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)

Embryonic development is initiated after the fertilizing sperm contacts the egg and triggers a process termed "egg activation," resulting in calcium release, cortical granule exocytosis, recruitment of maternal mRNAs, and cell cycle resumption. Heterotrimeric guanine nucleotide-binding proteins (G proteins) may be involved in mouse egg activation since inhibition of G protein beta gamma subunits partially inhibits sperm-induced cell cycle resumption. In addition, specific events of egg activation can be initiated in the absence of sperm by acetylcholine stimulation of mouse eggs overexpressing the human m1 muscarinic receptor, a G protein-coupled receptor. In somatic cell, G proteins in the Gq family couple ligand stimulation of the m1 muscarinic receptor to activation of phospholipase C, resulting in the production of inositol 1,4,5-trisphosphate (IP3) and IP3-mediated release of intracellular calcium. Since IP3-mediated calcium release is involved in egg activation at fertilization, we have examined the role of Gq family G proteins in both sperm-independent (muscarinic receptor-mediated) and sperm-induced egg activation using a function-blocking antibody raised against the common C-terminal region of Gq and G11 proteins. We show that this antibody effectively inhibits Gq family G proteins in mouse eggs by demonstrating that the antibody inhibits egg activation in response to stimulation of the m1 muscarinic receptor. This same antibody, however, does not inhibit sperm-induced egg activation events. These results indicate that although activation of Gq family G proteins can result in egg activation in the mouse, it is unlikely that these proteins are used by the sperm to initiate egg activation at fertilization.
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PMID:Evidence that Gq family G proteins do not function in mouse egg activation at fertilization. 964 Mar 35

In the estrogen-treated rat myometrium, carbachol increased the generation of inositol phosphates by stimulating the muscarinic receptor-Gq/G11-phospholipase C-beta3 (PLC-beta3) cascade. Exposure to carbachol resulted in a rapid and specific (homologous) attenuation of the subsequent muscarinic responses in terms of inositol phosphate production, PLC-beta3 translocation to membrane, and contraction. Refractoriness was accompanied by a reduction of membrane muscarinic binding sites and an uncoupled state of residual receptors. Protein kinase C (PKC) altered the functionality of muscarinic receptors and contributed to the initial period of desensitization. A delayed phase of the muscarinic refractoriness was PKC independent and was associated with a downregulation of Gqalpha/G11alpha. Atropine failed to induce desensitization as well as Gqalpha/G11alpha downregulation, indicating that both events involve active occupancy of the receptor. Prolonged exposure to AlF-4 reduced subsequent AlF-4 as well as carbachol-mediated inositol phosphate responses and similarly induced downregulation of Gqalpha/G11alpha. Data suggest that a decrease in the level of Gqalpha/G11alpha is subsequent to its activation and may account for heterologous desensitization.
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PMID:Carbachol-induced desensitization of PLC-beta pathway in rat myometrium: downregulation of Gqalpha/G11alpha. 973 Sep 45

In most tissues and cells the opioid receptor-like (ORL1) receptor regulates effectors primarily through the pertussis toxin (PTX)-sensitive guanine nucleotide-binding regulatory proteins (G proteins) Gi/Go. Many Gi-coupled receptors possess additional capability to interact with one or more PTX-insensitive G proteins. Using the betagamma-induced stimulation of type 2 adenylyl cyclase as a readout, we screened the ability of ORL1 receptor to interact with a panel of PTX-insensitive G proteins. In the presence of PTX, activation of the ORL1 receptor resulted in the stimulation of type 2 adenylyl cyclase only in HEK 293 cells coexpressing the alpha subunit of Gz, G12, G14, or G16, but not in cells coexpressing G11, G13, or Gq. Coupling to both Gz and G16 was expected because close relatives of the ORL1 receptor, the opioid receptors, are known to couple productively to these G proteins. ORL1 receptor coupling to either G12 or G14 has not been demonstrated. As predicted by the type 2 adenylyl cyclase assays, activation of the ORL1 receptor resulted in the formation of inositol phosphates in COS-7 cells transiently cotransfected with Galpha14. The ORL1 receptor-mediated stimulation of phospholipase C was found to be Galpha14 dependent, agonist dose dependent, ligand selective, and PTX insensitive. We conclude that G14 can link the ORL1 receptor to regulation of phopholipase C.
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PMID:GalphaL1 (Galpha14) couples the opioid receptor-like1 receptor to stimulation of phospholipase C. 986 75

