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)

In the mammalian nervous system, serotonin (5-hydroxytryptamine) binds to distinct cell surface receptor subtypes that are defined by their ligand binding and effector-coupling properties. The 5HT1c receptor is a G-protein coupled receptor that stimulates phospholipase C-catalyzed hydrolysis of phosphatidylinositol bisphosphate, leading to the mobilization of intracellular calcium and to the activation of protein kinase C. By using somatic cell hybrid analysis and FISH, we have mapped the HTR1C locus to the human X chromosome, band q24 and to the mouse X chromosome region D-F4. Comparison of these map positions offers new insights into the evolution of human and murine X chromosomes. Since HTR1C is expressed in certain parts of the central nervous system and abnormal function of the serotoninergic system has been implicated in affective disorders, obsessive-compulsive disorder and epilepsy, establishing the precise map position of HTR1C is an important first step toward evaluating this locus as a candidate for mutations in these syndromes and in X-linked mental disorders.
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PMID:Serotonin receptor 1c gene assigned to X chromosome in human (band q24) and mouse (bands D-F4). 130 5

The gonadotropin-releasing hormone receptor (GnRH-R) desensitizes following chronic exposure to GnRH or its agonists. However, it is not certain whether the GnRH-R undergoes rapid homologous desensitization analogous to other members of the G-protein coupled receptor (GPCR) superfamily. This study investigated rapid desensitization events in two cell lines expressing the GnRH-R; (the pituitary gonadotrope alpha T3-1 cell line and the stably transfected human embryonal kidney cells, HEK-293). In both cell types, total inositol phosphate (IP) production did not desensitize, increasing linearly over 10 min. Short-term GnRH pretreatment also did not desensitize the rapid phase ( < or = sec) of the early Ins1,4,5P3 response despite a partial desensitization of the plateau phase ( > 1 min). It is likely that Ins1,4,5P3 metabolism rather than desensitization is responsible for this partial effect. In contrast, GnRH-stimulated calcium responses did desensitize in a dose-dependent fashion in both alpha T3-1 and HEK 293 cells expressing the GnRH-R. These results suggest that rapid GnRH-R desensitization occurs at a level beyond both the receptor and phospholipase C (PLC) activation. These events were receptor specific and not related to cell type, since similar rapid desensitization profiles were observed in both GnRH-R expressing pituitary and nonpituitary cell types. In contrast, profiles of GnRH-stimulated calcium responses were cell type specific.
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PMID:Rapid desensitization of GnRH-stimulated intracellular signalling events in alpha T3-1 and HEK-293 cells expressing the GnRH receptor. 758 62

Angiotensin II is an eight amino acid peptide which plays a major role in the regulation of cardiovascular homeostasis. The physiologic effects of angiotensin (Ang) II are mediated by a G-protein coupled receptor, termed AT1, which activates phospholipase C. A major factor regulating angiotensin II receptor function is the rapid desensitization following agonist stimulation. However, despite years of investigation, the mechanism by which the angiotensin receptor is regulated remains unclear. The cloning of the AT-1 receptor and the availability of cell lines which stabily express this receptor has helped elucidate these mechanisms. In this paper, we review the data from our laboratory concerning the post-translational regulation of the angiotensin receptor function.
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PMID:Desensitization of angiotensin receptor function. 769 89

With the development of subtype specific angiotensin II (Ang II) receptor antagonists and their introduction into the treatment of heart failure and hypertension, the regulation of the Ang II receptor with its subtypes AT1 and Ang T2 gains clinical importance. In cell cultures, the number of surface AT1 is clearly down-regulated by Ang II exposure. Down-regulation can be due to reversible internalization, to phosphorylation and to reduced synthesis and involves protein kinase C and phospholipase C mediated pathways. In this respect, the AT1 behaves as a typical G-protein coupled receptor. Aldosterone, cAMP, norepinephrine and extracellular glucose concentrations can contribute to AT1 regulation. There are very few data regarding the regulation of the subtype AT2, indicating modulation by a number of growth factors and by Ang II. In whole animal models receptor regulation deviates partially from cell cultures. In the rat, the two subtypes AT1A and AT1B are differentially regulated and the expression of subtypes is organ specific. In most experiments, including our own experiences, the AT1, in the adrenals was up-regulated by Ang II infusion and down-regulated by angiotensin converting enzyme inhibitors (ACEI) or Ang II receptor antagonists. Differing effects were observed in other organs. In humans, a number of studies seeking an association between Ang II levels, Ang II receptor regulation and physiological events have been conducted in platelets. In pregnant women, a negative correlation between plasma Ang II levels and Ang II binding and an association between receptor regulation and pregnancy-induced hypertension has been described.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of the angiotensin receptor subtypes in cell cultures, animal models and human diseases. 771 21

