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)

The beta gamma complex of G-proteins regulates effectors independently of the G alpha subunits, such that upon activation G proteins give may signal downstream along one or both pathways. The G beta 5 isoform exhibits much less homology with other G beta isoforms (approximately 50%) and is preferentially expressed in brain. The G beta 5 isoform exhibits novel properties in its activation of effector pathways such as MAPK, phospholipase C-beta, and adenylyl cyclase type II when compared to G beta 1. Recently specific native complexes between G beta 5 and the regulator of G protein signaling (RGS) protein-7 (RGS7) and between G beta 5L (a splice variant with a 42 amino acid N-terminal extension) and RGS9 have been isolated from different retinal fractions. Such findings are not accounted for by current models as only the G alpha subunits and not G beta had been previously implicated in RGS protein function. These recent novel observations further reinforce the view of G beta 5 as a unique and highly specialized G protein subunit.
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PMID:New dimensions in G protein signalling: G beta 5 and the RGS proteins. 1081 78

We have investigated the effects of G protein-coupled receptor kinase (GRK) 3 and GRK6 on the phosphorylation and regulation of the M3 muscarinic acetylcholine receptor (mACh) endogenously expressed in SH-SY5Y cells. Overexpression of GRK3 or GRK6 enhanced M3 mACh receptor phosphorylation after high-concentration methacholine (100 microM, 1 min) addition. However, GRK6 was more potent, increasing receptor phosphorylation even after low (3 microM, 1 min) agonist stimulation. Compared with plasmid-transfected control cells expressing equivalent M3 mACh receptor number, GRK3- or GRK6-overexpressing cells exhibited a reduced phospholipase C activity reflected by a lower accumulation of total [3H]inositol phosphates and Ins(1,4,5)P3 mass. In addition, direct stimulation of G protein activation of phospholipase C (by AlF4(-)) was inhibited in GRK3- but not GRK6-overexpressing cells. Guanosine-5'-O-(3-[35S]thio)triphosphate binding and immunoprecipitation of Galpha(q/11) indicated that acute methacholine-stimulated receptor/Galpha(q/11) coupling was unaffected by GRK overexpression. In contrast, agonist pretreatment of cells for 3 min caused M3 mACh receptor uncoupling from Galpha(q/11), which was markedly enhanced by GRK6 overexpression, particularly at lower agonist pretreatment concentrations. However, the increased M3 mACh receptor phosphorylation seen in clones overexpressing GRK3 was not accompanied by increased receptor-Galpha(q/11) uncoupling. Overall, these data suggest that GRK3 and GRK6 use different pathways to desensitize the M3 mACh receptor. GRK6 seems to act as a classical GRK, inducing increased receptor phosphorylation accompanied by an uncoupling of receptor and Galpha(q/11). Conversely, GRK3 may cause desensitization independently of receptor phosphorylation, possibly via Gbetagamma binding and/or direct Galpha(q) binding via its regulator of G protein signaling domain to inhibit phospholipase C activity.
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PMID:G protein-coupled receptor kinases 3 and 6 use different pathways to desensitize the endogenous M3 muscarinic acetylcholine receptor in human SH-SY5Y cells. 1145 19

