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)

Studies were performed to identify the receptor that mediates AVP-stimulated phosphoinositide (PI) hydrolysis in cultured rat inner medullary collecting tubule (RIMCT) cells. While the selective V1 receptor agonist [Ho1, Phe2, Orn8] VT has no effect on inositol trisphosphate (IP3) production over the range of 10(-13)-10(-7) M, the selective V2 receptor agonist VDAVP stimulates IP3 production in dose-dependent fashion. Oxytocin stimulates IP3 production in dose-dependent fashion as well. AVP-stimulated phospholipase C activity is not inhibited by the V1 receptor antagonist d(CH2)5Tyr(Me)AVP(10(-7) M) but is eliminated by the V2 receptor antagonist d(CH2)5DTyr(Et)VAVP (10(-7) M). Similarly, the response to oxytocin is eliminated by the V2 receptor antagonist. The selective oxytocin receptor agonist [Thr4, Gly7] oxytocin does not stimulate cAMP production in RIMCT cells but does promote PI hydrolysis. The selective oxytocin receptor antagonist desGlyNH2d(CH2)5[Tyr(Me)-Thr4]OVT (10(-7) M) does not inhibit AVP-stimulated cAMP production but eliminates IP3 production in response to AVP or the V2 receptor agonist VDAVP. These studies demonstrate that AVP or a V2 receptor agonist stimulate PI hydrolysis in cultured RIMCT cells via occupancy of the oxytocin receptor.
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PMID:Vasopressin-stimulated phosphoinositide hydrolysis in cultured rat inner medullary collecting duct cells is mediated by the oxytocin receptor. 164 53

We explored the nature and time course of the multiple signal transduction pathways for V1-vascular vasopressin (AVP) receptors of A7r5 aortic smooth muscle cells in culture by using radioligand binding techniques, intracellular calcium monitoring, and polyphosphoinositide and phospholipid analyses. V1-vascular AVP receptors of A7r5 cells were characterized by the agonist radioligand [3H]AVP and the antagonist radioligand [3H]d(CH2)5Tyr(Me)AVP. Affinity and capacity of agonist but not antagonist binding were modulated by MgCl2 and aluminum fluoride, suggesting that the receptors are coupled to a guanine nucleotide regulatory protein. In fura-2-loaded A7r5 cells, AVP induced within seconds a dose-dependent increase of free intracellular Ca++ ([Ca++]i) consisting of a rapid transient spike and a sustained increase lasting for 3-5 min. The baseline [Ca++]i was 136 +/- 18 nM, the maximum [Ca++]i response to AVP was 1,582 +/- 297 nM, and AVP ED50 was 1.87 +/- 0.15 nM. Diverse experiments performed with EGTA, 1,2-bis(O-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethylester, Mn++, ionomycin, terbutylbenzo hydroquinone, and nicardipine suggested that the initial spike resulted from both intracellular Ca++ release from the endoplasmic reticulum and extracellular Ca++ influx, whereas the sustained phase depended on dihydropyridine-insensitive extracellular Ca++ influx. Experiments done with indomethacin and arachidonic acid indicated that AVP-induced extracellular Ca++ influx was in part dependent on phospholipase A2 activation. In [3H]myoinositol and [3H]arachidonate-labeled A7r5 cells, AVP stimulated inositol 1,4,5 trisphosphate and 1,2 diacylglycerol production via activation of phospholipase C. Also, AVP stimulated a transphosphatidylation reaction through activation of phospholipase D in A7r5 cells labeled with [3H]1-O-alkyl lysoglycerophosphocholine. Thus, the stimulation of V1-vascular AVP receptors of A7r5 cells triggers several signaling pathways. The immediate and transient [Ca++]i rise due to mobilization of intracellular and extracellular Ca++ is associated with the activation of phospholipases A2 and C, and the sustained activation of phospholipase D.
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PMID:Multiple signaling pathways of V1-vascular vasopressin receptors of A7r5 cells. 165 17

