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 acute contractile function of the heart is controlled by the effects of released nonepinephrine (NE) on cardiac adrenergic receptors. NE can also act in a more chronic fashion to induce cardiomyocyte growth, characterized by cell enlargement (hypertrophy), increased protein synthesis, alterations in gene expression and addition of sarcomeres. These responses enhance cardiomyocyte contractile function and thus allow the heart to compensate for increased stress. The hypertrophic effects of NE are mediated through Gq-coupled alpha(1)-adrenergic receptors and are mimicked by the actions of other neurohormones (endothelin, prostaglandin F(2alpha) angiotensin II) that also act on Gq-coupled receptors. Activation of phospholipase C by Gq is necessary for these responses, and protein kinase C and MAP kinases have also been implicated. Gq stimulated cardiac hypertrophy is also evident in transgenic mouse models. In contrast, stimulation of G(s)-coupled beta-adrenergic receptors or G(i)-coupled receptors do not directly effect cardiomyocyte hypertrophy. Apoptosis is also induced by G-protein-coupled receptor stimulation in cardiomyocytes. Sustained or excessive activation of either Gq- or Gs-signaling pathways results in apoptotic loss of cardiomyocytes both in vitro and in vivo. Apoptosis is associated with decreased ventricular function in the failing heart. Cardiomyocytes provide an ideal model system for understanding the basis for G-protein mediated hypertrophy and apoptosis, and the mechanisms responsible for the transition from compensatory to deleterious levels of signaling. This information may prove critical for designing interventions that prevent the pathophysiological consequences of heart failure.
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PMID:G-proteins in growth and apoptosis: lessons from the heart. 1131 10

Phagocyte migration and activation at sites of inflammation is mediated through chemoattractant receptors that are coupled to G-proteins. Early studies from our laboratory demonstrated G-protein-mediated phospholipase C activation by chemoattractants. Recently, this laboratory developed cellular and animal models to allow biochemical, cell biological and molecular genetic approaches to be used in determining the mechanisms of chemoattractant receptor function, regulation, and cross regulation. These studies provided evidence that chemoattractant receptors activate distinct pathways for chemotaxis and exocytosis and cross-regulate each other's function at multiple levels. A major site of regulation is through phosphorylation of receptors by G-protein-coupled receptor kinases and by protein kinase C. In addition, the activation of phospholipase C by chemoattractants is also regulated at additional sites distal to receptor phosphorylation. These may include modulation of G-protein activation by regulators of G-protein signaling (RGS) and modification of phospholipase C. Phosphorylation of phospholipase Cbeta3 by both protein kinase A and protein kinase C has been demonstrated. The function and regulation of chemoattractant receptors are also being examined in mouse models. In these studies, mice deficient in leukotriene B4 receptors have been generated by targeted gene disruption. These mice displayed reduced neutrophil accumulation in certain inflammation models and sex-related differences in platelet-activating-factor induced anaphylaxis.
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PMID:Function and regulation of chemoattractant receptors. 1133 62

The parathyroid hormone 1 receptor (PTH1R) is a class II G-protein-coupled receptor. PTH1R agonists include both PTH, a hormone that regulates blood calcium and phosphate, and PTH-related protein (PTHrP), a paracrine/autocrine factor that is essential for development, particularly of the skeleton. Adenylyl cyclase activation is thought to be responsible for most cellular responses to PTH and PTHrP, although many actions appear to be independent of adenylyl cyclase. Here we show that the PTH1R binds to Na(+)/H(+) exchanger regulatory factors (NHERF) 1 and 2 through a PDZ-domain interaction in vitro and in PTH target cells. NHERF2 simultaneously binds phospholipase C beta 1 and an atypical, carboxyl-terminal PDZ consensus motif, ETVM, of the PTH1R through PDZ1 and PDZ2, respectively. PTH treatment of cells that express the NHERF2 PTH1R complex markedly activates phospholipase C beta and inhibits adenylyl cyclase through stimulation of inhibitory G proteins (G(i/o) proteins). NHERF-mediated assembly of PTH1R and phospholipase C beta is a unique mechanism to regulate PTH signalling in cells and membranes of polarized cells that express NHERF, which may account for many tissue- and cell-specific actions of PTH/PTHrP and may also be relevant to signalling by many G-protein-coupled receptors.
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PMID:Na(+)/H(+ ) exchanger regulatory factor 2 directs parathyroid hormone 1 receptor signalling. 1207 54