Recently we demonstrated that ginsenosides, the active ingredients of Panax ginseng, enhanced Ca(2+)-activated Cl(-) current in the Xenopus oocyte through a signal transduction mechanism involving the activation of pertussis toxin-insensitive G protein and phospholipase C (PLC). However, it has not yet been determined precisely which G protein subunit(s) and which PLC isoform(s) participate in the ginsenoside signaling. To provide answers to these questions, we investigated the changes in ginsenoside effect on the Cl(-) current after intraoocyte injections of the cRNAs coding various G protein subunits, a regulator of G protein signaling (RGS2), and G beta gamma-binding proteins. In addition, we examined which of mammalian PLC beta 1-3 antibodies injected into the oocyte inhibited the action of ginsenosides on the Cl(-) current. Injection of G alpha(q) or G alpha(11) cRNA increased the basal Cl(-) current recorded 48 h after, and it further prevented ginsenosides from enhancing the Cl(-) current, whereas G alpha(i2) and G alpha(oA) cRNA injection had no significant effect. The changes following G alpha(q) cRNA injection were prevented when G beta(1)gamma(2) and G alpha(q) subunits were co-expressed by simultaneous injection of the cRNAs coding these subunits. Injection of cRNA coding G alpha(q)Q209L, a constitutively active mutant that does not bind to G beta gamma, produced effects similar to those of G alpha(q) cRNA injection. The effects of G alpha(q)Q209L cRNA injection, however, were not prevented by co-injection of G beta(1)gamma(2) cRNA. Injection of the cRNA coding RGS2, which interacts most selectively with G alpha(q/11) among various identified RGS isoforms and stimulates the hydrolysis of GTP to GDP in active GTP-bound G alpha subunit, resulted in a severe attenuation of ginsenoside effect on the Cl(-) current. Finally, antibodies against PLC beta 3, but not -beta 1 and -beta 2, markedly attenuated the ginsenoside effect examined at 3-h postinjection. These results suggest that G alpha(q/11) coupled to mammalian PLC beta 3-like enzyme mediates ginsenoside effect on Ca(2+)-activated Cl(-) current in the Xenopus oocyte.
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PMID:G alpha(q/11) coupled to mammalian phospholipase C beta 3-like enzyme mediates the ginsenoside effect on Ca(2+)-activated Cl(-) current in the Xenopus oocyte. 1167 55

G protein-coupled receptors (GPCRs) transduce cellular signals from hormones, neurotransmitters, light, and odorants by activating heterotrimeric guanine nucleotide-binding (G) proteins. For many GPCRs, short term regulation is initiated by agonist-dependent phosphorylation by GPCR kinases (GRKs), such as GRK2, resulting in G protein/receptor uncoupling. GRK2 also regulates signaling by binding G alpha(q/ll) and inhibiting G alpha(q) stimulation of the effector phospholipase C beta. The binding site for G alpha(q/ll) resides within the amino-terminal domain of GRK2, which is homologous to the regulator of G protein signaling (RGS) family of proteins. To map the Galpha(q/ll) binding site on GRK2, we carried out site-directed mutagenesis of the RGS homology (RH) domain and identified eight residues, which when mutated, alter binding to G alpha(q/ll). These mutations do not alter the ability of full-length GRK2 to phosphorylate rhodopsin, an activity that also requires the amino-terminal domain. Mutations causing G alpha(q/ll) binding defects impair recruitment to the plasma membrane by activated G alpha(q) and regulation of G alpha(q)-stimulated phospholipase C beta activity when introduced into full-length GRK2. Two different protein interaction sites have previously been identified on RH domains. The G alpha binding sites on RGS4 and RGS9, called the "A" site, is localized to the loops between helices alpha 3 and alpha 4, alpha 5 and alpha 6, and alpha 7 and alpha 8. The adenomatous polyposis coli (APC) binding site of axin involves residues on alpha helices 3, 4, and 5 (the "B" site) of its RH domain. We demonstrate that the G alpha(q/ll) binding site on the GRK2 RH domain is distinct from the "A" and "B" sites and maps primarily to the COOH terminus of its alpha 5 helix. We suggest that this novel protein interaction site on an RH domain be designated the "C" site.
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PMID:G protein-coupled receptor Kinase 2/G alpha q/11 interaction. A novel surface on a regulator of G protein signaling homology domain for binding G alpha subunits. 1242 30

