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)

We have previously reported that parathyroid hormone (PTH) and PTH related protein (PTHrP) stimulate expression of interleukin-6 (IL-6) and leukemia inhibitory factor (LIF) in osteoblasts in vitro. In the current study, we have developed a model of hormone injection into the subcutaneous space overlying mouse parietal bones to demonstrate that similar processes occur in osteoblasts in vivo. Specifically, PTH and PTHrP rapidly and transiently induce expression of the mRNAs encoding IL-6 and LIF. The effects are dose-dependent, with a maximal stimulation of approximately 50-fold for each cytokine. Although PTH and PTHrP activate both adenyl cyclase and phospholipase C-dependent signal transduction pathways, stimulation of IL-6 and LIF depends on adenyl cyclase since it is not reproduced by PTH(3-34), a partial agonist that only activates phospholipase C. These results confirm our previous in vitro studies and support the hypothesis that IL-6 and/or LIF are physiologically important mediators of at least some of the actions of PTH and PTHrP.
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PMID:In vivo demonstration that parathyroid hormone and parathyroid hormone-related protein stimulate expression by osteoblasts of interleukin-6 and leukemia inhibitory factor. 872 72

1. We sought to reconstitute and characterize G-protein linked phosphatidyl-D-inositol 4,5-bisphosphate (PIP2)-directed phospholipase C (PLC) isoform activity in pig aortic vascular smooth muscle. 2. Six soluble PLC isoforms, namely gamma 1, delta 1 and beta 1 to beta 4 were partially separated by heparin affinity chromatography and were identified by Western blotting using specific antibodies. 3. In separate experiments, PLC activity was measured in the eluted fractions. Four of the partially resolved PLC isoforms gamma 1, beta 4, beta 2 and beta 1, showed corresponding activity using exogenous [3H]-PIP2 as substrate. 4. The isolated soluble PLC isoforms were reconstituted with receptors and guanyl nucleotide regulatory proteins (G-proteins) by addition of plasma membranes, the phospholipids which had been prelabelled with [3H]-myo-inositol. When so reconstituted PLC beta 2, beta 3 and beta 4 were inhibited (40 +/- 9, 47 +/- 12 and 40 +/- 5% respectively n = 12, +/-s.e.mean and each P < 0.05) by the addition of 1 mM guanosine 5'[beta gamma-imido]triphosphate (p[NH]ppG). 5. By contrast, when plasma membranes were preincubated with pertussis toxin to inhibit the activity of G-protein subunits G alpha i/alpha o the activities of PLC beta 2, beta 3 and beta 4 were stimulated (46 +/- 11, 31 +/- 9 and 37 +/- 8% respectively, n = 12, +/- s.e.mean and each P < 0.05) by the addition of p[NH]ppG. 6. Using well resolved fractions containing only PLC beta 3, time-dependent activity in the presence of p[NH]ppG was measurable only with membranes pretreated with pertussis toxin. 7. PLC beta 3 activity, measured with pertussis pretreated membranes, showed a dose-dependent increase in the presence of p[NH]ppG or guanosine 5'-[gamma-thio]triphosphate (GTP[S]). This increase with 10 microM p[NH]ppG or GTP[S] 10% +/- 4 and 12% +/- 5 respectively (both P < 0.05 vs control without GTP analogue +/- s.e.mean, n = 10) was abolished by 50 microM guanosine 5'-[beta-thio]diphosphate (GDP[S]) which also reduced constitutive PLC beta 3 activity by 9% +/- 4. 8. G-protein antibodies were used to neutralize PLC activity. Antibody to G alpha q/alpha 11, added to membrane fractions pretreated with pertussis toxin and assayed with GTP[S], reduced PLC beta 3 activity by 21% +/- 6 P < 0.02, n = 6, but was without effect on non-pertussis pretreated membranes. Antibodies to G alpha i1/alpha i2 had no effect. Antibodies to G-protein beta subunits had no effect on PLC beta 3 activity with pertussis pretreated preparations but activity without pertussis pretreatment was increased by 30% +/- 10, P < 0.03, n = 6. All results were expressed as % change from controls containing rabbit IgG. 9. In conclusion, pig aortic vascular smooth muscle contains six PLC isoforms. Activation of pertussis sensitive G-protein by GTP analogues results in inhibition of PLC beta 3 activity from liberated G-protein beta gamma subunits. Stimulation of PLC beta 3 activity is associated with a G-protein of the G alpha q family acting through the alpha subunit. The results suggest that the G-protein linked PLC beta isoforms in vascular smooth muscle demonstrate dual regulation by an inhibitory pertussis-sensitive pathway and a stimulatory G-protein of the G alpha q family, which is the case for PLC beta 3. This dual regulation is analogous to that of adenyl cyclase.
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PMID:Phospholipase C isoforms in vascular smooth muscle and their regulation by G-proteins. 879 75