We report saturable, high-affinity, specific, reversible binding sites for both [3H]arginine vasopressin ([3H]AVP) and d(CH2)5Tyr(Me)-[3H]AVP, a V1-selective antagonist, in cultured smooth muscle cells obtained from rat aorta (RA) and rat mesenteric artery (RMA). Specific binding of [3H]AVP had the following characteristics in adherent monolayers of RA and RMA smooth muscle cells: dissociation constant (KD) = 1.42 and 1.23 nM and maximal binding capacity (Bmax) = 9,500 and 29,910 sites/cell, respectively. Lower KD and higher Bmax values were detected for 3H-labeled V1 antagonist binding to both types of cells. Complete dissociation of [3H]-AVP binding to RA cells occurred in a biphasic manner with two rate constants of dissociation, suggesting high- and low-affinity states of the binding site for the agonist interaction. Partial dissociation of the antagonist-specific binding occurred, and it was monophasic, suggesting interaction of the 3H-labeled V1 antagonist radioligand to the high-affinity binding state. Inhibition constant (Ki) values determined by competitive inhibition of [3H]AVP binding to RA cells by a series of AVP-related peptide analogues and antagonists were consistent with the saturation data. AVP in a concentration-dependent manner induced the accumulation of inositol phosphates [mean effective concentration (EC50) 1 nM] in the adherent RA cells. The free cytosolic Ca2+ level in the dispersed RA smooth muscle cells was increased by AVP (EC50 8.1 nM). Pretreatment with the V1 antagonist abolished these AVP-evoked responses. The data support the conclusion that the agonist binding occurs at a homogeneous population of V1-subtype receptors in the high-affinity (KD = approximately 1 nM) state and that these receptors are functionally coupled to phospholipase C.
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PMID:Vasopressin (V1) receptor characteristics in rat aortic smooth muscle cells. 183 12

Ouabain-sensitive 86Rb+ uptake by isolated rat hepatocytes was studied to elucidate how Ca2+-mobilizing hormones stimulate the Na+-pump. Stimulation of this uptake was observed with concentrations of vasopressin ([8-arginine]vasopressin, AVP), angiotensin II, and norepinephrine which elicited Ca2+ mobilization and phosphorylase activation. These results suggested that changes in cytosolic Ca2+, mediated by inositol trisphosphate, might trigger sodium pump stimulation by AVP. However, in hepatocytes incubated in Ca2+-free Krebs-Henseleit buffer, Na+-pump activity was not altered over 15 min by either 1.5 mM EGTA or 1.5 mM Ca2+. Furthermore, incubation of cells in 5 mM EGTA for 15-30 min drastically impaired the ability of AVP to increase cytosolic Ca2+, but only modestly attenuated AVP-stimulated Na+-pump activity. Two tumor promoters, phorbol myristate acetate (PMA) and mezerein, stimulated Na+/K+-ATPase-mediated transport activity. Similarly, addition of synthetic diacylglycerols or of exogenous phospholipase C from Clostridium perfringens to increase endogenous diacylglycerol levels also resulted in a stimulation of the Na+-pump in the absence of changes in cytosolic or total cellular Ca2+ levels. Stimulation of the Na+-pump by the combination of maximal concentrations of PMA and AVP did not produce an additive response, and both agents displayed a transient time course, suggesting that the two agents share a common mechanism. Stimulation of the Na+-pump by AVP and PMA was not blocked by amiloride analogs which inhibit Na+/H+ exchange, but these compounds blocked the action of insulin. These data suggest that the elevated Na+/K+-ATPase-mediated transport activity observed in hepatocytes following exposure to Ca2+-mobilizing hormones is a consequence of stimulated diacylglycerol formation and may involve protein kinase C.
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PMID:The hormone-sensitive hepatic Na+-pump. Evidence for regulation by diacylglycerol and tumor promoters. 302 43

