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)

1. Extracellular adenosine triphosphate (ATP) is mitogenic for vascular smooth muscle cells (VSMC) and stimulates several events that are important for cell proliferation: DNA synthesis, protein synthesis, increase of cell number, immediate early genes, cell-cycle progression, and tyrosine phosphorylation. 2. Receptor characterization indicates mitogenic effects of both P2U and P2Y receptors. The P2X receptor is lost in cultured VSMC and is not involved. Several related biological substances such as UTP, ITP, GTP, AP4A, ADP, and UDP are also mitogenic. 3. Signal transduction is mediated via Gq-proteins, phospholipase C beta, phospholipase D, diacyl glycerol, protein kinase C alpha, delta, Raf-1, MEK, and MAPK. 4. ATP acts synergistically with polypeptide growth factors (PDGF, bFGF, IGF-1, EGF, insulin) and growth factors acting via G-protein-coupled receptors (noradrenaline, neuropeptide Y, 5-hydroxytryptamine, angiotensin II, endothelin-1). 5. The mitogenic effects have been demonstrated in rat, porcine, and bovine VSMC and cells from human coronary arteries, aorta, and subcutaneous arteries and veins. 6. The trophic effects on VSMC and the abundant sources for extracellular ATP in the vessel wall make a pathophysiological role probable in the development of atherosclerosis, neointima-formation after angioplasty, and possibly hypertension.
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PMID:Extracellular ATP: a growth factor for vascular smooth muscle cells. 959 70

1. Previous studies have shown that ATP and UTP are able to stimulate phospholipase C (PLC) and proliferation in cultured aortic smooth muscle cells. Here we set out to characterize the receptor responsible, and investigate a possible role for p42 and p44 mitogen activated protein kinase (MAPK) in the proliferative response. 2. The phospholipase C response of spontaneously hypertensive rat (SHR) derived aortic smooth muscle cells in culture showed that the response to ATP was partial compared to the response to UTP. 3. Further studies characterized the responses of the SHR derived cells. UTP was the only full agonist with the SHR cells; UDP gave a partial response while ADP, 2-methythio-ATP and alpha,beta-methylene ATP were essentially ineffective. The response to UDP was almost lost in the presence of hexokinase, consistent with this being due to extracellular conversion to UTP. These observations are inconsistent with the response being mediated by either P2Y1 or P2Y6 receptors. 4. When increasing concentrations of ATP were present with a maximally effective concentration of UTP, the size of the response diminished, consistent with UTP and ATP acting at a single population of receptors for which ATP was a partial agonist. This is inconsistent with a response mainly at P2Y2 receptors. 5. 1321N1 cells transfected with human P2Y4 receptors gave a similar agonist response profile, with ATP being partial compared to UTP, loss of response to UDP with hexokinase treatment, and with the response to UTP diminishing in the presence of increasing concentrations of ATP. 6. Use of the reverse transcriptase-polymerase chain reaction confirmed the presence of mRNA encoding P2Y4 receptors in SHR derived vascular smooth muscle cells. Transcripts for P2Y2, P2Y4 and P2Y6 receptors, but not P2Y1 receptors, were detected. 7. Stimulation of SHR derived cells with UTP enhanced the tyrosine phosphorylation of both p42 and p44 MAPK, and the incorporation of [3H]-thymidine into DNA. Both these responses were diminished in the presence of an inhibitor of activation of MAPK. 8 These results lead to the conclusion that in SHR derived cultured aortic smooth muscle cells, PLC responses to extracellular UTP and ATP are predominantly at P2Y4 receptors, and suggest that these receptors are coupled to mitogenesis via p42/p44 MAPK.
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PMID:Evidence that P2Y4 nucleotide receptors are involved in the regulation of rat aortic smooth muscle cells by UTP and ATP. 969 Aug 62