We have recently demonstrated that the beta subunit of the heterotrimeric G-proteins is endogenously mono-ADP-ribosylated in intact cells. The modified betagamma heterodimer loses its ability to inhibit calmodulin-stimulated type 1 adenylate cyclase and, remarkably, is de-ADP-ribosylated by a cytosolic hydrolase that completes an ADP-/de-ADP-ribosylation cycle of potential physiological relevance. In the present study, we show that this ADP-ribosylation might indeed be a general mechanism for termination of betagamma signalling, since the ADP-ribosylated betagamma subunit is also unable to activate both phosphoinositide 3-kinase-gamma and phospholipase C-beta2. Moreover, we show that beta subunit ADP-ribosylation is induced by G-protein-coupled receptor activation, since hormone stimulation of Chinese-hamster ovary plasma membranes leads to increases in beta subunit labelling. This occurs when betagamma is in its active heterodimeric conformation, since full inhibition of this modification can be achieved by binding of GDP-alphai3 to the betagamma heterodimer. Taken together, these findings delineate a pathway that arises from the activation of a G-protein-coupled receptor and leads to the inhibition of betagamma activity through its reversible mono-ADP-ribosylation.
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PMID:Endogenous mono-ADP-ribosylation of the free Gbetagamma prevents stimulation of phosphoinositide 3-kinase-gamma and phospholipase C-beta2 and is activated by G-protein-coupled receptors. 1214 26

G-protein-coupled receptors receive many different signals to activate different functions such as cellgrowth, proliferation, and migration. KiSS1 is a metastasis suppressor gene that has been shown to inhibit metastasis of human melanomas and breast carcinomas. The human KiSS1 gene encodes a COOH-terminally amidated active peptide, and this peptide is the ligand of a novel G-protein-coupled receptor. However, the mechanism of the antimetastatic actions of KiSS1 and its G-protein-coupled receptor has not been elucidated. In this study, we identified the mouse homologues of the KiSS1 peptide and its G-protein-coupled receptor and characterized the signaling pathways mediated by the activation of the KiSS1 receptor. Although human and mouse KiSS1 proteins share relatively low overall homology (52%), the active peptides (10-amino-acid residues) are highly conserved between mouse and human KiSS1 proteins, varying by only one conserved amino acid [Tyr (Y) to Phe (F)]. Activation of the receptor by KiSS1 peptide leads to the activation of G-protein-activated phospholipase C (PLC-beta), which suggests direct coupling of the KiSS1 peptide to the Galphaq-mediate PLC-Ca2+ signaling pathway. Furthermore, activation of the KiSS1 receptor inhibits cell proliferation and cell migration, key characteristics of tumor metastasis.
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PMID:Identification and characterization of mouse metastasis-suppressor KiSS1 and its G-protein-coupled receptor. 1235 43

Developing axons are guided to their appropriate targets by environmental cues through the activation of specific receptors and intracellular signaling pathways. Here we report that gradients of pituitary adenylate cyclase-activating polypeptide (PACAP), a neuropeptide widely expressed in the developing nervous system, induce marked attraction of Xenopus growth cones in vitro. PACAP exerted its chemoattractive effects through PAC1, a PACAP-selective G-protein-coupled receptor (GPRC) expressed at the growth cone. Furthermore, the attraction depended on localized cAMP signaling because it was completely blocked either by global elevation of intracellular cAMP levels using forskolin or by inhibition of protein kinase A using specific inhibitors. Moreover, local direct elevation of intracellular cAMP by focal photolysis of caged cAMP compounds was sufficient to induce growth cone attraction. On the other hand, blockade of Ca2+, phospholipase C, or phosphatidyl inositol-3 kinase signaling pathways did not affect PACAP-induced growth cone attraction. Finally, PACAP-induced attraction also involved the Rho family of small GTPases and required local protein synthesis. Taken together, our results establish cAMP signaling as an independent pathway capable of mediating growth cone attraction induced by a physiologically relevant peptide acting through GPCRs. Such a direct cAMP pathway could potentially operate in other guidance systems for the accurate wiring of the nervous system.
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PMID:Direct cAMP signaling through G-protein-coupled receptors mediates growth cone attraction induced by pituitary adenylate cyclase-activating polypeptide. 1265 86

