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 effects of vasoconstrictor-receptor (neuropeptide Y, alpha-adrenergic, serotonergic, histaminergic) stimulation on currents through ATP-sensitive potassium (KATP) channels in arterial smooth muscle cells were examined. Whole-cell KATP currents, activated by the synthetic KATP channel opener pinacidil or by the endogenous vasodilator, calcitonin gene-related peptide, which acts through protein kinase A, were measured in smooth muscle cells isolated from mesenteric arteries of rabbit. Stimulation of NPY-, alpha 1-, serotonin (5-HT2)-, and histamine (H1)-receptors inhibited KATP currents by 40-56%. The signal transduction pathway that links these receptors to KATP channels was investigated. An inhibitor of phospholipase C (D609) and of protein kinase C (GF 109203X) reduced the inhibitory effect of these vasoconstrictors on KATP currents from 40-56% to 11-23%. Activators of protein kinase C, a diacylglycerol analogue and phorbol 12-myristate 13-acetate (PMA), inhibited KATP currents by 87.3 and 84.2%, respectively. KATP currents, activated by calcitonin gene-related peptide, were also inhibited (47-87%) by serotonin, phenylephrine, and PMA. We propose that KATP channels in these arterial myocytes are subject to dual modulation by protein kinase C (inhibition) and protein kinase A (activation).
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PMID:Vasoconstrictors inhibit ATP-sensitive K+ channels in arterial smooth muscle through protein kinase C. 889 79

1. D-Myo inositol 1,2,6 trisphosphate (alpha-trinositol, pp56), an isomer of the second messenger substance, inositol 1,4,5 trisphosphate, has an interesting pharmacological profile that includes antagonism of a number of neuropeptide Y (NPY)-mediated cellular processes. The ability of pp56 to inhibit selectively the myocardial contraction mediated by NPY in relation to the responses to other cardioactive peptides, including endothelin-1, calcitonin gene-related peptide (CGRP), secretin and vasoactive intestinal peptide (VIP), was assessed. In order to investigate the possible interaction of pp56 with mechanisms of inositol phosphate signalling generated in heart muscle cells by activation of the beta-isoenzyme of phospholipase C (PLC beta), noradrenaline was used as a positive control, and isoprenaline and forskolin were included as negative controls. 2. Ventricular cardiomyocytes, isolated from the hearts of adult rats, were stimulated to contract at 0.5 Hz in the presence of calcium ion (2 mM). The concentrations of agonists used were in the region of their maximally effective concentrations for myocyte contraction and the concentration of pp56 was in the range of 1-100 microM. Contractile activity was monitored by video microscopy and maximum shortening determined by image analysis. 3. In the absence of agonist, contractile amplitudes following 20 min preincubation with pp56 were not different from that observed in the absence of pp56. Pp56 (1-100 microM) inhibited significantly the positive contractile response to noradrenaline (5 microM) in the presence of propranolol (500 nM), such that the response was almost completely attenuated at the highest concentration of the inhibitor. Pp56 did not inhibit the positive contractile responses to forskolin (40 microM) or isoprenaline (100 nM). 4. NPY alone does not influence the basal level of contraction of cardiomyocytes, but can attenuate isoprenaline-stimulated contraction and can increase contractile amplitude from basal when the transient outward current is blocked with 4-aminopyridine. In the presence of isoprenaline (100 nM), the negative response to NPY (100 nM) was attenuated significantly by pp56 (1-100 microM). With 4-aminopyridine, the positive contractile response to NPY (200 nM) was decreased by pp56, although this was not statistically significant. 5. Pp56 inhibited the positive contractile responses to CGRP (1 nM) and endothelin-1 (20 nM) completely, but did not affect the responses to secretin (20 nM) or VIP (20 nM). 6. In conclusion, these data challenge the previously obtained selectivity of pp56 as an antagonist of NPY-mediated cellular processes, since responses to CGRP and endothelin-1 were at least equally sensitive. Furthermore, as pp56 discriminated clearly in its inhibition of responses to alpha-adrenoceptor by comparison with beta-adrenoceptor/adenylate cyclase stimulation, it appears that pp56 may be a useful pharmacological agent with which to distinguish between PLC beta-dependent and PLC beta-independent coupling mechanisms. On this basis, further evidence has been obtained that, in rat cardiomyocytes, the contractile responses to NPY, CGRP and endothelin-1 are attributable to the activation of PLC beta-dependent pathways, whereas the responses to secretin and VIP are mediated by PLC beta-independent pathways.
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PMID:Use of D-myo inositol 1,2,6 trisphosphate to inhibit contractile activity in rat ventricular cardiomyocytes induced by neuropeptide Y and other cardioactive peptides through phospholipase C. 942 11