The early signaling mechanism of sphingosine 1-phosphate (S1P) on extracellular signal-regulated kinase (ERK) activation was investigated in C6 glioma cells. S1P activated the enzyme in association with a shift in the mobility on electrophoresis reflecting phosphorylation of both ERK1/ERK2 at as low as 10 nM. The lipid-induced ERK1/2 activation was partially inhibited by treatment of the cells with either phorbol 12-myristate 13-acetate (a long-term treatment to desensitize protein kinase C) or pertussis toxin (PTX) and was completely inhibited by a simultaneous treatment with both agents. Similarly, either calphostin C, an inhibitor of protein kinase C, or U73122, an inhibitor of phospholipase C, partially inhibited the S1Pinduced ERK1/2 activation in the nontreated cells with PTX and completely in the toxin-treated cells. On the other hand, the S1P-induced ERK activation was hardly affected by ethanol, which switched the product of phospholipase D from phosphatidic acid to metabolism-resistant phosphatidylethanol. S1P was able to activate ERK1/2 without a detectable increase in the intracellular content of the lipid, but sphingosine, a substrate of sphingosine kinase, which is an enzyme for S1P generation in the cells, hardly affected the ERK1/2 activation in spite of a marked elevation of intracellular S1P accumulation. This indicates that intracellular increase in S1P is not necessary for the S1P-induced ERK activation, and hence suggests the extracellular action mechanism of S1P. Supporting this idea, mRNAs of recently identified S1P specific receptors, Edg-1 and AGR16/H218, were expressed in C6 cells. Taken together, these results suggested that S1P acts on C6 cells extracellularly possibly through S1P receptors which are linked to at least two signaling pathways, i.e., the PTX-sensitive Gi/Go protein pathway and the toxin-insensitive Gq/G11-phospholipase C-PKC pathway, resulting in the activation of ERK.
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PMID:Possible involvement of cell surface receptors in sphingosine 1-phosphate-induced activation of extracellular signal-regulated kinase in C6 glioma cells. 988 6

The hypothalamic decapeptide gonadotrophin-releasing hormone (GnRH) binds to high affinity receptors on pituitary gonadotrophs. These receptors mediate the effects of GnRH on secretion and synthesis of gonadotrophins. The GnRH receptor is coupled to Gq/G11, which activates phospholipase C. This enzyme leads to the generation of several second messenger molecules. Among these, diacylglycerol (DG) and inositol 1,4,5-tris-phosphate (IP3) are critically important. DG leads to activation of protein kinase C and IP3 releases Ca2+ from intracellular pools. Both events result in secretion and synthesis of luteinizing hormone (LH) and follicle stimulating hormone (FSH). In addition, other components of the GnRH signal transduction pathway are involved in cellular responses to GnRH. GnRH receptors and their functions are regulated by GnRH itself or other hormones such as ovarian steroids. The prolonged exposure of pituitary gonadotrophs to GnRH leads to desensitization and consequently to suppressed LH and FSH secretion. This mechanism is employed for the clinical use of GnRH agonists. GnRH antagonists act by competitive binding to the pituitary GnRH receptors. Apart from the well-established pituitary actions of GnRH, receptors for the decapeptide have been demonstrated in a variety of extrapituitary tissues. Here we report on the ovarian actions of GnRH which are predominantly inhibitory in the rat ovary. In the human ovary the existence of GnRH receptors is controversial. Recent reports have demonstrated the mRNA for the GnRH receptor in the human ovary. However, to date there is no consensus on the ovarian actions of GnRH or its analogues.
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PMID:Pituitary and extrapituitary actions of gonadotrophin-releasing hormone and its analogues. 1057 34