Microfluorometric measurements in Fura-2-loaded single cultured human vascular endothelial cells were used to characterize the intracellular calcium [Ca2+]i responses triggered by extracellular application of adenosine 5'-triphosphate (ATP) and other nucleotides. Application of ATP or uridine 5'-triphosphate (UTP) gave rise to dose-dependent elevations of [Ca2+]i in all the cells tested. At saturating concentrations of agonist, the [Ca2+]i response was biphasic, with an early peak and a sustained plateau. Unlike peak responses, the sustained Ca2+ plateau was sensitive to removal of Ca2+ from the external medium. Mn2+ quenching revealed the presence of Ca2+ influx during the agonist-induced calcium plateau. The agonist-evoked calcium plateau was inhibited in a dose-dependent manner by the Cl-channel blocker NPPB, by the divalent cation Ni2+ and by the imidazole antimycotic econazole. Previously, these compounds have been shown to block store-operated Ca2+ entry. The two phases of the agonist-evoked [Ca2+]i response were blocked by the specific phospholipase C inhibitor U-73122 and by intracellular injection of low molecular weight heparin, suggesting the involvement of IP3-sensitive intracellular Ca2+ stores. The pharmacological profile of the response, using different nucleotides and analogues, ATP = UTP > ADP = UDP, and no responses to P2X1 and P2Y1 agonists, suggested the involvement of P2Y2 receptors. The expression of mRNA for the P2Y2 receptor was detected by RT-PCR analysis. These results indicate that P2Y2 receptors linked to intracellular Ca2+ mobilization are present in human vascular endothelial cells. The initial [Ca2+]i mobilization is followed by a phase of elevated [Ca2+]i influx.
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PMID:Calcium signalling through nucleotide receptor P2Y2 in cultured human vascular endothelium. 980 12

Bovine adrenal zona fasciculata (AZF) cells express a noninactivating K+ current (IAC) that sets the resting membrane potential and may mediate depolarization-dependent cortisol secretion. External ATP stimulates cortisol secretion through activation of a nucleotide receptor. In whole-cell patch clamp recordings from bovine AZF cells, we found that ATP selectively inhibited IAC K+ current by a maximum of 75.7 +/- 3% (n = 13) with a 50% inhibitory concentration of 1.3 microM. A rapidly inactivating A-type K+ current was not inhibited by ATP. Other nucleotides, including ADP and the pyrimidines UTP and UDP, also inhibited IAC, whereas 2-methylthio-ATP (2-MeSATP) and CTP were completely ineffective. The rank order of potency for six nucleotides was UTP = ADP > ATP > UDP >> 2-MeSATP = CTP. At maximally effective concentrations, UTP, ADP, and UDP inhibited IAC current by 81.4 +/- 5.2% (n = 7), 70.7 +/- 7.2% (n = 4), and 65.2 +/- 7.9% (n = 5), respectively. Inhibition of IAC by external ATP was reduced from 71. 3 +/- 3.2% to 22.8 +/- 4.5% (n = 18) by substituting guanosine 5'-O-2-(thio) diphosphate for GTP in the patch pipette. Inhibition of IAC by external ATP (10 microM) was markedly suppressed (to 17.3 +/- 5.5%, n = 9) by the nonspecific protein kinase antagonist staurosporine (1 microM) and eliminated by substituting the nonhydrolyzable ATP analog 5-adenylyl-imidodiphosphate or UTP for ATP in the pipette. ATP-mediated inhibition of IAC was not altered by the kinase C antagonist calphostin C, the calmodulin inhibitory peptide, or by buffering the intracellular (pipette) Ca++ with 20 mM 1,2-bis-(2-aminophenoxy)ethane-N, N,N',N'-tetraacetic acid. In current clamp recordings, ATP and UTP (but not CTP) depolarized AZF cells at concentrations that inhibited IAC K+ current. These results demonstrate that bovine AZF cells express a nucleotide receptor with a P2Y3 agonist profile that is coupled to the inhibition of IAC K+ channels through a GTP-binding protein. The inhibition of IAC K+ current and associated membrane depolarization are the first cellular responses demonstrated to be mediated through this receptor. Nucleotide inhibition of IAC proceeds through a pathway that is independent of phospholipase C, but that requires ATP hydrolysis. The identification of a new signaling pathway in AZF cells, whereby activation of a nucleotide receptor is coupled to membrane depolarization through inhibition of a specific K+ channel, suggests a mechanism for ATP-stimulated corticosteroid secretion that depends on depolarization-dependent Ca++ entry. This may be a means of synchronizing the stress-induced secretion of corticosteroids and catecholamines from the adrenal gland.
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PMID:Purine and pyrimidine nucleotides inhibit a noninactivating K+ current and depolarize adrenal cortical cells through a G protein-coupled receptor. 992 30