The dynamics of inositol 1,4,5-trisphosphate (Ins (1,4,5)P3) production during periods of G-protein-coupled receptor-mediated Ca2+ oscillations have been investigated using the pleckstrin homology (PH) domain of phospholipase C (PLC) delta1 tagged with enhanced green fluorescent protein (eGFP-PHPLCdelta1). Activation of noradrenergic alpha1B and muscarinic M3 receptors recombinantly expressed in the same Chinese hamster ovary cell indicates that Ca2+ responses to these G-protein-coupled receptors are stimulus strength-dependent. Thus, activation of alpha1B receptors produced transient base-line Ca2+ oscillations, sinusoidal Ca2+ oscillations, and then a steady-state plateau level of Ca2+ as the level of agonist stimulation increased. Activation of M3 receptors, which have a higher coupling efficiency than alpha1B receptors, produced a sustained increase in intracellular Ca2+ even at low levels of agonist stimulation. Confocal imaging of eGFP-PHPLCdelta1 visualized periodic increases in Ins(1,4,5)P3 production underlying the base-line Ca2+ oscillations. Ins(1,4,5)P3 oscillations were blocked by thapsigargin but not by protein kinase C down-regulation. The net effect of increasing intracellular Ca2+ was stimulatory to Ins(1,4,5)P3 production, and dual imaging experiments indicated that receptor-mediated Ins(1,4,5)P3 production was sensitive to changes in intracellular Ca2+ between basal and approximately 200 nM. Together, these data suggest that alpha1B receptor-mediated Ins(1,4,5)P3 oscillations result from a positive feedback effect of Ca2+ onto phospholipase C. The mechanisms underlying alpha1B receptor-mediated Ca2+ responses are therefore different from those for the metabotropic glutamate receptor 5a, where Ins(1,4,5)P3 oscillations are the primary driving force for oscillatory Ca2+ responses (Nash, M. S., Young, K. W., Challiss, R. A. J., and Nahorski, S. R. (2001) Nature 413, 381-382). For alpha1B receptors the Ca2+-dependent Ins(1,4,5)P3 production may serve to augment the existing regenerative Ca2+-induced Ca2+-release process; however, the sensitivity to Ca2+ feedback is such that only transient base-line Ca2+ spikes may be capable of causing Ins(1,4,5)P3 oscillations.
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PMID:Role of Ca2+ feedback on single cell inositol 1,4,5-trisphosphate oscillations mediated by G-protein-coupled receptors. 1267 Sep 45

Angiotensin II (AngII) plays a critical role in control of cardiovascular and renal homeostasis. In addition to its physiological action as a vasoconstrictor, growing evidence supports the notion that AngII contributes to cardiovascular diseases such as hypertension, atherosclerosis, and heart failure. The physiological and pathological actions of AngII in adults are mediated largely via the AngII type 1 receptor (AT1R), a heterotrimeric G-protein-coupled receptor (GPCR). Besides coupling with heterotrimeric G proteins to activate phospholipase C-beta (PLC-beta), AT1R also activates receptor tyrosine kinases (PDGF-R, EGF-R and IGF-R) and non-receptor tyrosine kinases (Src, Fyn, Yes, proline-rich tyrosine kinase 2 (Pyk2), focal adhesion kinase (FAK) and JAK2). These tyrosine kinases play critical roles in AngII-stimulated cell signal events.
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PMID:Angiotensin II signaling pathways mediated by tyrosine kinases. 1267 64