The PTH/PTHrP receptor stimulates both adenylate cyclase- and phospholipase C-dependent signaling pathways via different G proteins. The biological actions of PTH on bone are modified by steroid hormones. PTH induces expression of regulator of G protein signaling (RGS)-2, a putative preferential inhibitor of G(q)-mediated phospholipase C activation. We investigated whether steroid hormones interfere with PTH signaling by modulating PTH-induced RGS-2 expression in osteoblast-like UMR 106-01 cells. PTH (1-34) rapidly and transiently induced expression of RGS-2 mRNA and protein via the cAMP/protein kinase A pathway within 30 min, with maximal protein abundance after 2 h. PTH-induced RGS-2 preferentially bound to Galpha(q), compared with Galpha(s) protein. 1,25-(OH)(2)D(3) pretreatment enhanced PTH-induced RGS-2 mRNA and protein accumulation, whereas dexamethasone preincubation had an attenuating effect. These effects were due to modulation of the RGS-2 gene transcription rate, which increased by 35% with 1,25-(OH)(2)D(3) and decreased by 63% with dexamethasone pretreatment. RGS-2 mRNA half-life was not affected by either steroid. The transcriptional effects of dexamethasone and 1,25-(OH)(2)D(3) were independent of PTH/PTHrP receptor activation and were not explained by effects on cAMP accumulation, cAMP response element-binding protein expression or phosphorylation, or the abundance of the osteoblast-specific transcription factor core-binding factor alpha (CBFa1/Runx2), a known activator of RGS-2 expression. In conclusion, glucocorticoids and 1,25-(OH)(2)D(3) inversely modulate PTH-induced RGS-2 gene transcription. Regulation of RGS-2 may constitute a novel mechanism by which steroids modulate signaling via the PTH/PTHrP receptor and other G protein-coupled receptors in bone.
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PMID:Vitamin D and dexamethasone inversely regulate parathyroid hormone-induced regulator of G protein signaling-2 expression in osteoblast-like cells. 1274 12

We have shown previously that activation of endogenously expressed, Galphaq/11-coupled P2Y2 nucleotide receptors with UTP reveals an intracellular Ca2+ response to activation of recombinant, Galphai-coupled CXC chemokine receptor 2 (CXCR2) in human embryonic kidney cells. Here, we characterize further this cross talk and demonstrate that phospholipase C (PLC) and inositol 1,4,5-trisphosphate [Ins(1,4,5)P3]-dependent Ca2+ release underlies this potentiation. The putative Ins(1,4,5)P3 receptor antagonist 2-aminoethoxydiphenyl borane reduced the response to CXCR2 activation by interleukin-8, as did sustained inhibition of phosphatidylinositol 4-kinase with wortmannin, suggesting the involvement of phosphoinositides in the potentiation. Against a Li+ block of inositol monophosphatase activity, costimulation of P2Y2 nucleotide receptors and CXCR2 caused phosphoinositide accumulation that was significantly greater than that after activation of P2Y2 nucleotide receptors or CXCR2 alone, and was more than additive. Thus, PLC activity, as well as Ca2+ release, was enhanced. In these cells, agonist-mediated Ca2+ release was incremental in nature, suggesting that a potentiation of Ins(1,4,5)P3 generation in the presence of coactivation of P2Y2 nucleotide receptors and CXCR2 would be sufficient for additional Ca2+ release. Potentiated Ca2+ signaling by CXCR2 was markedly attenuated by expression of either regulator of G protein signaling 2 or the Gbetagamma-scavenger Galphat1 (transducin alpha subunit), indicating the involvement of Galphaq and Gbetagamma subunits, respectively.
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PMID:Cross talk between P2Y2 nucleotide receptors and CXC chemokine receptor 2 resulting in enhanced Ca2+ signaling involves enhancement of phospholipase C activity and is enabled by incremental Ca2+ release in human embryonic kidney cells. 1297 84