The purpose of this study was to compare the efficiency of two different Gq protein-coupled receptors (AT1 receptor for angiotensin II and B2 receptor for bradykinin) to activate phospholipase C (PLC). When the receptors were expressed at a similar level of 0.5 pmol/mg of protein, inositol trisphosphate (IP) accumulation elicited by AT1 receptor was four times higher than that elicited by B2 receptor. Genistein and pertussis toxin did not modify AT1 receptor- or B2 receptor-induced IP accumulation. These results indicate that in COS-7 cells, the two receptors activate PLC beta through G proteins of the Gq family. AT1 or B2 receptors were co-expressed with the alpha subunit of either Gq or G11. Both alpha subunits potentiated to the same extent AT1 receptor-induced IP accumulation. alpha 11 was also as efficient as alpha q to potentiate B2 receptor-induced response. Interestingly, however, the potentiating effect of alpha q and alpha 11 was more important (by 5-fold) on AT1 receptor-mediated response than on B2 receptor-mediated response. These results demonstrate that the extent of activation of PLC beta by different Gq-coupled receptors depends on the level of expression of these receptors and on their coupling efficiency. These are important parameters that determine the relative contribution of specific hormones to different biological processes.
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PMID:The bradykinin B2 receptor couples less efficiently than the angiotensin AT1 receptor to the G protein Gq in transiently transfected COS-7 cells. 1063 60

1. The signalling pathway underlying histamine activation of non-selective cation channels was investigated in single equine tracheal myocytes. Application of histamine (100 microM) activated the transient calcium-activated chloride current (ICl(Ca)) and sustained, low amplitude non-selective cation current (ICat). The H1 receptor antagonist pyrilamine (10 microM) blocked activation of ICl(Ca) and ICat. Simultaneous application of histamine (100 microM) and caffeine (8 mM) during H1 receptor blockade activated ICl(Ca), but not ICat. Neither the H2 receptor antagonist cimetidine (20 microM) nor the H3 receptor antagonist thioperamide (20 microM) prevented activation of ICl(Ca) and ICat. 2. Intracellular dialysis of anti-Galphai/Galphao antibodies completely blocked activation of ICat by histamine, whereas ICl(Ca) was not affected. By contrast, anti-Galphaq/Galpha11 antibodies greatly inhibited ICl(Ca), but did not alter activation of ICat. 3. 1-Oleoyl-2-acetyl-sn-glycerol (OAG, 20-100 microM) did not induce any current or affect currents activated by histamine or methacholine (mACH). Simultaneous application of OAG and caffeine activated ICl(Ca), but not ICat, indicating that a rise in [Ca2+]i and stimulation of diacylglycerol-sensitive protein kinase C (PKC) is not sufficient to activate ICat. The phospholipase C inhibitor U73122 (2 microM) blocked histamine activation of ICl(Ca) and ICat, but simultaneous exposure of myocytes to histamine and caffeine restored both ICl(Ca) and ICat in the presence of U73122. 4. Histamine and mACH activated currents with equivalent I-V relationships. The currents activated by these agonists were not additive; following activation of ICat by mACH, histamine failed to induce an additional membrane current. Similarly, mACH did not induce an additional current after full activation of ICat by histamine. 5. We conclude that H1 histamine receptors activate ICat through coupling to Gi/Go proteins. Activation of ICat also requires intracellular calcium release, mediated by H1 receptors coupling to Gq/G11 proteins. This coupling is analogous to the activation of ICat by co-stimulation of M2 and M3 receptors.
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PMID:Signalling pathway for histamine activation of non-selective cation channels in equine tracheal myocytes. 1067 49

