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)

Norepinephrine (NE)-evoked vasoconstrictor and pressor responses are reduced after prolonged exposure; such desensitization is observed both clinically and experimentally. The vasoconstrictor neuropeptide Y (NPY) coexists with NE in perivascular sympathetic nerves, and the results of both in vivo and in vitro studies have indicated functional cooperation between NE and NPY. We propose that NPY becomes increasingly important in situations of high sympathetic activity associated with blunted NE responses. Prolonged NE infusion in conscious rats resulted in adrenergic desensitization; however, NPY administration restored the responsiveness to NE. In naive rats, NE greatly enhanced the pressor action of NPY. An analogous phenomenon was observed in the rabbit isolated pulmonary artery, which failed to respond to NPY unless preexposed to NE; this action of NE was only partly inhibited by conventional adrenoceptor and Ca2+ influx blockade. Conversely, NPY enhanced NE-evoked constriction, in particular when the alpha-adrenoceptor reserve was eliminated. It is proposed that threshold synergism, in part caused by converging stimulation of phospholipase C, accounts for much of the NPY/NE cooperativity. We conclude that 1) NPY and NE cooperate to produce vasoconstriction, both in vivo and in vitro; 2) NPY has the capacity to reverse adrenergic desensitization but not vice versa; 3) NE enhances NPY-evoked vasoconstriction, in part independently of conventional adrenoceptor blockade; 4) threshold synergism phenomena, but not "receptor-receptor interactions," account for (most of) the observed NPY/NE cooperation; and 5) when present, alpha-adrenoceptor reserve prevents the lowering of the NE threshold by NPY.
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PMID:Norepinephrine and neuropeptide Y: vasoconstrictor cooperation in vivo and in vitro. 196 41

Fetal rat dorsal root ganglion neurons (7-8 days in culture) were labeled with [3H]arachidonic acid for 24 h. Stimulation with 10 microM bradykinin (BK) for 30 s resulted in nearly 2-fold increases in levels of radioactive diglyceride and arachidonic acid. A similar result was obtained in the absence of receptor stimulation using the Ca2+ channel agonist BAY K 8644 (10 microM, in the presence of 100 mM potassium chloride) or the Ca2+ ionophore, ionomycin (2.5 microM). If Ca2+ influx was inhibited by adding 3 mM Co2+, a blocker of voltage-sensitive calcium channels, or 2.5 mM EDTA, then BK-stimulated accumulation of both arachidonate and diglyceride was inhibited. These data suggest Ca2+ influx is required for ligand-stimulated accumulation of both arachidonate (a product of diglyceride-lipase or phospholipase A2) and diglyceride (a product of phospholipase C). Two distinct populations of channels may be involved in these reactions since pretreatment with 10 microM nifedipine or 50 microM verapamil (agents which block a subset of voltage-sensitive Ca2+ channels) inhibited BK-stimulated accumulation of arachidonic acid, but did not inhibit diglyceride accumulation. Such functional discrimination appears to have physiological importance; the inhibitory effect of nifedipine and verapamil on BK-stimulated arachidonate release was mimicked by pretreatment with peptides which decrease Ca2+ channel conductance in dorsal root ganglion neurons. The three peptides used were 1 microM neuropeptide Y, 10 microM somatostatin, and 10 microM [N-MePhe3,D-Pro4]-morphiceptin. The effect of neuropeptide Y was blocked by pretreatment with pertussis toxin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation by neuropeptides of bradykinin-stimulated second messenger release in dorsal root ganglion neurons. 197 11