Effects of ATP on the intracellular free calcium ion concentration ([Ca2+]i) in the rabbit eye suprachoroid were investigated by means of fura-2 microfluorophotometry. ATP application (10 to 100 microM) elicited a dose-dependent biphasic [Ca2+]i-increase: a fast phase typically peaking within 30 s and a following slow plateau phase, which lasted during the presence of ATP. The slow plateau phase was markedly diminished by removal of extracellular Ca2+, whereas the fast phase remained. An inhibitor of Ca2+ release from the sarcoplasmic reticulum (TMB-8), an endoplasmic Ca2+-ATPase inhibitor (thapsigargin) and a phospholipase C (PLC) inhibitor (U-73122) diminished the fast phase. A P2 receptor antagonist (Suramin) inhibited the ATP-induced [Ca2+]i-response. The potency order of ATP and related substances in producing the [Ca2+]i-elevation was UTP approximately equals ATP>ATP-gamma-S>ITP>ADP. beta,gamma-MethyleneATP, 2-methylthioATP and UDP evoked no response. This order is consistent with the P2Y2 receptor characteristics. Cross-desensitization between ATP and UTP excludes the co-existence of the other types of receptors. In conclusion, the ATP-induced [Ca2+]i-elevation in the rabbit eye suprachoroid was elicited by the Ca2+ release from the PLC-dependent, thapsigargin-sensitive intracellular Ca2+ storage sites by activating P2Y2 nucleotide receptors.
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PMID:P2Y2 receptor elevates intracellular calcium concentration in rabbit eye suprachoroid. 1080 22

UTP stimulates transmitter release and inhibits M-type K(+) channels in rat superior cervical ganglion neurons via G protein-coupled P2Y receptors. To investigate the underlying signaling mechanisms, we treated the neurons with either pertussis or cholera toxin; neither treatment altered the inhibition of M-type K(+) channels by 10 microM UTP. However, pertussis toxin reduced UTP-evoked [(3)H]noradrenaline release by 66%. UTP, UDP, ATP, and ADP caused accumulation of inositol trisphosphate in a pertussis toxin-insensitive manner. Pharmacological inhibition of inositol trisphosphate-induced Ca(2+) release (by inhibition of phospholipase C, of inositol trisphosphate receptors, and of the endoplasmic Ca(2+)-ATPase) prevented the UTP-dependent inhibition of M currents but failed to alter UTP-evoked [(3)H]noradrenaline release. Chelation of intracellular Ca(2+) by 1,2-bis(2-aminophenoxy)ethane-N, N,N',N'-tetraacetic acid also reduced the inhibition of M currents by UTP. In addition, all these manipulations attenuated the inhibition of M currents by bradykinin, but hardly affected the inhibitory action of oxotremorine M. These results demonstrate that UTP inhibits M-type K(+) channels via an inositol trisphosphate-dependent signaling cascade that is also used by bradykinin but not by muscarinic acetylcholine receptors. In contrast, the secretagogue action of UTP is largely independent of this signaling cascade but involves pertussis toxin-sensitive G proteins. Thus, UTP-sensitive P2Y receptors excite sympathetic neurons via at least two different signal transduction mechanisms.
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PMID:Two different signaling mechanisms involved in the excitation of rat sympathetic neurons by uridine nucleotides. 1082 87

Experiments were performed to characterize the P2 purinoceptor subtype responsible for cytoplasmic calcium mobilization in cells from the initial part of rabbit distal convoluted tubule (DCT). Free calcium concentration was measured in a DCT cell line (DC1) with the probe fura 2. Both ATP and UTP increased cytosolic Ca(2+) concentration ([Ca(2+)](i); EC(50) 3 and 6 microM, respectively). The order of potency for nucleotide analogs was ATP = UTP > adenosine 5'-O-[thiotriphosphate] >> ADP > UDP, which is consistent with the pharmacology of the P2Y2 receptor subtype. The increased [Ca(2+)](i) responses to ATP and UTP were strongly inhibited by suramin. Pretreatment of cells with pertussis toxin (PTX) attenuated the action of both nucleotides. Inhibition of phospholipase C with U-73122 totally blocked the [Ca(2+)](i) response to ATP. Thus ATP- and UTP-stimulated [Ca(2+)](i) mobilization in DC1 cells appears to be mediated via the activation of P2Y2 purinoceptors coupled to a G protein mechanism that is partially sensitive to PTX. Calcium flux measurements showed that lanthanum- and nifedipine-sensitive calcium channels are involved in the [Ca(2+)](i) response to ATP.
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PMID:Extracellular ATP increases [CA(2+)](i) in distal tubule cells. I. Evidence for a P2Y2 purinoceptor. 1089 91

