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)

Engagement of the T cell receptor (TCR).CD3 complex results in the induction of multiple intracellular events, with protein tyrosine kinases playing a pivotal role in their initiation. Biochemical studies also exist suggesting the involvement of heterotrimeric GTP-binding proteins (G proteins); however, the functional consequence of this participation in TCR.CD3-mediated signaling is unresolved. Here, we report TCR.CD3-mediated guanine nucleotide exchange among the 42-kDa G protein alpha subunits of the G alpha q/11 family, their physical association with CD3 epsilon, and the G alpha 11-dependent activation of phospholipase C beta. Protein tyrosine kinase inhibitors, however, abrogate TCR.CD3-mediated G protein activation. Quite interesting is the observation that cells transfected with a function-deficient mutant of G alpha 11 display diminished tyrosine phosphorylation of TCR.CD3 zeta and epsilon chains, as well as ZAP-70, upon anti-CD3 antibody triggering. These data indicate the involvement of the G alpha q/11 family in TCR.CD3 signaling at a step proximal to the receptor and suggest a reciprocal regulation between tyrosine kinases and G proteins in T cells.
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PMID:Interaction between G proteins and tyrosine kinases upon T cell receptor.CD3-mediated signaling. 853 May

The connection between agonist-induced desensitization and down-regulation of 5-hydroxytryptamine2A (5-HT2A) receptors was examined in a clonal cell line that stably expresses the 5-HT2A receptor. Brief (2-hr) and prolonged (24-hr) exposure to the agonist quipazine or the agonist 4-iodo-(2,5-dimethoxy)- phenylisopropylamine (DOI) diminished 5-HT2A receptor-mediated phosphoinositide hydrolysis; no change in 5-HT2A receptor number or affinity was measured after 24 hr of exposure to DOI or quipazine. Immunohistochemical studies demonstrated that a 24-hr exposure to DOI did not alter surface 5-HT2A receptor immunoreactivity. Western blot analysis with G alpha q- and G alpha 11-selective antibodies indicate that a 24-hr agonist exposure did not alter the levels of phospholipase C-dependent G proteins. These results suggest that desensitization after prolonged DOI exposure can occur via a process independent of the levels of phospholipase C-coupled G proteins. Studies with a mutant 5-HT2A receptor (F340L) indicated that binding per se is not sufficient for desensitization. Down-regulation of the protein kinase C isozymes alpha and epsilon by overnight exposure to phorbol-12,13-dibutyrate attenuated the intermediate phase (i.e., after 2-6 hr of agonist exposure) of DOI- and quipazine-induced desensitization. These results indicate that the intermediate phase of DOI-induced desensitization is mediated by the alpha- and/or epsilon-protein kinase C isozymes but that neither is involved in the later phase (i.e., after 24 hr of agonist exposure) of desensitization.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:5-Hydroxytryptamine2A (5-HT2A) receptor desensitization can occur without down-regulation. 853 Nov 39

Persistent stimulation of specific protein kinase pathways has been proposed as a key feature of receptor tyrosine kinases and intracellular oncoproteins that signal neuronal differentiation of rat pheochromocytoma (PC12) cells. Among the protein serine/threonine kinases identified to date, the p42/44 mitogen-activated protein (MAP) kinases have been highlighted for their potential role in signalling PC12 cell differentiation. We report here that retrovirus-mediated expression of GTPase-deficient, constitutively active forms of the heterotrimeric Gq family members, G alpha qQ209L and G alpha 16Q212L, in PC12 cells induces neuronal differentiation as indicated by neurite outgrowth and the increased expression of voltage-dependent sodium channels. Differentiation was not observed after cellular expression of GTPase-deficient forms of alpha i2 or alpha 0, indicating selectivity for the Gq family of G proteins. As predicted, overexpression of alpha qQ209L and alpha 16Q212L constitutively elevated basal phospholipase C activity approximately 10-fold in PC12 cells. Significantly, little or no p42/44 MAP kinase activity was detected in PC12 cells differentiated with alpha 16Q212L or alpha qQ209L, although these proteins were strongly activated following expression of constitutively active cRaf-1. Rather, a persistent threefold activation of the cJun NH2-terminal kinases (JNKs) was observed in PC12 cells expressing alpha qQ209L and alpha 16Q212L. This level of JNK activation was similar to that achieved with nerve growth factor, a strong inducer of PC12 cell differentiation. Supportive of a role for JNK activation in PC12 cell differentiation, retrovirus-mediated overexpression of cJun, a JNK target, in PC12 cells induced neurite outgrowth. The results define a p42/44 MAP kinase-independent mechanism for differentiation of PC12 cells and suggest that persistent activation of the JNK members of the proline-directed protein kinase family by GTPase-deficient G alpha q and G alpha 16 subunits is sufficient to induce differentiation of PC12 cells.
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PMID:GTPase-deficient G alpha 16 and G alpha q induce PC12 cell differentiation and persistent activation of cJun NH2-terminal kinases. 855 93

