor activation or AIF4-markedly increased inositol phosphate accumulation. These results suggest that a P2-purinergic receptor subtype with distinct signaling properties exists on C6-2B rat glioma cells. Although this receptor expresses the general pharmacological specificity of a phospholipase C-coupled P2Y-purinergic receptor, it may represent a unique receptor subtype since it inhibits adenylyl cyclase.
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PMID:Identification of a P2Y-purinergic receptor that inhibits adenylyl cyclase. 826 74

ATP stimulates arachidonic acid mobilization and eicosanoid production in cultured astrocytes via P2Y-purinergic receptors. To assist in determining the mechanism of phospholipase A2 activation and the role of calcium in eicosanoid production, cultures were pretreated with pertussis toxin (PTx). ATP-evoked eicosanoid release was inhibited by PTx in a concentration-dependent fashion. Inositol phospholipid hydrolysis was partially attenuated by PTx, but the concentrations required were approximately 50 times greater than those for inhibition of eicosanoid production, suggesting that phospholipase C activation is not necessary for eicosanoid synthesis. Stimulation of eicosanoid release by other P2Y-purinergic receptor agonists was also inhibited by PTx; however, PTx had no effect on eicosanoid release evoked by ionomycin or thapsigargin, nor did it affect ATP-stimulated calcium influx or mobilization from intracellular stores. Increases in intracellular free calcium concentration alone were insufficient to stimulate eicosanoid production, but maximal production was dependent upon the concentration of extracellular calcium. These results suggest that the P2Y-purinergic receptor is coupled to phospholipase A2 via a guanine nucleotide-binding protein, and that extracellular calcium may also be involved in the synthesis of eicosanoids by astrocytes.
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PMID:Purinergic P2Y receptors on astrocytes are directly coupled to phospholipase A2. 838 60

We describe the reconstitution and purification of a membrane-associated phosphoinositide-specific phospholipase C (PIC) from turkey erythrocyte ghosts. This PIC is responsive to a G-protein coupled to P2y purinergic receptors which are expressed in turkey erythrocytes. Reconstitution is achieved by adding partially purified PIC to [3H]inositol-prelabelled turkey erythrocyte membranes depleted of their endogenous PIC (acceptor membranes). PIC activity is associated with a 52 kDa polypeptide on SDS-polyacrylamide gel electrophoresis. Addition of a 307-fold purified enzyme to the acceptor membranes has no effect on basal PIC activity, but markedly increases the response to GTP gamma S and P2y-purinergic receptor activation.
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PMID:Characterization of a membrane-associated, receptor and G-protein responsive phosphoinositide-specific phospholipase C from avian erythrocytes. 839 7

Release of mucins from cultured airway surface epithelial cells can be stimulated by extracellular ATP via a P2-purinergic receptor-mediated mechanism (K. C. Kim and B. C. Lee. 1991. Br. J. Pharmacol. 103:1053-1056). In this report, we studied the mechanism by which extracellular ATP induces the mucin release. We found that: (1) ATP increased both mucin release and generation of inositol phosphates in a dose-dependent fashion, and their dose-effect relationships were almost superimposed; (2) the increases in both mucin release and the phosphatidylinositol phosphate (PI) turnover by extracellular ATP were partially, but almost equally, blocked by the pretreatment with pertussis toxin (42% for mucin release and 44% for PI turnover). We conclude that in cultured airway goblet cells extracellular ATP stimulates mucin release by a signal transduction mechanism, which seems to involve coupling of ATP-activated P2 purinoceptors with phospholipase C, at least in part, via pertussis toxin-sensitive GTP-binding proteins. This may be an important finding in understanding the regulation of mucin release by airway goblet cells, since a number of agents present in the airway could influence this signal transduction pathway and subsequently modulate the mucin secretion.
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PMID:Involvement of a signal transduction mechanism in ATP-induced mucin release from cultured airway goblet cells. 842 4

Schwann cells play an important role in both the development and regeneration of peripheral nerves. Proliferation and differentiation of Schwann cells are critically dependent on changes in the levels of cAMP. ATP is a fast excitatory transmitter in the peripheral nervous system, inducing depolarization of the vagus nerve through occupancy of P2-purinergic receptors. In the present study we demonstrate that extracellular ATP stimulates phospholipase C and inhibits adenylate cyclase activities in cultured Schwann cells. Addition of ATP inhibited, in a concentration-dependent manner, forskolin- or isoprenaline-stimulated adenylate cyclase activity. The rank order of potency corresponding to different purinergic receptor agonists was 2-methylthio-ATP > ATP = ADP > or = adenosine 5'-[gamma-thio]triphosphate (ATP[S]) > UTP, consistent with the involvement of a P2y subtype. Adenosine and adenosine 5'-[alpha,beta-methylene]-triphosphate (pp[CH2pA) were ineffective. Preincubation with pertussis toxin completely blocked this inhibitory effect. When Schwann cells were pre-labelled with myo-[3H]inositol and incubated in Hanks' balanced salt solution containing Ca2+ and Mg2+, addition of ATP[S] resulted in a concentration-dependent increase in the release of InsP with a concomitant increase in intracellular free [Ca2+] ([Ca2+]i). Under these conditions, the effects of both ATP and UTP were of lower magnitude. Removal of Ca2+ and Mg2+ from the assay medium resulted in a significant increase in the effects of ATP[S], ATP and UTP. The decreased response observed in the presence of both bivalent cations (1.2 mM Ca2+ and 1 mM Mg2+) could not be explained either by increased degradation of ATP by Ca2+/Mg2+-dependent nucleotidases or by cation influx. The rank order of potency for the effects of agonists on phospholipase C activity was ATP[S] = adenosine 5'[gamma-imido]triphosphate > ATP -UTP > ADP, indicating the involvement of a P(2U) receptor subtype in this response. Adenosine, AMP and pp[CH2]pA were ineffective. These results demonstrate that immortalized Schwann cells express P(2U) and P(2Y) purinoceptors, which are coupled to stimulation of phospholipase C and inhibition of adenylate cyclase, respectively. Our observations unveil signal-transduction pathways that may be used by ATP to regulate proliferation and differentiation of Schwann cells, and ultimately to influence nerve homeostasis.
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PMID:P2-purigenic receptors regulate phospholipase C and adenylate cyclase activities in immortalized Schwann cells. 867 70


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