P2Y receptors are a class of G protein-coupled receptors activated primarily by ATP, UTP, and UDP. Five mammalian P2Y receptors have been cloned so far including P2Y1, P2Y2, P2Y4, P2Y6, and P2Y11. P2Y1, P2Y2, and P2Y6 couple to the activation of phospholipase C, whereas P2Y4 and P2Y11 couple to the activation of both phospholipase C and the adenylyl cyclase pathways. Additional ADP receptors linked to Galpha(i) have been described but have not yet been cloned. SP1999 is an orphan G protein-coupled receptor, which is highly expressed in brain, spinal cord, and blood platelets. In the present study, we demonstrate that SP1999 is a Galpha(i)-coupled receptor that is potently activated by ADP. In an effort to identify ligands for SP1999, fractionated rat spinal cord extracts were assayed for Ca(2+) mobilization activity against Chinese hamster ovary cells transiently transfected with SP1999 and chimeric Galpha subunits (Galpha(q/i)). A substance that selectively activated SP1999-transfected cells was identified and purified through a series of chromatographic steps. Mass spectral analysis of the purified material definitively identified it as ADP. ADP was subsequently shown to inhibit forskolin-stimulated adenylyl cyclase activity through selective activation of SP1999 with an EC(50) of 60 nM. Other nucleotides were able to activate SP1999 with a rank order of potency 2-MeS-ATP = 2-MeS-ADP > ADP = adenosine 5'-O-2-(thio)diphosphate > 2-Cl-ATP > adenosine 5'-O-(thiotriphosphate). Thus, SP1999 is a novel, Galpha(i)-linked receptor for ADP.
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PMID:ADP is the cognate ligand for the orphan G protein-coupled receptor SP1999. 1110 74

Membrane-bound P2-receptors mediate the actions of extracellular nucleotides in cell-to-cell signalling. P2X-receptors are ligand-gated ion channels, whereas P2Y-receptors belong to the superfamily of G-protein-coupled receptors. So far, the P2Y family is composed of eight cloned and functionally defined subtypes. Five of them (P2Y1, P2Y2, P2Y4, P2Y6 and P2Y11) are present in human tissues. The P2Y3-, p2y8- and tp2y-receptors may be species orthologues. The principal physiological agonists of the cloned human P2Y-receptors are ADP (P2Y1), UTP/ATP (P2Y2), UTP (P2Y4), UDP (P2Y6) and ATP (P2Y11). The rat P2Y4-receptor is activated by both UTP and ATP. Specific patterns of polar amino acid residues in the exofacial portions of transmembrane domains (TMs) 6 and 7 of the P2Y-receptors may account for the ligand specificity of the subtypes. Suramin acts as an antagonist at most P2Y-receptors with the exception of P2Y4- and tp2y-receptors. PPADS has been shown to block P2Y1-, the human P2Y4- and P2Y6-receptors. The nucleotide analogue 2'-deoxy-N6-methyladenosine-3',5'-bisphosphate (MRS 2179), in contrast, seems to be a potent and selective antagonist at the P2Y1-receptor. All cloned and functionally expressed P2Y-receptors are able to couple to phospholipase C. The P2Y11-receptor mediates in addition a stimulation of adenylate cyclase and the tp2y-receptor an inhibition of this signal transduction pathway. Other functionally defined subtypes, e.g., the receptor mediating an inhibition of adenylate cyclase in blood platelets, are not yet cloned. The distribution of P2Y1 mRNA is widespread. The receptor plays a crucial role in blood platelet aggregation and mediates the adenine nucleotide-induced release of the endothelium-derived relaxing factor nitric oxide. P2Y1-receptors may also be involved in the modulation of neuro-neural signalling transmission. P2Y2 transcripts are abundantly distributed. One important example for its functional role is the control of chloride ion fluxes in airway epithelia. The P2Y4-receptor is highly expressed in the placenta. The distribution of the P2Y6-receptor is widespread including heart, blood vessels and brain. The P2Y11-receptor may play a role in the differentiation of immunocytes.
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PMID:Molecular pharmacology of P2Y-receptors. 1111 26

In the present study, the P2Y receptor(s) mediating the effects of the pyrimidines UTP and UDP on phospholipase C activation in the mouse neuroblastoma x rat glioma hybrid cell line NG108-15 was investigated. Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) analysis detected transcripts for the P2Y(6) and P2Y(2) receptors, but not for P2Y(1) and P2Y(4.) UTP and UDP were equipotent agonists and their effects were partially additive. Suramin, reactive blue 2 and pyridoxal phosphate-6-azophenyl-2',4'disulfonic acid (PPADS) antagonised the phospholipase C response to both UTP and UDP. High micromolar concentrations of adenosine, 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS-21680), 2',3'-O-isopropylideneadenosine (iPAdo) and adenosine 3':5'-cyclic monophosphate (3',5'-cAMP) were able to antagonise the effect of UTP on phospholipase C but not that of UDP. The additivity of the UTP and UDP responses, novel P2 receptor antagonist profile and the distinguishing action of adenosine may indicate the expression of a pyrimidine selective P2Y receptor in addition to the P2Y(6) type in these cells.
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PMID:Pharmacological characterisation of pyrimidinoceptor responses in NG108-15 cells. 1127 90


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