Receptors for regulatory peptides (hormones or neurotransmitters) play a pivotal role in the ability of cells to taste the rich neuroendocrine environment of the gut. Recognition of low concentration of peptides with a high specificity and translation of the peptide-receptor interaction into a biological response through different signalling pathways (adenylyl cyclase-cAMP or phospholipase C-phosphatidylinositol) are crucial properties of receptors. While many new receptors have been identified and thereafter characterized functionally during the 1980s, molecular biology now emerges as the privileged way for the structural characterization and discovery of receptors. Different strategies of receptor cloning have been developed which may or may not require prior receptor purification. Among cloning strategies that do not require receptor purification, homology screening of cDNA libraries, expression of receptor cDNA or mRNA in Xenopus laevis oocytes or in COS cells, and the polymerase chain reaction method achieved great success, e.g. cloning of receptors for cholecystokinin, gastrin, glucagon-like peptide 1, gastrin-releasing peptide/bombesin, neuromedin K, neuropeptide Y, neurotensin, opioids, secretin, somatostatin, substance K, substance P and vasoactive intestinal peptide. All these receptors belong to the superfamily of G-protein-coupled receptors which consist of a single polypeptide chain (350-450 amino acids) with seven transmembrane segments, an N-terminal extracellular domain and a C-terminal cytoplasmic domain. In this chapter, we have detailed the properties of three receptors which play an important role in digestive tract physiology and illustrate various signal transduction pathways: pancreatic beta-cell galanin receptors which mediate inhibition of insulin release and intestinal epithelial receptors for vasoactive intestinal peptide and peptide YY, which mediate the stimulation and inhibition of water and electrolyte secretion, respectively.
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PMID:Receptors for gut regulatory peptides. 751 Sep 49

The common pathway of heterogenous mast cell activation as mediated by antigens is through the cross-linking of IgE bound to Fc epsilon RI receptors. The peptidergic pathway of mast cell activation, achieved by cationic secretagogues, is restricted to "serosal" mast cells, the experimental models being rat peritoneal and human skin mast cells. Cationic secretagogues include positively charged peptides but also various amines such as compound 48/80 and natural polyamines. An early intracellular event of this pathway is the activation of pertussis toxin-sensitive G proteins. The correlation observed between the ability of basic compounds to trigger mast cell exocytosis and their potency to activate purified G proteins strongly suggests that cationic compounds activate mast cell G proteins via a receptor-independent but membrane-assisted process. In this paper, alternative mechanisms are discussed. The consequence of G protein stimulation is the activation of phospholipase C with an increase in inositol triphosphates. Natural polyamines are relatively poor triggers of mast cells (10(-4) to 10(-2) M). Neuropeptides such as substance P, neuropeptide Y or vasoactive intestinal peptide, peptidic hormones such as kinins, and venoms such as mastoparan and mast cell degranulating peptide, are all active in a concentration range from 10(-7) to 10(-4) M. The cationic anaphylatoxin C3a also stimulates mast cells at concentrations below precursor complement C3 blood levels. The component C3 of the complement system is one of only a few plasma proteins having activation fragments (i.e. C3a) that can be generated at micromolar levels. The effects of basic secretagogues defines a peptidergic pathway of mast cell activation, which represents a potentially toxic process considering the tissue effects caused by exogenous basic compounds such as venom peptides and certain amine containing drugs. Peptidergic activation of mast cells may also be a pathophysiological process having an important role in neurogenic inflammation and in diseases involving extensive activation of the blood complement cascade.
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PMID:Peptidergic pathway in human skin and rat peritoneal mast cell activation. 751 63

Receptor-induced binding of the stable GTP analogue, guanosine 5'-[gamma-thio]triphosphate (GTP [gamma S]), to guanine nucleotide-binding regulatory proteins (G proteins) was measured in various permeabilized cells. In myeloid differentiated human leukemia (HL-60) cells, permeabilized with either digitonin, streptolysin O or Staphylococcus aureus alpha-toxin, binding of GTP[gamma S] induced by three distinct chemoattractant receptors was observed. The extent of receptor-stimulated GTP[gamma S] binding (maximally about 2-fold) was independent of the type of permeabilizing agent used. In human erythroleukemia cells permeabilized with digitonin, agonist activation of thrombin and neuropeptide Y receptors increased GTP[gamma S] binding by 1.8- and 1.5-fold, respectively. Finally, in adherently grown human embryonic kidney cells permeabilized with digitonin, activation of the stably expressed human muscarinic m3 receptor increased GTP[gamma S] binding by about 1.6-fold. In digitonin-permeabilized HL-60 cells, a quantitative analysis of formyl peptide receptors and interacting G proteins was performed. About 50,000 formyl peptide receptors per cell were detected. Agonist binding to these receptors was fully sensitive to regulation by guanine nucleotides and pertussis toxin. The number of high-affinity GTP[gamma S] binding sites, most likely representing heterotrimeric G proteins, was calculated to be about 670,000 per cell. Stimulation of formyl peptide receptors led to the activation of about 130,000 of high-affinity GTP[gamma S] binding sites, indicating a ratio of about three activated G proteins per one agonist-activated receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Analysis of receptor-G protein interactions in permeabilized cells. 763 Apr 24