1. Extracellular adenosine triphosphate (ATP) is mitogenic for vascular smooth muscle cells (VSMC) and stimulates several events that are important for cell proliferation: DNA synthesis, protein synthesis, increase of cell number, immediate early genes, cell-cycle progression, and tyrosine phosphorylation. 2. Receptor characterization indicates mitogenic effects of both P2U and P2Y receptors. The P2X receptor is lost in cultured VSMC and is not involved. Several related biological substances such as UTP, ITP, GTP, AP4A, ADP, and UDP are also mitogenic. 3. Signal transduction is mediated via Gq-proteins, phospholipase C beta, phospholipase D, diacyl glycerol, protein kinase C alpha, delta, Raf-1, MEK, and MAPK. 4. ATP acts synergistically with polypeptide growth factors (PDGF, bFGF, IGF-1, EGF, insulin) and growth factors acting via G-protein-coupled receptors (noradrenaline, neuropeptide Y, 5-hydroxytryptamine, angiotensin II, endothelin-1). 5. The mitogenic effects have been demonstrated in rat, porcine, and bovine VSMC and cells from human coronary arteries, aorta, and subcutaneous arteries and veins. 6. The trophic effects on VSMC and the abundant sources for extracellular ATP in the vessel wall make a pathophysiological role probable in the development of atherosclerosis, neointima-formation after angioplasty, and possibly hypertension.
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PMID:Extracellular ATP: a growth factor for vascular smooth muscle cells. 959 70

Binding of a Y1-subtype-selective agonist of neuropeptide Y (NPY) receptor, (Leu31,Pro34)human peptide YY (LP-PYY), to particulates from four rat brain areas (parietal cortex area 1, piriform cortex, anterior hypothalamus and hippocampus) showed a distinct response to LP-PYY and PYY, a uniformly low sensitivity to ligands selective for the Y2, Y4 and Y5 NPY receptor subtypes and high sensitivity to a Y1 site-selective antagonist, BIBP-3226. The Y1 binding was sensitive to guanine nucleotide-binding protein (G protein) agonist and antagonist nucleotides, with the rank order of guanosine 5'-O-(thiotriphosphate) (GTP gamma S) > GTP > GDP > guanosine 5'-O-(thiodiphosphate). However, guanine nucleotides did not affect about one third of the specific Y1 binding. Most of Y1 binding could be inhibited by a G protein nucleotide site/docking site receptor mimic, mastoparan analog MAS-7. In all areas examined, the Y1 binding of LP-PYY was little affected by up to 100 microM of the antagonists of K+, Na+ and Ca++ channels, protein kinase C, phospholipase A2, phospholipase D and phosphatidylinositol 3-kinase, phospholipase substrate phospholipids, steroids or detergents. However, the binding was potently inhibited by phospholipase C inhibitors (especially the aminosteroid U-73122), which also dissociated the bound Y1 ligand in steady-state conditions. U-73122 also displaced the Y1 binding insensitive to GTP gamma S. Ligand association with the brain Y1 NPY receptor thus strongly depends on activity of both G proteins and phospholipase C, implying specific interactions of these transducers/effectors with the receptor molecule in ligand binding. A portion of brain Y1 sites could be directly coupled to phospholipase(s) C.
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PMID:Characterization of G protein and phospholipase C-coupled agonist binding to the Y1 neuropeptide Y receptor in rat brain: sensitivity to G protein activators and inhibitors and to inhibitors of phospholipase C. 965 83