We have previously shown that the high-affinity binding of substance P (SP) to its receptor is dependent on an interaction with a PTX-insensitive G protein. This G protein couples SP receptor activation to stimulation of its effector, phospholipase C. In this study, we combined photoaffinity labeling, chemical cross-linking techniques, and immunological characterization using sequence-specific antibody probes to identify G proteins that couple to the SP receptor. First we covalently labeled the SP receptor present on rat submaxillary gland membranes with a radioiodinated photoreactive derivative of SP, p-benzoyl-L-phenylalanine(8)-substance P (125I-[Bpa8]SP). Photoincorporation of this SP derivative was susceptible to guanine nucleotide inhibition, indicating that the receptor was coupled to its G protein during labeling. We then used a chemical cross-linking agent to covalently link the photoaffinity labeled SP receptor and its associated G protein. Cross-linking generated a 96 kDa product, formation of which was prevented by the addition of a guanine nucleotide, but not an adenine nucleotide, following photolabeling, but prior to cross-linking. Furthermore, the 96 kDa cross-linked complex was absent in membranes which had been depleted of G proteins by treatment with alkaline buffer prior to addition of the cross-linking agent. Reductive cleavage of the cross-link in the isolated 96 kDa complex yields two products: the 53 kDa SP receptor and a 42 kDa protein identified by immunoblot analysis as either G alpha q or G alpha 11. Antisera against a common sequence within G alpha s, G alpha i, and G alpha o showed no immunoreactivity to the complex or its cleavage products. These results provide the first direct evidence of specific interaction between photoaffinity labeled SP receptor and the alpha subunits of Gq and G11, members of a family of G proteins known to be associated with pertussis toxin-insensitive phospholipase C activation.
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PMID:Chemical cross-linking of the substance P (NK-1) receptor to the alpha subunits of the G proteins Gq and G11. 860 28

Parafollicular (PF) cells secrete 5-hydroxytryptamine in response to increased extracellular Ca2+ ([Ca2+]e). This stimulus causes Cl- channels in PF secretory vesicles to open, leading to vesicle acidification. PF cells express a plasmalemmal heptahelical receptor (CaR) that binds Ca2+, Gd3+, and Ba2+. We now report that the CaR mediates vesicle acidification. Ca2+, Gd3+, and Ba2+ induced vesicle acidification, which was independent of channel-mediated Ca2+ entry. Agonist-induced vesicle acidification was blocked by pertussis toxin, inhibitors of phosphatidylinositol-phospholipase C, calmodulin, NO synthase, guanylyl cyclase, or protein kinase G. PF cells contained NO synthase immunoreactivity, and vesicles were acidified by NO donors and dibutyryl cGMP. [Ca2+]e, and Gd3+ mobilized thapsigargin-sensitive internal Ca2+ stores. [35S]G alpha i and [35S]G alpha q were immunoprecipitated from PF membranes incubated with agonists in the presence of [35S]adenosine 5'-O-(thiotriphosphate). Labeling of G alpha i but not G alpha q was antagonized by pertussis toxin. Vesicles acidified in response to activation of protein kinase C; however, protein kinase C inhibition blocked calcium channel- but not CaR-dependent acidification. We propose the following signal transduction pathway: CaR -> Gi -> phosphatidylinositol-phospholipase C -> inositol 1,4,5-trisphosphate -> [Ca2+]i -> Ca2+/calmodulin -> NO synthase -> NO -> guanylyl cyclase -> cGMP -> protein kinase G -> opens vesicular Cl- channel.
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PMID:Acidification of serotonin-containing secretory vesicles induced by a plasma membrane calcium receptor. 862 45