The effects of neuropeptide Y on isometric tension simultaneously measured with cytosolic Ca2+ concentration ([Ca2+]cyt) and Ca2+ sensitivity of contractile elements were studied in isolated canine basilar arteries. Neuropeptide Y (1-100 nM) increased [Ca2+]cyt and tension in a concentration-dependent and parallel manner, whereas 9,11-dideoxy-11 alpha,9 alpha-epoxymethano prostaglandin F2 alpha (U46619) (10-100 nM), a thromboxane A2 mimetic, produced a large contraction with a small increase in [Ca2+]cyt. Ca2+ channel antagonists such as d-cis-diltiazem (10 mM) abolished both [Ca2+]cyt and tension augmented by neuropeptide Y. In Ca(2+)-free solution containing 0.2 mM EGTA, neuropeptide Y did not change [Ca2+]cyt and tension, whereas U46619 transiently increased both of them. Furthermore, neuropeptide Y apparently did not affect the Ca2+ sensitivity when assessed in the artery permeabilized with Staphylococcus aureus alpha-toxin, whereas U46619 augmented it. These findings suggest that neuropeptide Y-induced contraction in the canine basilar artery is produced mainly by Ca2+ influx through L-type Ca2+ channels.
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PMID:Ca2+ handling mechanisms underlying neuropeptide Y-induced contraction in canine basilar artery. 778 12

We have recently demonstrated the ability of neuropeptide Y to augment norepinephrine-stimulated contractions of the rat tail artery. In [3H]myo-inositol labeled segments of rat tail artery, addition of a concentration of neuropeptide Y (10(-8) M) known to potentiate contractile responses produced no effect on the basal accumulation of [3H]inositol phosphates. Addition of norepinephrine (10(-7) M), however, resulted in the rapid accumulation of [3H]inositol 1,4,5-trisphosphate to 325 +/- 29% of basal levels within 5 min. This effect of norepinephrine on [3H]inositol 1,4,5-trisphosphate accumulation was mirrored by significant increases (274 +/- 25% of control) in total [3H]inositol phosphates. When neuropeptide Y and norepinephrine were added together, the norepinephrine-stimulated increase in [3H]inositol 1,4,5-trisphosphate was significantly augmented (467 +/- 35% of control) as was the increase measured in total [3H]inositol phosphates (366 +/- 21% of control). We suggest that the ability of neuropeptide Y to augment norepinephrine-induced contraction of the rat tail artery is due, at least in part, to the ability of neuropeptide Y to increase norepinephrine-stimulated phospholipase C activity in vascular smooth muscle and may represent the mechanism of action of this co-neurotransmitter in vivo.
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PMID:Neuropeptide Y potentiates norepinephrine-stimulated inositol phosphate production in the rat tail artery. 801 53

The effect of neuropeptide Y on the number and affinity of catecholamine receptors in the ventricular myocardium was investigated. Receptor binding studies showed that incubation of cardiac membrane in the presence of neuropeptide Y (NPY, 10(-7) M) decreased the number of alpha/beta-adrenoceptor binding sites (Bmax) without affecting the affinity (KD) of these receptors. Although not able to modulate the contractility by itself, NPY was able to decrease the positive inotropic effects of phenylephrine and isoproterenol in the isolated, perfused myocardium. Ca2+/Mg(2+)-ATPase activity, measured from the sarcolemma, sarcoplasmic reticulum and myofibrils, was unaltered whereas the activity of sarcolemmal Na+/K(+)-ATPase was decreased when NPY was included in the media. On the other hand, NPY was shown to increase the phosphoinositide-phospholipase C associated with the sarcolemma. These findings support the hypothesis that NPY modulates postsynaptic adrenergic receptors in the myocardium and can affect the adrenergic-induced, inotropic response.
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PMID:Adrenoreceptor-mediated effect of neuropeptide Y decreases cardiac inotropic responses. 803 15