Extracellular nucleotides are potent Ca2+ mobilizing agents. A variety of receptors for extracellular ATP are recognised. Some are involved in fast neuronal transmission and operate as ligand-gated ion channels. Others are involved in the paracrine or autocrine modulation of cell function. Many receptors of this type are coupled to phosphoinositide-specific phospholipase C and, in some cases, other phospholipases. One of these receptors (P2z), however, also appears to operate, at least in part, as a ligand-gated ion channel. Pharmacological data suggest that one nucleotide receptor subtype (currently designated P2U) responds selectively to either a purine nucleotide, ATP, or a pyrimidine nucleotide, UTP. According to an alternative view, ATP and UTP recognise distinct receptors. Because of the diversity of receptors for extracellular nucleotides this may be the case in some cells. Nevertheless, a G-protein coupled receptor that confers both ATP and UTP sensitivity has been cloned, expressed in cultured cell lines and sequenced. This receptor appears to have two ligand binding domains that may partially overlap. The nature of this overlap is discussed and a simple model presented. Activation of the receptor protein via one or other ligand binding domain may underlie some of the more subtle differences between the effects of ATP and UTP.
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PMID:Review: Ca(2+)-mobilizing receptors for ATP and UTP. 773 60

Endothelin-1 (ET-1) and parathyroid hormone (PTH) increase calcium transients in rodent osteoblastic cells. To investigate the role of phospholipase C (PLC) in these hormone-stimulated calcium signals, the effects of U-73122 (1-[6-[[17 beta-3-methoxyestra-1,3,5(10)- trien-17-yl]amino]hexyl]-1H-pyrrole-2,5-dione), a reported PLC inhibitor, and its inactive analog, U-73343 (1-[6[[17 beta-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]- 1H-pyrrolidine-2,5-dione), were determined. Intracellular calcium transients were measured in UMR-106 cells with the fluorescent indicator fluo-3. In normal calcium containing medium, prior exposure (3 min) to U-73122 inhibited ET-1 and PTH stimulated calcium transients in a dose-dependent (0.2-10 microM) manner with an IC50 of 1.5-1.8 microM. A concentration of 6-8 microM was required for complete inhibition of responses to 100 nM ET-1 or PTH. U-73343 elicited no effects over this concentration range. In cells in which external calcium was reduced to less than 1 microM by the addition of EGTA, ET-1 signals were completely inhibited by 4-6 microM U-73122 and the IC50 was 0.8 microM. In the low external calcium medium, the PTH response was abolished by 2 microM U-73122 (IC50 = 0.5 microM). U-73122, 8 microM, significantly (P < 0.01) inhibited the effect of ET-1 on inositol trisphosphate production at 3 min whereas U-73343 did not. Pertussis toxin (100 ng/ml) likewise significantly inhibited the effect of ET-1 on phosphoinositol turnover as well as on intracellular calcium concentration. In conclusion, the results support the hypothesis that PLC plays a role in the calcium transients elicited by ET-1 and PTH, and that ET-1 transmits its signal in part via a pertussis toxin sensitive G-protein coupled receptor. Furthermore they suggest that U-73122 is useful for investigating PLC-mediated process in osteoblastic cells.
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PMID:U-73122, a phospholipase C antagonist, inhibits effects of endothelin-1 and parathyroid hormone on signal transduction in UMR-106 osteoblastic cells. 780 18

Arginine-vasopressin (AVP) plays a determinant role in the normal ACTH response to stress in mammals. We cloned a human cDNA coding a 424 amino acid G-protein coupled receptor structurally related to the vasopressin/oxytocin receptor family. When expressed in COS cells, this receptor binds AVP with a high affinity (Kd = 0.55 +/- 0.13 nM) and is functionally coupled to phospholipase C. Competition studies with peptidic or non peptidic AVP analogues reveal that it is pharmacologically distinct from V1a and V2 AVP receptors and therefore it is designated V3. RT-PCR analysis shows that the human V3 receptor is expressed in normal pituitary and also in kidney, but is undetectable in liver, myometrium and adrenal gland. Northern blot analysis reveals a approximately 4.8 kb messenger in human corticotropic pituitary adenomas.
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PMID:Cloning and characterization of the human V3 pituitary vasopressin receptor. 780 41

