Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Atrial natriuretic peptide (ANP) regulates a variety of physiological parameters, including the blood pressure and intravascular volume, by interacting with its receptors present on the plasma membrane. ANP receptors are of three subtypes: ANP-A, -B and -C receptors. ANP-A and ANP-B receptors are guanylyl cyclase receptors, whereas ANP-C receptors are coupled to adenylyl cyclase inhibition or phospholipase C activation through inhibitory guanine nucleotide-regulating protein. Unlike other G protein-coupled receptors, ANP-C receptors have a single transmembrane domain and a short cytoplasmic domain of 37 amino acids, the cytoplasmic domain has a structural specificity like those of other single-transmembrane-domain receptors and 37 amino-acid cytoplasmic domain peptide is able to exert is inhibitory effect on adenylyl cyclase. The activation of ANP-C receptor by C-ANP(4-23) (a ring-deleted peptide of ANP) and C-type natriuretic peptide inhibits the mitogen-activated protein kinase activity stimulated by endothelin-3, platelet-derived growth factor and phorbol-12 myristate 13-acetate. C-ANP also inhibits mitogen-induced stimulation of DNA synthesis, indicating that the ANP-C receptor plays a role in cell proliferation through an inhibition of mitogen-activated protein kinase and suggesting that the ANP-C receptor might also be coupled to other signal transduction mechanism(s) or that there might be an interaction of the ANP-C receptor with some other signalling pathways. ANP receptor binding is decreased in most organs in hypertensive subjects and hypertensive animals. This decrease is consistent with there being fewer guanylyl cyclase-coupled receptors in the kidney and vasculature and selective inhibition of the ANP-C receptor in the thymus and spleen. Platelet ANP-C receptors are decreased in number in hypertensive patients and spontaneously hypertensive rats. ANP-A, -B and -C receptors are decreased in number in deoxycorticosterone acetate-salt-treated kidneys and vasculature; however, the responsiveness of adenylyl cyclase to ANP is augmented in the vasculature and heart and is attenuated completely in platelets. These alterations in ANP receptor subtypes may be related to the pathophysiology of hypertension. Several hormones such as angiotensin II, ANP and catecholamines, the levels of which are increased in hypertension, downregulate or upregulate ANP-C receptors and ANP-C receptor-mediated inhibition of adenylyl cyclase. It can be suggested that the antihypertensive action of several types of drugs such as angiotensin converting enzyme inhibitors, angiotensin type 1 receptor antagonists and beta2-adrenergic antagonists may partly be attributed to their ability to modulate the expression and function of the ANP-C receptor.
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PMID:Atrial natriuretic peptide-C receptor and membrane signalling in hypertension. 928 Feb 3

No ligand has hitherto been designated for the Eph receptor tyrosine kinase family member, EphB6. Here, expression of an EphB6 ligand in the pro-B leukemic cell line, Reh, is demonstrated by binding of soluble EphB6-Fc fusion protein to the Reh cells. The ligand belongs to the subgroup of membrane spanning ligands, as suggested by the fact that phosphatidylinositol-specific phospholipase C treatment did not abrogate binding of EphB6-Fc. Two transmembrane Eph receptor ligands, ephrin-B1 and ephrin-B2, were identified in Reh cells. Analysis of EphB6-Fc fusion protein binding to ephrin-B1 or ephrin-B2 transfected COS cells revealed a high-affinity saturable binding between EphB6-Fc and ephrin-B2, but not with ephrin-B1. In mice, EphB6 has previously been shown to be expressed in thymus. Here, we show expression of EphB6 in human thymus, as well as the expression of ephrin-B2 in both human and mouse thymus. We conclude that ephrin-B2 may be a physiological ligand for the EphB6 receptor.
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PMID:Ephrin-B2 is a candidate ligand for the Eph receptor, EphB6. 1064 35