Gonadotropin and TSH receptors represent a subgroup of seven transmembrane-spanning, G protein-coupled receptors with a large extracellular ligand-binding region. After ligand binding to their receptors, the majority of actions of gonadotropins and TSH are believed to be mediated by the cAMP-protein kinase A pathway. Although formation of inositol phosphates (IP) has been reported after stimulation of rodent gonadotropin receptors, activation of phospholipase C after ligand binding of human LH or FSH receptors has not been investigated. Human gonadotropin receptors were transiently expressed in 293 cells, and the agonist-induced stimulation of IP formation was measured. The LH receptor responded to a saturating dose of human CG (hCG) with a 5.2-fold increase of IPs whereas the FSH receptor responded to a saturating dose of FSH with only a 50% increase. On the basis of these differences and in view of the homologous nature of the two gonadotropin receptors, chimeric receptors were constructed using domain transfer to identify the regions in the human LH receptor important for phosphatidylinositol hydrolysis. Chimeric receptors containing the entire extracellular region of the FSH receptor and the seven transmembrane region plus the cytoplasmic tail of the LH receptor responded to FSH treatment with a 4.7-fold increase in IP accumulation. In contrast, the chimeric receptor with the extracellular region of the LH receptor and the TM region plus the cytoplasmic tail of the FSH receptor responded minimally (50%) to hCG treatment. When the C-terminal third (from TM V to the cytoplasmic tail) of the FSH receptor was replaced with the LH receptor sequence, the chimeric receptor still responded to FSH treatment with a large (6.2-fold) increase in IP release, similar to that of the wild type LH receptor (to hCG), suggesting that C-terminal third of the human LH receptor confers IP signaling ability. This functional domain was further divided into two areas, namely TM V to TM VI and TM VII to the cytoplasmic tail. The chimeric receptors F(I-IV)L(V-VI)F(VII-C)R and F(I-VI)L-VII-C)R, in which these two regions of the FSH receptor were replaced by the corresponding sequences of the LH receptor, responded to FSH treatment with partial increases in phosphatidylinositol hydrolysis (2.0- and 3.7-fold, respectively). Furthermore, when TM VII and the cytoplasmic tail of the LH receptor were replaced with the corresponding sequence of the FSH receptor, this chimeric receptor showed a diminished (2.0-fold) response to hCG in IP release. For all the chimeric receptor constructs analyzed, overall expression, equilibrium binding constants, and adenyl cyclase activation were not altered. Thus, unlike studies using chimeric muscarinic and dopaminergic receptors in which the second and third intracellular loops were found to be important for IP signaling, the entire C-terminal third of the human LH receptor is important for IP release. Future analysis using the chimeric receptor approach should provide new information on the structure-function relationship of gonadotropin, TSH, and other seven transmembrane-spanning receptors.
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PMID:The C-terminal third of the human luteinizing hormone (LH) receptor is important for inositol phosphate release: analysis using chimeric human LH/follicle-stimulating hormone receptors. 888 47