The heterotrimeric Gs protein-adenylyl cyclase (AC) cascade plays a pivotal role in controlling hormone secretion by endocrine glands. Consequently, deficiency of the alpha-subunit of Gs leads to endocrine hypofunction and hypoplasia in the affected cells whereas AC hyperactivity results from activating point mutations within the Gs-alpha gene. The latter, termed gsp oncogenes, are found primarily in a subset of growth hormone (GH)-secreting human pituitary tumours (somatotrophinomas) and are thus associated with excessive GH secretion. We present here evidence that another type of defect in human somatotrophinomas may be overexpression of the Gs-alpha subunit. Immunohistochemistry using an antibody against recombinant human Gs-alpha revealed high levels of expression in 25 of 39 somatotrophinomas but weak staining in normal human pituitary cells. These results were confirmed by Western blot analysis. Additionally, cholera toxin-mediated ADP-ribosylation in the presence of 32P-labelled NAD+ resulted in an autoradiographic signal intensity which correlated directly with magnitude of immunostaining and amount of antigen shown by Western blot analysis, providing evidence for overexpression of functionally active subunit. Finally, reconstitution assays were applied and directly demonstrated the increased activity of overexpressed Gs-alpha. In vivo, the effect of Gs-alpha on AC activity may be partially counterregulated by high levels of inhibitory G protein that also occurred in these tumours. In culture, GH-releasing hormone (GHRH) had markedly reduced effects on GH secretion by somatotrophinomas exhibiting Gs-alpha overexpression, whereas powerful stimulation occurred in weakly staining tumours. In contrast to these observations with Gs-alpha, immunostaining for the phospholipase C-coupled G11-alpha subunit was relatively weak in all somatotrophinomas studied and synthetic GH-releasing peptide, which acts via a specific G11-coupled receptor, led to powerful and consistent stimulation of GH secretion by different tumours. These results indicate that Gs-alpha overexpression is associated with dysfunction in hormone secretion by some somatotrophinomas.
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PMID:Overexpression of stimulatory G protein alpha-subunit is a hallmark of most human somatotrophic pituitary tumours and is associated with resistance to GH-releasing hormone. 1108 Nov 79

1. Madin-Darby canine kidney (MDCK) cells, a well- differentiated renal epithelial cell line derived from distal tubule/collecting duct, respond to extracellular nucleotides by altering ion flux and the production of arachidonic acid-derived products, in particular prostaglandin E2 (PGE2). Our work has defined the receptors and signalling events involved in such responses. 2. We have found evidence for expression of at least three P2Y receptor subtypes (P2Y1, P2Y2 and P2Y11) in MDCK-D1 cells, a subclone from parental MDCK. 3. These receptors appear to couple to increases in calcium and protein kinase C activity, probably via a Gq/G11-mediated activation of phospholipase C. 4. In addition, P2Y receptor activation can promote a prominent increase in cAMP. This includes both a P2Y2 receptor-mediated cyclo-oxygenase (COX)-dependent component and another COX-independent component mediated by other P2Y receptors. 5. We have documented that changing media in which cells are grown releases ATP and, in turn, activates P2Y receptors. Such release of ATP contributes in a major way to basal cAMP levels in these cells. 6. The data indicate that MDCK cells are a useful model to define the regulation of epithelial cells by extracellular nucleotides. Of particular note, spontaneous or stretch-induced release of ATP and subsequent activation of one or more P2Y receptors contributes to establishing the basal activity of signalling pathways.
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PMID:P2Y receptors of MDCK cells: epithelial cell regulation by extracellular nucleotides. 1133 12

The small GTPase RhoA is involved in the regulation of various cellular functions like the remodeling of the actin cytoskeleton and the induction of transcriptional activity. G-protein-coupled receptors (GPCRs), which are able to activate Gq/G11 and G12/G13 are major upstream regulators of RhoA activity, and G12/G13 have been shown to couple GPCRs to the activation of Rho by regulating the activity of a subfamily of RhoGEF proteins. However, the possible contribution of Gq/G11 to the regulation of RhoA activity via GPCRs is controversial. We have used a genetic approach to study the role of heterotrimeric G-proteins in the activation of RhoA via endogenous GPCRs. In pertussis toxin-treated Galpha12/Galpha13-deficient as well as in Galphaq/Galpha11-deficient mouse embryonic fibroblasts (MEFs), in which coupling of receptors is restricted to Gq/G11 and G12/G13, respectively, receptor activation results in Rho activation. Rho activation induced by receptor agonists via Gq/G11 occurs with lower potency than Rho activation via G12/G13. Activation of RhoA via Gq/G11 is not affected by the phospholipase-C blocker U73122 or the Ca2+-chelator BAPTA, but can be blocked by a dominant-negative mutant of the RhoGEF protein LARG. Our data clearly show that G12/G13 as well as Gq/G11 alone can couple GPCRs to the rapid activation of RhoA. Gq/G11-mediated RhoA activation occurs independently of phospholipase C-beta and appears to involve LARG.
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PMID:Receptor-dependent RhoA activation in G12/G13-deficient cells: genetic evidence for an involvement of Gq/G11. 1277 Nov 55


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