This study examined the time course and possible mechanisms of agonist-induced desensitization of 5-hydroxytryptamine serotonin 2A receptors in the rat frontal cortex and hypothalamic paraventricular nucleus after 1, 4, and 7 days of treatment with (-)-1-(2,5-dimethoxy-4-iodophenyl)2-aminopropane HCl [(-)-DOI] (1 mg/kg i.p.), a selective 5-HT(2A/2C) receptor agonist. In the frontal cortex, 5-HT-mediated phospholipase C (PLC) enzyme activity decreased by 24 to 30% after 4 to 7 days of (-)-DOI treatment without any significant changes in the guanosine 5'-3-O-(thio)triphosphate-mediated PLC enzyme activity. Additionally, treatment with (-)-DOI did not significantly change the levels of G(alpha11), regulator of G protein signaling (RGS)4, or RGS7 proteins in the frontal cortex, whereas G(alphaq) protein levels in the frontal cortex decreased (47%) only after 7 daily (-)-DOI injections. The functional status of 5-HT(2A) receptors in the hypothalamic paraventricular nucleus was examined using 5-HT(2A) receptor-mediated increases in plasma hormone levels. Plasma adrenocorticotrophic hormone (ACTH) and oxytocin measurements showed that 5-HT(2A) receptor desensitization began after only 1 day of (-)-DOI treatment, and the desensitization continued to increase after 4 and 7 days of treatment (ACTH response decreased 64.2-67.7%; oxytocin response decreased 82.3-90.1%). There were no significant alterations in levels of G(alphaq) or G(alpha11) lamic paraventricular proteins in the hypothanucleus. In conclusion, these results suggest that chronically administered (-)-DOI induces desensitization of 5-HT(2A) receptors in vivo, via a reduction in the ability of 5-HT(2A) receptors to activate G proteins without consistently altering levels of G(alpha) proteins or RGS proteins.
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PMID:Agonist-induced serotonin 2A receptor desensitization in the rat frontal cortex and hypothalamus. 1497 28

Although muscarinic acetylcholine receptors (mAChRs) regulate proliferation in many cell types, the signaling pathways involved are unclear. The participation of the small GTPases Rac1 and RhoA in M(3) mAChR-mediated inhibition of proliferation was investigated by activating M(3) mAChRs stably transfected in Chinese hamster ovary cells stably coexpressing hemagglutinin (HA)-tagged wild-type or mutant Rac1 or RhoA proteins. Activation of M(3) mAChRs activates both Rac1 and RhoA and inhibits cell proliferation in all cell lines tested. mAChR-mediated inhibition of proliferation is diminished in cells expressing dominant-negative HA-Rac1(Asn17) (m3DNRac) but is enhanced in cells expressing HA-Rac1 (m3WTRac) or constitutively active HA-Rac(Val12) (m3CARac). The activation of mAChRs in m3WTRac and m3CARac cells also induces apoptosis. Expression of wild-type or mutant RhoA proteins does not alter mAChR-mediated inhibition of proliferation. mAChR-induced inhibition of proliferation is abrogated in all cell lines when Galpha(q/11) signaling is terminated by transient expression of the COOH-terminal fragment of phospholipase C (PLC-beta1ct), the NH(2)-terminal fragment of G protein-coupled receptor kinase, or the regulator of G protein signaling 2. Pretreatment of all cells expressing wild-type or mutant Rac1 proteins with edelfosine, a phosphatidylinositol-specific PLC inhibitor, or Go 6976, which inhibits conventional protein kinase C (PKC) isoforms, diminishes the M(3) mAChR's ability to inhibit proliferation. Our results identify Galpha(q/11), PLC, and PKC as participants in the M(3) mAChR-mediated inhibition of cell proliferation. These findings indicate that in the context of high Rac1 activity, but not RhoA activity, M(3) mAChR-mediated activation of these participants triggers cell death.
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PMID:Elevated Rac1 activity changes the M3 muscarinic acetylcholine receptor-mediated inhibition of proliferation to induction of cell death. 1510 36