In porcine aortic smooth muscle cells, neuropeptide Y (NPY) stimulates mobilization of CA(2+) from intracellular store sites via Y1 receptors. However, it has been debated whether or not Ca(2+) mobilization by Y1 receptors depends on the generation of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] following activation of phospholipase C. To examine this question, we studied the effect of U73122, an inhibitor of phospholipase C-mediated inositol phosphate accumulation on the NPY-induced rise in cytosolic free Ca(2+) concentration ([Ca(2+)]i) in comparison with that on angiotensin II (AII)-induced [Ca(2+)]i increase, which is dependent on Ins(1,4,5)P3 generation. Digital-imaging microscopy study using the Ca(2+)-sensitive dye fura-2 revealed that application of AII induced a rapid but transient [Ca(2+)]i increase in a single cell, arising from intracellular calcium stores. Application of NPY to the same cell induced a [Ca(2+)]i rise with a pattern similar to that induced by AII. AII increased the formation of Ins(1,4,5)P3 by about 3.0 fold, while the NPY-induced [Ca(2+) formation was very small. U73122 completely inhibited not only Ins(1,4,5)P3 synthesis, but also Ca(2+) mobilization induced by either agonist. The effect of U73122 on the NPY-induced Ca(2+)i increase was about 10-fold more potent that on the AII-induced one. U73343, an inactive analog of U733343, had no influence on any of the AII- and NPY-mediated effects. Herbimycin A completely inhibited the platelet-derived growth factor-induced [Ca(2+]i increase but had no effect on the NPY-induced [Ca(2+)]i increase, indicating that phospholipase C-gamma is not involved in the NPY effect. These results suggest that NPY-induced Ca2+ mobilization from intracellular stores in porcine smooth muscle cells is secondary to the very small generation of Ins(1,4,5)P3 following stimulation of phospholipase C-beta, which may account for the hypersensitivity of the NPY effect to U73122.
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PMID:Neuropeptide YY1 receptors-mediated increase in intracellular Ca2+ concentration via phospholipase C-dependent pathway in porcine aortic smooth muscle cells. 869 Jul 10

Activation of receptors on postganglionic sympathetic nerve endings can alter the amount of noradrenaline release during a train of nerve impulses. These changes may be produced by the enzyme-linked synthesis of second messenger molecules within the nerve terminal. Cyclic AMP analogues enhance noradrenaline release and two hormones adrenaline and ACTH appear to enhance noradrenaline release through activation of adenylate cyclase. Activation of the phospholipase C/protein kinase C pathway also elevates stimulation-induced noradrenaline release and angiotensin enhancement of noradrenaline release appears to act through this pathway. On the other hand, receptors which inhibit noradrenaline release (alpha 2-adrenoceptors, muscarinic M2 receptors and neuropeptide Y receptors) do not act through either of these signal transduction pathways. Since these inhibitory systems are neurotransmitter activated and relay information on a nerve pulse to nerve pulse time scale back to the nerve ending a fast activation and deactivation rate of modulation is required. This may be better served by direct modulation of ion channels without a slow intervening enzyme step. Activation of protein kinase C by phorbol esters produces relatively large increases (two-threefold) in stimulation-induced noradrenaline release and this enzyme may also have a physiological role. Protein kinase C may be an appropriate target for drugs to manipulate transmitter release and development of selective activators and inhibitors of the many protein kinase C isoenzymes may prove clinically useful in diseases with inappropriate transmitter release profiles.
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PMID:Second messenger pathways in the modulation of neurotransmitter release. 877 Mar 58


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