The binding of two peptide YY/neuropeptide Y analogues selective for major subtypes of neuropeptide Y (NPY) receptors was compared in particulates from rabbit kidney cortex employing modulators of activity of G-proteins, phospholipase enzymes, and ion channels. The binding of (Leu31,Pro34)human peptide YY resembled the patterns observed previously for the brain tissue Y1 receptor, exhibiting a high sensitivity to monovalent cations, disulfide disruptors, guanosine polyphosphates and phospholipase C inhibitors. However, this binding was bimodal in response to human pancreatic polypeptide and to peptides selective for the Y2 subtype of the NPY receptor, displaying a large component pharmacologically similar to the brain Y5 receptor. This kidney Y5-like binding largely shared the sensitivity to monovalent cations, guanine nucleotides and phospholipase C inhibitors found for either the kidney or the brain Y1 receptor, and also was activated by Ca2+ ion. Both Y1- and Y5-like binding in the kidney displayed a uniformly low reactivity to a nonpeptidic Y1 antagonist, BIBP-3226, and to a receptor peptide mimetic, mastoparan analogue MAS-7. The kidney Y2 binding shared the low sensitivity to ionic environment observed for the brain Y2 subtype, and was only partially sensitive to guanine nucleotides or to MAS-7. The Y2 liganding had a sensitivity to phospholipase C inhibitors similar to the Y1/Y5 binding. This reactivity was retained in the fraction of the Y2 receptor persisting detergent solubilization in a high-affinity form, which, however, was activated rather than inhibited by G-protein agonists.
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PMID:Characterization of Y1, Y2 and Y5 subtypes of the neuropeptide Y (NPY) receptor in rabbit kidney. Sensitivity of ligand binding to guanine nucleotides and phospholipase C inhibitors. 980 2

Sites sensitive to human and rat pancreatic polypeptides (hPP and rPP) accounted for more than 30% of the specific binding of [125I](Leu31,Pro34) human peptide YY (LP-PYY) in particulates from rabbit kidney cortex, and about 10% of the specific binding in membranes from rabbit hypothalamus. The binding of [125I]hPP or [125I]rPP showed a high-affinity displacement with either hPP, rPP, LP-PYY, neuropeptide Y or peptide YY (Ki below 50 pM for all), while being quite insensitive to Y2-selective ligands. The PP binding had a high sensitivity to alkali cations and inhibitors of phospholipase C, very similar to that of LP-PYY binding 'masked' by excess cold hPP. However, as different from the Y1-like LP-PYY binding, but similar to the binding of the Y2-selective ligand [125I]human peptide YY(3-36) (hPYY(3-36)), the PP binding showed a low sensitivity to guanosine polyphosphates. The PP binding was much more sensitive to N5-substituted amiloride inhibitors of Na+ transport than the binding of LP-PYY, or that of hPYY(3-36). The inhibition of PP binding by N5-substituted amilorides was not enhanced by guanine nucleotides or by phospholipase C blockers. However, pairing of N5-substituted amilorides disproportionately increased the inhibition of hPP binding. Thus, in rabbit kidney or hypothalamus, the high-affinity PP-responding sites share some of the basic properties of the Y1 and Y2 sites, but are distinguished from both by a high sensitivity to compounds affecting sodium transport. These PP/NPY receptors could associate with membrane structures involved in the control of ion balance and osmotic responses.
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PMID:Characterization of rabbit kidney and brain pancreatic polypeptide-binding neuropeptide Y receptors: differences with Y1 and Y2 sites in sensitivity to amiloride derivatives affecting sodium transport. 1045 51