Cross-linking of the B cell Ag receptor (BCR) induces the tyrosine phosphorylation of multiple cellular substrates, including phospholipase C (PLC)-gamma 2, which is involved in the activation of the phosphatidylinositol pathway. To assess the importance of PLC-gamma 2 in murine lymphopoiesis, the PLC-gamma 2 gene was inducibly ablated by using IFN-regulated Cre recombinase. Mice with a neonatally induced loss of PLC-gamma 2 function displayed reduced numbers of mature conventional B cells and peritoneal B1 cells and defective responses in vitro to BCR stimulation and in vivo to immunization with thymus-independent type II Ags. In contrast, T cell development and TCR-mediated proliferation were normal. Taken together, PLC-gamma 2 is a critical component of BCR signaling pathways and is required to promote B cell development.
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PMID:Cutting edge: essential role of phospholipase C-gamma 2 in B cell development and function. 1092 50

The neurohypophysial peptide oxytocin (OT) and OT-like hormones facilitate reproduction in all vertebrates at several levels. The major site of OT gene expression is the magnocellular neurons of the hypothalamic paraventricular and supraoptic nuclei. In response to a variety of stimuli such as suckling, parturition, or certain kinds of stress, the processed OT peptide is released from the posterior pituitary into the systemic circulation. Such stimuli also lead to an intranuclear release of OT. Moreover, oxytocinergic neurons display widespread projections throughout the central nervous system. However, OT is also synthesized in peripheral tissues, e.g., uterus, placenta, amnion, corpus luteum, testis, and heart. The OT receptor is a typical class I G protein-coupled receptor that is primarily coupled via G(q) proteins to phospholipase C-beta. The high-affinity receptor state requires both Mg(2+) and cholesterol, which probably function as allosteric modulators. The agonist-binding region of the receptor has been characterized by mutagenesis and molecular modeling and is different from the antagonist binding site. The function and physiological regulation of the OT system is strongly steroid dependent. However, this is, unexpectedly, only partially reflected by the promoter sequences in the OT receptor gene. The classical actions of OT are stimulation of uterine smooth muscle contraction during labor and milk ejection during lactation. While the essential role of OT for the milk let-down reflex has been confirmed in OT-deficient mice, OT's role in parturition is obviously more complex. Before the onset of labor, uterine sensitivity to OT markedly increases concomitant with a strong upregulation of OT receptors in the myometrium and, to a lesser extent, in the decidua where OT stimulates the release of PGF(2 alpha). Experiments with transgenic mice suggest that OT acts as a luteotrophic hormone opposing the luteolytic action of PGF(2 alpha). Thus, to initiate labor, it might be essential to generate sufficient PGF(2 alpha) to overcome the luteotrophic action of OT in late gestation. OT also plays an important role in many other reproduction-related functions, such as control of the estrous cycle length, follicle luteinization in the ovary, and ovarian steroidogenesis. In the male, OT is a potent stimulator of spontaneous erections in rats and is involved in ejaculation. OT receptors have also been identified in other tissues, including the kidney, heart, thymus, pancreas, and adipocytes. For example, in the rat, OT is a cardiovascular hormone acting in concert with atrial natriuretic peptide to induce natriuresis and kaliuresis. The central actions of OT range from the modulation of the neuroendocrine reflexes to the establishment of complex social and bonding behaviors related to the reproduction and care of the offspring. OT exerts potent antistress effects that may facilitate pair bonds. Overall, the regulation by gonadal and adrenal steroids is one of the most remarkable features of the OT system and is, unfortunately, the least understood. One has to conclude that the physiological regulation of the OT system will remain puzzling as long as the molecular mechanisms of genomic and nongenomic actions of steroids have not been clarified.
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PMID:The oxytocin receptor system: structure, function, and regulation. 1127 41