The complex pathway seen in patients with the systemic inflammatory response syndrome (SIRS) does not readily respond to mediator blockade. All such trials conducted in SIRS patients have shown no benefit in reducing mortality. We have shown experimentally that in sepsis, the administration of beta 2-adrenoceptor agonists reduces hepatic cellular injury, whereas administration of an alpha 1-adrenoceptor agonist increases hepatic cellular injury. Inflammatory mediators can cause a dose-related reversible change in target endothelial cells (ECs). There is a substantial body of literature describing the anti-inflammatory effects of beta 2-adrenoceptor agonists. They reduce both the increased permeability and the production of inflammatory mediators from ECs. Cellular transduction processes are involved when adrenergic receptor agonists modify either the anti-inflammatory or proinflammatory response to sepsis in ECs. Inflammatory mediators and alpha 1-adrenoceptor agonists stimulate their trimeric G protein-linked receptors to produce diacylglycerol (DAG) and increase the intracellular concentration of calcium. DAG is involved in the production of both inflammatory proteins and lipids. In addition, mitogen-activated protein kinase (MAPK) is activated which is also involved in the production of inflammatory proteins and lipids. beta 2-adrenoceptor agonists activate their trimeric G protein-linked receptors to produce the stimulatory G protein (Gs). Gs stimulates adenyl cyclase to form cyclic adenosine monophosphate (cAMP) and activate protein kinase A (PKA). PKA is involved in activating gene transcription agents to produce anti-inflammatory proteins such as interleukin-10. PKA also inhibits phospholipase C and MAPK. Although promising, the use of beta-adrenoceptor agonists or agonists that increase cellular cAMP to activate the cells' endogenous anti-inflammatory pathway requires further study.
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PMID:Cell surface adrenergic receptor stimulation modifies the endothelial response to SIRS. Systemic Inflammatory Response Syndrome. 896 76

Thyrotropin is the primary pituitary hormone which stimulates the growth and differentiation of thyroid cells. TSH binds a specific receptor present in the plasma membrane of thyroid cells and signals the G protein transducers, which activate different effectors, mainly adenyl cyclase and phospholipase C. The TSH receptor belongs to a broad class of receptors known as seven-loop receptors because they contain a long stretch of amino acids which cross the plasma membrane seven times. Mutations in the TSH receptor gene have been found in hyperfunctioning thyroid adenomas. These mutations are: (a) somatic (present only in the tumor), (b) dominant (only one copy of the gene is affected), and (c) lead to the constitutive activation of the cAMP signaling cascade. Most mutations which have been identified occur in the intracellular loop III and in the transmembrane domain VI. Germline mutations in the same regions of the receptor have been found in congenital nonautoimmune hyperthyroidism. In addition, germ line mutations have been described in the extracellular domain of the receptor leading to increased TSH levels. The clinical implications of these findings are discussed.
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PMID:Mutations of thyrotropin receptor gene. 929 24

By examining in vitro the effects of prostaglandin E-2 (PGE-2) and prostaglandin F-2alpha (PGF-2alpha) induced in the corpora lutea (CL) of pseudopregnant rabbits, we have demonstrated that these prostaglandins modulate luteal nitric oxide synthase (NOS) activity and progesterone production differently, depending on the age of the CL. On CL obtained on day 4 of pseudopregnancy (day-4), PGE-2 was found to depress NOS total activity to 13% of control and to significantly increase basal progesterone secretion by 61%, while PGF-2alpha had no effect. On day-9 CL, PGE-2 was ineffective, but PGF-2alpha caused a 2.5-fold increase of NOS activity and a marked decrease in progesterone production. Using specific inhibitors, we found that the regulatory actions of PGE-2 in vitro are mediated via the adenyl cyclase/protein kinase A (PKA) second messenger system, while the PGF-2alpha-induced luteolytic effects on day-9 CL depend upon activation of the phospholipase C/protein kinase C (PKC) system. The different responsiveness of day-4 and day-9 CL to PGE-2 and PGF-2alpha could depend on receptor availability for these two prostaglandins, even if other cellular mechanisms cannot be excluded. The present study supports a functional role for NOS in regulating the steroidogenic capacity of rabbit CL, and reveals a novel interaction between a stimulatory G-protein-coupled receptor and PKC/PKA-mediated signal transduction modulating NOS activity.
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PMID:Nitric oxide synthase activity and progesterone release by isolated corpora lutea of rabbits in the early and mid-luteal phases of pseudopregnancy are modulated differently by prostaglandin E-2 and prostaglandin F-2alpha via adenylate cyclase and phospholipase C. 1065 53