FMRFamide and related peptides (RFamides) were found to inhibit the association binding of iodinated human pancreatic polypeptide ([125I]hPP) to Y5-like neuropeptide Y (NPY) receptor in rodent tissues. An allosteric regulation of the activity of the rodent kidney PP-sensitive neuropeptide Y (NPY) receptor by RFamides was indicated by potency decrease with particle concentration in the inhibition of the association binding of 125I-labeled human pancreatic polypeptide (hPP) by RFamides at rabbit kidney membranes. The competition by C-terminal hexapeptide of hPP (LTRPRY.NH2) did not show such affinity change. The steady-state binding of hPP showed little sensitivity to any of the RFamides tested. The Y1-selective binding of [125I][Leu31,Pro34]hPYY (at 2 nM hPP) was much less sensitive to RFamides than the binding of [125I]hPP, albeit with some differences across tissue or cell types. The binding of Y2-selective agonist 125I-labeled human peptide YY (3-36) was quite insensitive to RFamides. The presence of a unique component in the inhibition of hPP binding by RFamides was further indicated by a degree of antagonism with phospholipase C inhibitor U-73122, and by an only limited cooperation with a N5-amiloride compound, and with alkylator chloroethylclonidine. Change of the chirality of individual residues in the FMRFamide molecule produced a significant reduction of inhibitory potency only with D-Phe in the C-terminal position. Substitution of the (C-3) L-Met by L-Leu greatly increased the inhibitory potency of RFamides relative to otherwise identical congeners. RFamides could act both as ligands of membrane neighbors of the PP receptor, and as competitors of Y5-like NPY receptor epitopes that accommodate the C-terminal aspects of agonist peptides.
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PMID:FMRFamides exert a unique modulation of rodent pancreatic polypeptide sensitive neuropeptide Y (NPY) receptors. 1073 78

The binding of [(125)I] orexin-A (Ox-A) to particulates from Chinese hamster ovary (CHO) cells expressing the cloned orexin-A receptor, or from rat forebrain areas, was sensitive to blockers of phosphatidylinositol-specific phospholipase C (PtdIns-PLC) U-73122 and ET-18-OCH(3), little affected by phospholipase A(2) inhibitor quinacrine, and not sensitive to D609, a xanthate inhibitor of phosphatidylcholine-selective PLC. Interaction of the receptor with a PtdIns-PLC was further indicated by a large sensitivity of the binding to Ca(2+). Up to 50% of the binding was sensitive to the G-protein nucleotide site agonist GTP-gamma-S. Ligand attachment to the orexin-A receptor thus depends on an association with both PtdIns-PLC and G-protein alpha-subunits. In all paradigms examined, the binding of [(125)I]orexin-A was competed by human/rat neuropeptide Y (hNPY) and porcine secretin with a potency similar to orexin-A (IC(50) range 30-100 nM). The rank order of potency for NPY-related peptides was hNPY > porcine peptide YY (pPYY) > (Leu(31), Pro(34)) human PYY > human PYY(3-36) > hNPY free acid > human pancreatic polypeptide. Among secretin-related peptides, the rank order of potency was porcine secretin > or = orexin-A > human pituitary adenylate cyclase-activating peptide > orexin-B > porcine vasoactive intestinal peptide. Among opioid peptides, rat beta-endorphin and camel delta-endorphin were much less active than NPY and secretin, and two enkephalins were inactive at 1 microM. In view of high abundance of NPY in forebrain, the above cross-reactivity could indicate a significant contribution of NPY to signaling via orexin-A receptors.
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PMID:Sensitivity of orexin-A binding to phospholipase C inhibitors, neuropeptide Y, and secretin. 1086 Aug 58