1,4-benzothiazine (1,4-B) derivatives exert numerous effects in vivo and in vitro, including neurotoxicity and antitumor cytotoxicity. To analyze the mechanisms responsible for 1,4-B-induced cytotoxicity, we performed experiments to evaluate the possible apoptotic effect. For that purpose, we used mouse thymocytes, a cell population well sensitive to induction of apoptosis that has been used to assay apoptosis in many experimental systems. Results indicate that a number of 1,4-B analogs are able to induce both thymocyte apoptosis in vitro and thymus cell loss in vivo. Moreover, analysis of the structure-activity relationship indicate that the sulfur (S) oxidation state, the presence of the carbonyl group, and the nature and position of the side chain modulate the apoptotic efficacy. Moreover, results of in vitro experiments show that the 1,4-B-induced apoptosis associates with different biochemical events including phosphatidylcholine-specific phospholipase C activation, acidic sphingomyelinase activation and ceramide generation, loss of mitochondrial membrane potential (DeltaPsi(m)) and cytochrome c release, and caspase-8, -9, and -3 activation. These results indicate that 1,4-B analogs induce apoptosis through a complex of biochemical events.
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PMID:Induction of apoptosis by 1,4-benzothiazine analogs in mouse thymocytes. 1186 15

Vav1 is a signal transducing protein required for T cell receptor (TCR) signals that drive positive and negative selection in the thymus. Furthermore, Vav1-deficient thymocytes show greatly reduced TCR-induced intracellular calcium flux. Using a novel genetic system which allows the study of signaling in highly enriched populations of CD4(+)CD8(+) double positive thymocytes, we have studied the mechanism by which Vav1 regulates TCR-induced calcium flux. We show that in Vav1-deficient double positive thymocytes, phosphorylation, and activation of phospholipase C-gamma1 (PLCgamma1) is defective. Furthermore, we demonstrate that Vav1 regulates PLCgamma1 phosphorylation by at least two distinct pathways. First, in the absence of Vav1 the Tec-family kinases Itk and Tec are no longer activated, most likely as a result of a defect in phosphoinositide 3-kinase (PI3K) activation. Second, Vav1-deficient thymocytes show defective assembly of a signaling complex containing PLCgamma1 and the adaptor molecule Src homology 2 domain-containing leukocyte phosphoprotein 76. We show that this latter function is independent of PI3K.
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PMID:Vav1 transduces T cell receptor signals to the activation of phospholipase C-gamma1 via phosphoinositide 3-kinase-dependent and -independent pathways. 1199 16

The Tec family tyrosine kinase Itk is critical for efficient signaling downstream of the TCR. Biochemically, Itk is directly phosphorylated and activated by Lck. Subsequently, Itk activates phospholipase C-gamma1, leading to calcium mobilization and extracellular signal-regulated kinase/mitogen-activated protein kinase activation. These observations suggested that Itk might play an important role in positive selection and CD4/CD8 lineage commitment during T cell development in the thymus. To test this, we crossed Itk-deficient mice to three lines of TCR transgenics and analyzed progeny on three different MHC backgrounds. Analysis of these mice revealed that fewer TCR transgenic T cells develop in the absence of Itk. In addition, examination of multiple T cell development markers indicates that multiple stages of positive selection are affected by the absence of Itk, but the T cells that do develop appear normal. In contrast to the defects in positive selection, CD4/CD8 lineage commitment seems to be intact in all the TCR transgenic itk(-/-) lines tested. Overall, these data indicate that altering TCR signals by the removal of Itk does not affect the appropriate differentiation of thymocytes based on their MHC specificity, but does impact the efficiency with which thymocytes complete their maturation process.
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PMID:The absence of Itk inhibits positive selection without changing lineage commitment. 1205 26