The heterotrimeric G proteins mediate a variety of cellular processes by coupling transmembrane receptors to different effector molecules, including adenylyl cyclases and inositol-phospholipid-specific phospholipase C (PLC)1-3. Activation of adenylyl cyclases results in the production of cyclic AMP and activation of cAMP-dependent protein kinase (PKA). Phospholipase C catalyses the hydrolysis of phosphatidylinositol-4,5-bisphosphate (PtdInsP2) to generate diacylglycerol and inositol-1,4,5-triphosphate (InsP2), leading to the activation of protein kinase C (PKC) and the mobilization of intracellular calcium. The various PLC isoforms appear to be activated by different receptors, and in some cases by different G-protein components. There are four well-characterized forms of PLC-beta and all of them are activated to various extents by the G alpha q family of G proteins. Specific activation of PLC isoforms beta 2 and beta 3 by G-protein beta gamma subunits has also been reported. Although it has been suggested that PLC activity might be modulated by the adenylyl cyclase pathway, no clear link has been established between the two pathways. Here we report that cAMP-dependent protein kinase specifically inhibits G beta gamma-activated PLC-beta 2 activity but not that of the G alpha-activated PLC isoforms, and that the effect of PKA is not mimicked by PKC isozymes. Furthermore, we show that PKA directly phosphorylates serine residues of the PLC-beta 2 protein both in vivo and in vitro. Our results provide an insight into the specificity and nature of the crosstalk between the two G-protein-coupled signal transduction pathways.
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PMID:Regulation by cAMP-dependent protein kinease of a G-protein-mediated phospholipase C. 865 10

The second messenger inositol-1,4,5-trisphosphate (InsP3) comes from two major pathways, one is initiated by a family of G protein-linked receptors and the other by receptors linked by tyrosine kinases. These separate receptors activate phospholipase C to hydrolyse phosphatidylinositol-4,5-bisphosphate to give both diacylglycerol and InsP3. The latter then mobilizes stored calcium and promotes an influx of external calcium. The alpha subunit of a newly discovered G protein (Gq) has recently been shown to stimulate the activity of PLC-beta 1. The alpha subunits of the Gq class of G proteins includes G alpha q, G alpha 11, G alpha 14, G alpha 15 and G alpha 16. The important pathologic changes in hypertension are arteriolar spasm and wall thickening. Many vasoactive substances can induce contractile response and proliferation of vascular smooth muscle cells and increase InsP3 level. However, the hypertension does not cause any persistent change in Gq.
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PMID:[G proteins-phosphoinositide pathways in hypertension]. 873 80

The PTH/PTH-related peptide (PTHrP) receptor and the calcitonin receptor mediate the action of their physiological ligands by activating two different effectors, adenylyl cyclase and phospholipase C. Whereas regulation of adenylyl cyclase via both receptors is thought to involve the G protein G(s), it is not known whether activation of phospholipase C results from coupling of the receptors to G(q) family members or whether beta gamma-subunit released from receptor-activated G(s) lead to phospholipase C activation. To elucidate the mechanism of this type of dual signaling, we reconstituted the signal transduction of the PTH/PTHrP and the calcitonin receptor in COS-7 and HEK293 cells. In COS-7 cells expressing the receptor alone, addition of the respective ligands resulted in the accumulation of cAMP and inositol phosphates. When cells were cotransfected with the cDNAs of receptor and different alpha-subunits of the Gq family (G alpha q, G alpha 11, G alpha 14, G alpha 15, and G alpha 16, a severalfold increase in the ligand-dependent inositol phosphate production could be observed, indicating that the receptors functionally interacted with all alpha-subunits of the G alpha q family. Additionally, whereas PTH treatment of HEK293 cells coexpressing both the PTH/PTHrP receptor and G alpha q increased both second messengers, the same treatment in cells expressing the PTH/PTHrP receptor alone increased only cAMP. Under all conditions tested, activation of phospholipase C via the PTH/PTHrP and calcitonin receptor required higher ligand concentrations than receptor-mediated adenylyl cyclase activation. Our data strongly support the idea that dual signaling of the PTH/PTHrP and calcitonin receptors is due to the a activation of different G proteins belonging to the G(s) and G(q) families.
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PMID:G alpha q family members couple parathyroid hormone (PTH)/PTH-related peptide and calcitonin receptors to phospholipase C in COS-7 cells. 873 87