Research on the mechanism for growth hormone secretagogue (GHS) induction of growth hormone secretion led to the discovery of the GHS receptor (GHS-R) and later to ghrelin, an endogenous ligand for GHS-R. The ability of ghrelin to induce an increase in the intracellular Ca(2+) concentration - [Ca(2+)](i) - in somatotropes was examined in dispersed porcine pituitary cells using a calcium imaging system. Somatotropes were functionally identified by application of human growth hormone releasing hormone. Ghrelin increased the [Ca(2+)](i) in a dose-dependent manner in 98% of the cells that responded to human growth hormone releasing hormone. In the presence of (D-Lys(3))-GHRP-6, a specific receptor antagonist of GHS-R, the increase in [Ca(2+)](i) evoked by ghrelin was decreased. Pretreatment of cultures with somatostatin or neuropeptide Y reduced the ghrelin-induced increase of [Ca(2+)](i). The stimulatory effect of ghrelin on somatotropes was greatly attenuated in low-calcium saline and blocked by nifedipine, an L-type calcium channel blocker, suggesting involvement of calcium channels. In a zero Na(+) solution, the stimulatory effect of ghrelin on somatotropes was decreased, suggesting that besides calcium channels, sodium channels are also involved in ghrelin-induced calcium transients. Either SQ-22536, an adenylyl cyclase inhibitor, or U73122, a phospholipase C inhibitor, decreased the stimulatory effects of ghrelin on [Ca(2+)](i) transiently, indicating the involvement of adenylyl cyclase-cyclic adenosine monophosphate and phospholipase C inositol 1,4,5-trisphosphate pathways. The nonpeptidyl GHS, L-692,585 (L-585), induced changes in [Ca(2+)](i) similar to those observed with ghrelin. Application of L-585 after ghrelin did not have additive effects on [Ca(2+)](i). Preapplication of L-585 blocked the stimulatory effect of ghrelin on somatotropes. Simultaneous application of ghrelin and L-585 did not cause an additive increase in [Ca(2+)](i). Our results suggest that the actions of ghrelin and synthetic GHS closely parallel each other, in a manner that is consistent with an increase of hormone secretion.
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PMID:Stimulatory effect of ghrelin on isolated porcine somatotropes. 1284 23

Activation of bovine chromaffin cell neuropeptide Y (NPY) receptors coupled to Gi (Y1) results in the enhancement of ATP-stimulated inositol phosphate formation. NPY alone does not alter inositol phosphate (InsP) formation in these cells, suggesting that some form of receptor cross talk is involved in this process. In some cell types, serial stimulation of Gi-linked and Gs- or Gq-linked receptors results in an increase in intracellular messenger production (cyclic AMP or InsP), a process referred to as heterologous sensitization. NPY preincubation with bovine chromaffin cells followed by the addition of ATP results in a dose-dependent increase in ATP-stimulated InsP formation (EC50 = 2.0 x 10-8 M), which is maximal within 1 min. InsP formation resulting from NPY preincubation persists for more than an hour after NPY removal, declining with time in a linear fashion. [Leu31Pro34]NPY and NPY are equally effective at producing sensitization, whereas NPY13-36 is ineffective, suggesting that NPY acts through the Y1 receptor. Confirmation of the receptor subtype identity was made by including the Y1-selective antagonist HU-404 during the preincubation, which prevented the sensitizing effect of NPY. NPY sensitization was blocked by pertussis toxin pretreatment, demonstrating Gi/Go involvement. ATP-stimulated InsP formation, with and without NPY preincubation, was sensitive to the phospholipase C inhibitor, U73122 [1-(6-([17beta-3-methoxyestra-1,3,5(10)-trien-17-yl]-amino)hexyl)-1H-pyrrole-2,5-dione]. In conclusion, short-term exposure of bovine chromaffin cells to NPY results in a long-lasting increase in the subsequent stimulation of InsP formation by ATP.
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PMID:Neuropeptide Y receptor-mediated sensitization of ATP-stimulated inositol phosphate formation. 1297 Mar 92


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