The dopamine D1 receptors (D1R), expressed in renal proximal tubules, participate in the regulation of sodium transport. A defect in the coupling of the D1R to its G protein/effector complex in renal tubules has been reported in various conditions associated with oxidative stress. Because G protein-coupled receptor kinases (GRKs) are known to play an important role in D1R desensitization, we tested the hypothesis that increased oxidative stress in obese Zucker rats may cause GRK2 upregulation and, subsequently, D1R dysfunction. Lean and obese rats were given normal diet or diet supplemented with antioxidant lipoic acid for 2 wk. Compared with lean rats, obese rats exhibited oxidative stress, D1R were uncoupled from G(q/11)alpha at basal level, and SKF-38393 failed to elicit D1R-G protein coupling, stimulate phospholipase C (PLC), and inhibit Na-K-ATPase activity. These animals showed increased basal protein kinase C (PKC) activity and membranous translocation of GRK2 and increased GKR2-G(q/11)alpha interaction and D1R serine phosphorylation. Enzymatic dephosphorylation of D1R restored SKF-38393-induced adenylyl cyclase stimulation but not PLC activation. Treatment of obese rats with lipoic acid restored D1R-G protein coupling and SKF-38393-induced PLC stimulation and Na-K-ATPase inhibition. Lipoic acid treatment also normalized PKC activity, GRK2 sequestration, and GKR2-G(q/11)alpha interaction. In conclusion, these data show that oxidative stress increases PKC activity causing GRK2 membranous translocation. GRK2 interacts with G(q/11)alpha and acts, at least in part, as a regulator of G protein signaling leading to the D1R-G(q/11)alpha uncoupling, causing inability of SKF-38393 to stimulate PLC and inhibit Na/K-ATPase. Lipoic acid, while reducing oxidative stress, normalized PKC activity and restored D1R-G(q/11)alpha-PLC signaling and the ability of SKF-38393 to inhibit Na-K-ATPase activity.
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PMID:Oxidative stress reduces renal dopamine D1 receptor-Gq/11alpha G protein-phospholipase C signaling involving G protein-coupled receptor kinase 2. 1745 51

Amphetamine (AMPH) and cocaine are indirect dopamine agonists that activate multiple signaling cascades in the striatum. Each cascade has a different subcellular location and duration of action that depend on the strength of the drug stimulus. In addition to activating D1 dopamine-Gs-coupled-protein kinase A signaling, acute psychostimulant administration activates extracellular-regulated kinase transiently in striatal cells; conversely, inhibition of extracellular-regulated kinase phosphorylation decreases the ability of psychostimulants to elevate locomotor behavior and opioid peptide gene expression. Moreover, a drug challenge in rats with a drug history augments and prolongs striatal extracellular-regulated kinase phosphorylation, possibly contributing to behavioral sensitization. In contrast, AMPH activates phosphoinositide-3 kinase substrates, like protein kinase B/Akt, only in the nuclei of striatal cells but this transient increase induced by AMPH is followed by a delayed decrease in protein kinase B/Akt phosphorylation whether or not the rats have a drug history, suggesting that the phosphoinositide-3 kinase pathway is not essential for AMPH-induced behavioral sensitization. Chronic AMPH or cocaine also alters the regulation of inhibitory G protein-coupled receptors in the striatum, as evident by a prolonged decrease in the level of regulator of G protein signaling 4 after non-contingent or contingent (self-administered) drug exposure. This decrease is exacerbated in behaviorally sensitized rats and reversed by re-exposure to a cocaine-paired environment. A decrease in regulator of G protein signaling 4 levels may weaken its interactions with metabotropic glutamate receptor 5, Galphaq, and phospholipase C beta that may enhance drug-induced signaling. Alteration of these protein-protein interactions suggests that the striatum responds to psychostimulants with a complex molecular repertoire that both modulates psychomotor effects and leads to long-term neuroadaptations.
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PMID:Regulation of psychostimulant-induced signaling and gene expression in the striatum. 1822 78


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