A method for rapidly evaluating functional interactions between ligands and G-protein--coupled receptors has been developed. The technology is based on the ability of animals to change color by controlling the position of pigmented organelles within skin cells called melanophores. cDNA coding for a receptor to be studied is expressed in immortalized frog melanophores. Stimulation of a receptor that normally functions to activate either adenyl cyclase or phospholipase C induces centrifugal melanosome translocation and cell darkening. Conversely, application of an agonist to cells expressing a receptor that operates to inhibit adenyl cyclase induces centripetal pigment movement and cell lightening. The simple optical change can be used to investigate ligand-receptor interactions at several levels, including single-cell analysis and high-throughput chemical screening. Current efforts are focused on (1) identifying small peptides that activate or block thromboxane. A(2) and platelet-activating factor (PAF) receptors and (2) cloning eicosanoid receptors.
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PMID:Tools for Investigating Functional Interactions Between Lipid-Derived Autacoids and their Receptors. 1186 62

Treatment of porcine thyroid slices with highly purified lecithinase C leads to a marked reduction in the ability to accumulate iodide ion. Although this response is less sensitive as a function of lecithinase concentration than is the ability to respond to thyrotropin with an increase in glucose oxidation, phospholipid synthesis or adenyl cyclase activity, it occurs when the baseline values of these parameters are not substantially altered.
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PMID:The effect of a purified preparation of lecithinase C on iodide transport. 1194 96

The enterochromaffin-like (ECL) cell controls gastric acid secretion via histamine, generated by l-histidine decarboxylase (HDC). HDC expression is regulated by gastrin. However, gastrin is not alone in controlling ECL cell function. For example, the neural peptide pituitary adenylate cyclase-activating polypeptide (PACAP) also increases ECL cell proliferation. To investigate a potential role of PACAP in regulating HDC expression, we generated a series of HDC promoter-luciferase reporter constructs and transiently transfected them into PC12 cells (stably expressing the gastrin-CCK-2 receptor). We found that PACAP regulates HDC promoter activity. This is temporally biphasic, involving both adenyl cyclase and phospholipase C-dependent pathways. Deletional analysis, block mutation, and EMSA demonstrated a PACAP-response element at -177 to -170, wholly necessary for the effects of PACAP and discrete from known gastrin-responsive elements. Discrete neural and endocrine pathways regulate ECL cells through different patterns of postreceptor signaling and promoter activation, which may be appropriate to their functions in vivo.
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PMID:PACAP and gastrin regulate the histidine decarboxylase promoter via distinct mechanisms. 1281 60

Somatostatin and its analogue octreotide have been used for two decades to treat oesophageal variceal haemorrhage. The drug was introduced because of its capacity to decrease portal venous pressure without major side effects. In clinical trials assessing the efficacy of somatostatin and long-acting analogues in arresting variceal haemorrhage, conflicting results have been obtained. Furthermore, in haemodynamic studies evaluating the effects of somatostatin and analogues in patients with cirrhosis, divergent effects were observed. The main reason for these differences is probably related to different affinities of the drugs for different somatostatin receptor subtypes. The effects of somatostatin and analogues are mediated via five different G-protein coupled receptors (somatostatin receptor subtypes 1-5), which regulate the activity of ion channels (Ca2+, K+, Na+ and Cl-) and enzymes (adenyl cyclase, phospholipase C, phospholipase A2, phosphoinositide 3-kinase and guanylate cyclase) responsible for the synthesis or degradation of intracellular second messengers including cyclic AMP, inositol 1,4,5-trisphosphate, diacylglycerol and cyclic GMP. Despite universal use of somatostatin, the cellular and biochemical mechanisms of its effects in portal hypertension are relatively poorly studied and remain incompletely understood. In this review, we summarize relevant signal transduction of somatostatin and analogues, the haemodynamic effects of the drugs and the possible mechanisms by which these effects are mediated.
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PMID:Pharmacological rationale for the use of somatostatin and analogues in portal hypertension. 1294 Sep 22


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