The action of angiotensin II (ANG II) was studied in single myocytes from rat portal vein, in which the cytoplasmic Ca++ concentration was estimated by emission from fluorescent dyes and the Ca++ channel current was measured with the whole-cell mode of the patch-clamp technique. ANG II stimulated Ca++ channel current through L-type Ca++ channels and initiated a slow and small increase in the cytoplasmic Ca++ concentration in cells in which intracellular Ca++ stores had been depleted by pretreatment with ryanodine and caffeine. Both Ca++ channel current stimulation and Ca++ responses were selectively inhibited by losartan, indicating activation of angiotensin AT1 receptors. Activation of Ca++ channels by ANG II was insensitive to treatment with pertussis toxin and cholera toxin. Intracellular applications of anti-G alpha q/alpha 11 and anti-phosphatidylinositol antibodies had no effect on the ANG II-induced stimulation of Ca++ channel current, indicating that phosphatidylinositol-specific phospholipase C was not involved in this signaling pathway. Down-regulation of protein kinase C and application of an inhibitor of protein kinase C blocked the ANG II-induced effects. Tricyclodecan-9-yl xanthogenate (an inhibitor of non-phosphatidylinositol-specific phospholipases C and phospholipases D) but not propranolol (an inhibitor of phospholipase D-derived diacylglycerol formation) suppressed the ANG II-induced effects. These data suggest that phosphatidylcholine-specific phospholipase C is involved in the ANG II signaling pathway leading to stimulation of L-type Ca++ channels by protein kinase C.
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PMID:Angiotensin II-mediated activation of L-type calcium channels involves phosphatidylinositol hydrolysis-independent activation of protein kinase C in rat portal vein myocytes. 876 93

Bombesin stimulation of inositol 1,4,5-trisphosphate (Ins P3) formation in rat sonicated pancreatic acinar cells was inhibited by an antibody directed against the pertussis toxin (PTX)-sensitive GTP-binding G alpha i3 protein but not by an anti-G alpha q-11 antibody. After solubilization and gel filtration, [125I-Tyr4]bombesin binding sites were recovered in a peak of protein of 67 approximately 90 kDa with a maximal enrichment corresponding to a molecular mass of 83-kDa. Results obtained from the non-hydrolysable GTP analog guanosine-5'-[gamma-thio]triphosphate (GTP gamma S) binding, PTX-stimulated ADP-ribosylation and immunoblotting showed that the 83-kDa fraction contained the G alpha i3 protein but not the G alpha q-11 protein. Furthermore, GTP gamma S increased the bombesin binding dissociation constant (KD) from 0.32 to 0.60 nM, while the anti-G alpha i3 antibody decreased the maximal binding capacity (Bmax) from 50 to 25 fmol/mg protein without affecting the KD. Mixing solubilized bombesin binding sites with a phospholipase C (PLC) preparation from rat pancreas reconstituted a bombesin-stimulated PLC activity which was markedly inhibited by the anti-G alpha i3 antibody but unaffected by the anti-G alpha q-11 antibody. In addition, this stimulation was inhibited by an anti-PLC beta 1 antibody. This result supports the involvement of the PLC beta 1 isoform in bombesin receptor activation.
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PMID:Bombesin activation of phospholipase C beta 1 in rat acinar pancreatic cells involves the pertussis toxin-sensitive G alpha i3 protein. 879 79


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