Peptides which stimulate the formation of inositol phosphates (InoPs) in lymphocyte cell lines were identified by screening synthetic peptide libraries composed of random sequences of hexapeptides. The peptides containing the consensus sequence XKYX(P/V)M were found to be most active in the phospholipase C (PLC)-mediated formation of InoPs in a human B myeloma cell line, U266. The peptides also stimulated the phosphoinositide hydrolysis and the release of [Ca2+]i in HL60 and U937 cell lines. On the other hand, these peptides showed no effect in the following cell lines: NIH3T3, PC12, Daudi, Sp2, Jurkat, H9, Molt-4, SupT-1, K562, and RBL-2H3. The result suggests the possibility that the peptides may have cell type specificity. Experiments with one of the active peptides, WKYMVM-NH2 showed that its action mimics the effect of AlF4- which is a G-protein activator in the InoPs generation, and pertussis toxin partially blocked the InoPs accumulation and [Ca2+]i release induced by the peptide in the U266 cells. Binding assays with the peptide labeled with 125I showed that U266 cells have a saturable number of binding sites for the peptide. Taken together, these results suggest that the peptides could activate PLC-mediated signal transduction via a pertussis toxin-sensitive G-protein coupled receptor in certain cell types.
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PMID:Identification of the peptides that stimulate the phosphoinositide hydrolysis in lymphocyte cell lines from peptide libraries. 862 7

Hormone replacement should provide a serum hormone profile similar to that found in normal physiology. This is generally impractical because hormones are usually released episodically and therefore require frequent administration. However, rather than replacing the hormone directly, in theory, one could administer a mimic or amplifier of the pulse generator that controls pulsatile release of the particular hormone. Using growth hormone (GH) as a paradigm we sought such a mimetic that would provide episodic GH release when administered by the oral route. A GH secretagogue MK0677, is described that has these ideal properties; following oral administration MK0677 amplifies episodic GH release. Mechanistically, it synergizes with growth hormone releasing hormone (GHRH) through a receptor and signal transduction pathway distinct from that of GHRH and is a functional antagonist of somatostatin (SRIF). MK0677 also acts on the arcuate nucleus and appears to stimulate GHRH release. By using 35S-MK0677, a new G-protein coupled receptor for MK0677 was characterized in the plasma membrane fraction of pituitary and hypothalamic tissue. The receptor is present in very low abundance and couples to phospholipase C. Other ligands selective for this receptor also cause synchronization of well-defined pathways leading to GH release. Repeated oral treatment of dogs once daily with MK0677 initiates amplified pulsatile GH release accompanied by increases in IGF-1 that are sustained. The unique biological properties of MK0677 and other synthetic ligands that bind to the same receptor force us to predict that these ligands mimic a naturally occurring hormone that regulates pulsatile GH release. Understanding the regulatory mechanisms involved in this paradigm has broad implications for the control of pulsatile rhythms in the endocrine system.
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PMID:Modulation of pulsatile GH release through a novel receptor in hypothalamus and pituitary gland. 870 Oct 83

Mammalian bombesin-like peptides gastrin-releasing peptide (GRP) and neuromedin B (NMB) are regulatory neuropeptides involved in numerous physiologic processes, and have been implicated as autocrine and/or paracrine growth factors in human lung carcinoma. Three structurally and pharmacologically distinct bombesin receptor subtypes have been isolated and characterized: the gastrin releasing peptide receptor (GRP-R), the neuromedin B receptor (NMB-R), and bombesin receptor subtype-3 (BRS-3). The three receptors are structurally related, sharing about 50% amino acid identity. They are members of the G-protein coupled receptor superfamily with a seven predicted transmembrane segment topology characteristic of receptors in this family. The signal transduction pathway for GRP-R and NMB-R involves coupling to a pertussis-toxin insensitive G-protein, activation of phospholipase C (PLC), generation of inositol trisphosphate (IP3), release of intracellular calcium, and activation of protein kinase C. While all three bombesin receptors are activated by bombesin agonists, GRP-R, NMB-R, and BRS-3 have very different affinities for the mammalian bombesin-like peptides GRP and NMB, as well as bombesin receptor antagonists. The three bombesin receptor subtypes are expressed in an overlapping subset of human lung carcinoma cell lines. Any therapeutic strategy based on modulation of bombesin growth responses in human lung carcinoma would be well served to take into account the pharmacologic heterogeneity of the relevant receptors.
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PMID:Bombesin receptor structure and expression in human lung carcinoma cell lines. 880 6


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