We have previously shown 1,4-benzothiazine (1,4-B) derivatives induce thymocyte apoptosis in vitro and thymus cell loss in vivo. Apoptosis is mediated through a complex of biochemical events including phosphatidylcholine specific-phospholipase C (PC-PLC) activation, acidic sphingomyelinase (aSMase) activation and ceramide generation, caspase-8 and caspase-3 activation. As preliminary analysis of the structure-activity relationship (SAR) suggested some structural features were responsible for apoptosis, we synthesised several derivatives and tested for apoptosis activity at equimolar concentrations. In particular, we synthesised analogues that differed in the nature of skeleton (1,4-benzothiazine, 1,4-benzoxazine and 1,2,3,4-tetrahydroquinoline) and in the nature of side chain (imidazole, benzimidazole or piperazine as azole substituent; presence, absence or transformation of alcoholic group). Results of apoptosis induction indicate that transforming the 1,4-benzothiazine skeleton into 1,2,3,4-tetrahydroquinoline does not result in significant change. Transformation into 1,4-benzoxazine decreased activity. Replacing imidazole at the side chain with different piperazines also decreased activity while replacing it with benzimidazole does not change apoptotic activity. Finally, removal of the alcoholic group by dehydration to olefin, or by transforming it into ether, increased activity. Moreover, in an attempt to analyse further the SAR characteristics that are responsible for 1,4-B-activated apoptosis we tested the effect on caspase-8,-9 and-3 activation. 1,4-B analogues activate caspases and the structural requirements correlate with those responsible for apoptosis induction.
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PMID:1,4-benzothiazine analogues and apoptosis: structure-activity relationship. 1283 34

Linker for activation of T cells (LAT) is a scaffolding adaptor protein that is critical for T cell development and function. A mutation of LAT (Y136F) that disrupts phospholipase C-gamma1 activation and subsequent calcium influx causes a partial block in T cell development and leads to a severe lymphoproliferative disease in homozygous knock-in mice. One possible contribution to the fatal disease of LAT Y136F knock-in mice could be from autoreactive T cells generated in these mice because of altered thymocyte selection. To examine the impact of the LAT Y136F mutation on thymocyte positive and negative selection, we bred this mutation onto the HY T cell receptor (TCR) transgenic, recombination activating gene-2 knockout background. Female mice with this genotype showed a severe defect in positive selection, whereas male mice exhibited a phenotype resembling positive selection (i.e., development and survival of CD8(hi) HY TCR-specific T cells) instead of negative selection. These results support the hypothesis that in non-TCR transgenic, LAT Y136F knock-in mice, altered thymocyte selection leads to the survival and proliferation of autoreactive T cells that would otherwise be negatively selected in the thymus.
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PMID:Mutation of the phospholipase C-gamma1-binding site of LAT affects both positive and negative thymocyte selection. 1579 36

Half of congenital muscular dystrophy cases arise from laminin alpha2 (merosin) deficiency, and merosin-deficient mice (Lama2dy) exhibit a dystrophic phenotype. The abnormal development of thymus in Lama2dy mice, the occurrence of acetylcholinesterase (AChE) in the gland and the impaired distribution of AChE molecules in skeletal muscle of the mouse mutant prompted us to compare the levels of AChE mRNAs and enzyme species in thymus of control and Lama2dy mice. AChE activity in normal thymus (mean +/- SD 1.42 +/- 0.28 micromol acetylthiocholine/h/mg protein, U/mg) was decreased by approximately 50% in dystrophic thymus (0.77 +/- 0.23 U/mg) (p = 0.007), whereas butyrylcholinesterase activity was little affected. RT-PCR assays revealed variable levels of R, H and T AChE mRNAs in thymus, bone marrow and spinal cord. Control thymus contained amphiphilic AChE dimers (G2A, 64%) and monomers (G1A, 19%), as well as hydrophilic tetramers (G4H, 9%) and monomers (G1H, 8%). The dimers consisted of glycosylphosphatidylinositol-anchored H subunits. Western blot assays with anti-AChE antibodies suggested the occurrence of inactive AChE in mouse thymus. Despite the decrease in AChE activity in Lama2dy thymus, no differences between thymuses from control and dystrophic mice were observed in the distribution of AChE forms, phosphatidylinositol-specific phospholipase C sensitivity, binding to lectins and size of AChE subunits.
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PMID:Muscular dystrophy by merosin deficiency decreases acetylcholinesterase activity in thymus of Lama2dy mice. 1613 75


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