Prostaglandin (PG) F(2alpha), a member of the prostanoid bioactive lipid family, is secreted by human endometrium throughout the menstrual cycle and is present in both menstrual fluid and medium of endometrial explants in culture. PGF(2alpha) mediates its effects through a seven-transmembrane G-protein-coupled receptor (FP). The aim of this study was to examine the temporal expression, signaling, and role of FP receptor in the human endometrium. Quantitative RT-PCR analysis demonstrated highest expression of FP receptor in the mid- to late-proliferative phase, compared with early-proliferative and secretory phase endometrium. In situ hybridization studies localized FP receptor mRNA expression to the epithelial cell compartment during the mid- to late-proliferative phase. Moreover, treatment of endometrial tissue with 1-100 nM PGF(2alpha) induced a concentration-dependent increase in inositol phosphate mobilization, indicating functional FP receptor expression. The Ishikawa human endometrial epithelial cell line was used to investigate further the signaling and role of PGF(2alpha) in endometrial epithelial cells. Ishikawa cells endogenously express the FP receptor, and treatment with 1-100 nM PGF(2alpha) elicits a concentration-dependent increase in inositol phosphate release. Moreover, treatment of Ishikawa cells with 100 nM PGF(2alpha) induced phosphorylation of ERK1/2 that was abolished when cells were cotreated with 50 micro M PD98059 (MAPK kinase inhibitor) or 10 micro M U73122 [phospholipase C (PLC) inhibitor]. Treatment of Ishikawa cells with PGF(2alpha) for 24 h induced a significant concentration-dependent increase in Ishikawa cell proliferation. Coincubation of the cells with 50 micro M PD98059 or 2 micro M U73122 demonstrated that PLC inhibition significantly reduced PGF(2alpha)-induced proliferation, whereas MAPK kinase inhibition had no effect. In summary, these studies demonstrate increased FP receptor expression in endometrial epithelial cells during the proliferative phase of the menstrual cycle and identify a role for PGF(2alpha) in epithelial cell proliferation via a PLC-dependent pathway.
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PMID:Prostaglandin (PG) F(2alpha) receptor expression and signaling in human endometrium: role of PGF(2alpha) in epithelial cell proliferation. 1267 80

Somatostatin receptors are members of the G-protein-coupled receptor superfamily and exert their principal effects by coupling to inhibitory G-proteins. We used fura-2-based digital calcium imaging and assayed for [3H]inositol phosphates (IPs) to study the effects of somatostatin on intracellular calcium signaling in neuroblastomaxglioma NG108-15 cells. Both somatostatin-14 and octreotide induced concentration-dependent increases in intracellular Ca(2+) concentration ([Ca(2+)](i)). Thirty-four percent of the cells responded to treatment with 100 nM somatostatin-14. Somatostatin-induced responses were not blocked by the removal of extracellular calcium; instead, they were abolished by pretreatment with 100 nM thapsigargin, an agent that depletes and prevents refilling of intracellular Ca(2+) stores. Pretreatment with the inositol 1,4,5-trisphosphate (IP(3)) receptor antagonist xestospongin C (10 microM) for 20 min inhibited markedly the somatostatin-induced response. Somatostatin (100 nM) increased [3H]IPs formation. U73122 (1 microM), an inhibitor of phospholipase C (PLC), completely blocked the somatostatin-induced [Ca(2+)](i) increases and the formation of [3H]IPs. Pretreatment with pertussis toxin (PTX, 200 ng/ml) for 24 h blocked the somatostatin-induced responses. Thus, we conclude that activation of endogenous somatostatin receptors in NG108-15 cells induces the release of calcium from IP(3)-sensitive intracellular stores through PTX-sensitive G-protein-coupled PLC.
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PMID:Endogenous somatostatin receptors mobilize calcium from inositol 1,4,5-trisphosphate-sensitive stores in NG108-15 cells. 1276 99


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