Vasopressin (VP) elicits almost identical insulin-stimulatory dose responses in isolated mouse islets and hamster beta (HIT) cells. We have further pharmacologically characterized HIT cell VP receptors by comparing the potencies of a series of VP agonists including the novel V1b agonist, desamino(D-3-(3'-pyridyl)-Ala2,Arg8)VP (d(D-3-Pal)VP), in stimulating insulin secretion and inositol phosphate (IP) production. The relative orders of potency of VP analogues were parallel in both respects: desamino-Arg-VP (dAVP) > Arg-vasotocin (AVT) = VP > oxytocin (OXY) > desamino-D-Arg-VP (dDAVP) > d(D-3-Pal)VP. dAVP, the most potent agonist tested, behaved as a V1 but non-V1a agonist. The potency of d(D-3-Pal)VP relative to VP was 1:134 in stimulating insulin secretion and 1:40 with respect to IP production. In HIT cell monolayers, the relative order of affinity of analogues in competition for binding with [3H]AVP was: dAVP > AVT = VP > V1a antagonist > OXY > dDAVP > V2 antagonist = d(D-3-Pal)VP, in parallel with their biological activity. The relative orders of potency and affinity parallel those reported for corticotrophic V1b receptors. Binding studies with hamster liver membranes indicate that the hepatic VP receptor belongs to the V1a class. We conclude that VP activates phospholipase C and interacts with functional VP receptors of the V1 type, which do not belong to the V1a subclass and which are similar to V1b receptors.
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PMID:Similarities between hamster pancreatic islet beta (HIT) cell vasopressin receptors and V1b receptors. 749 May 38

Vasopressin (AVP), the antidiuretic hormone, is a cyclic nonapeptide that acts through binding to G protein-coupled specific membrane receptors pharmacologically divided into three subtypes (V1a, V1b, and V2) linked to distinct second messengers. Within the family of human AVP receptors, the V2 AVP receptor has been cloned, but the structure of the human V1a and V1b AVP receptors remains unknown. We report here the structure and functional expression of a human V1a AVP receptor complementary DNA isolated from human liver cDNA libraries. Cloning and sequencing of a full-length clone isolated a 1472-nucleotide sequence encoding a 418-amino acid polypeptide with seven putative transmembrane domains typical of G protein-coupled receptors. Amino acid sequence identity with the rat liver V1a AVP receptor, the human and rat V2 AVP receptors, and the human oxytocin receptor was 72, 36, 37, and 45%, respectively. Functional characterization of the cloned receptor was done by transient expression in COS-7 cells and stable expression in Chinese hamster ovary cells. Localization of the expressed receptor at the cellular surface was illustrated by using the fluorescent linear analog phenylacetyl-D-Tyr(Et)-Phe-Gln-Asn-Lys-Pro-Arg-NH2 coupled to fluorescein-avidin by dodecabiotin. Competition binding experiments with phenylacetyl-D-Tyr(Et)-Phe-Val-Asn-Lys-Pro-[125I]Tyr-NH2 and AVP analogs revealed high affinity specific binding sites of the V1a subtype. Saturation binding experiments with [3H]AVP confirmed the presence of a single class of high affinity binding sites. Measurement of AVP-induced inositol phosphate production and calcium mobilization confirmed that the expressed V1a AVP receptor is coupled to phospholipase C via a pertussis toxin-insensitive pathway. Thus, the human V1a AVP receptor belongs to the superfamily of seven-transmembrane segment receptors with a significant sequence identity with the other members of the AVP-oxytocin family of receptors.
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PMID:Molecular cloning, sequencing, and functional expression of a cDNA encoding the human V1a vasopressin receptor. 810 69

Results presented in this study demonstrate that, in rat glomerulosa cells, fluoroaluminate (AlF4-) alone stimulates both cAMP accumulation (maximal stimulation 10-fold, ED50, 24 mM) and total inositol phosphate accumulation (maximal stimulation 12-fold, ED50 14 mM). Despite a transient accumulation of Ins(1,4,5)P3 after AlF4- stimulation, no rapid and transient intracellular calcium mobilization was observed. In contrast to angiotensin II (Ang II) or vasopressin (AVP), AlF4- induces only a slow and sustained increase in intracellular Ca2+. We demonstrate that this increase results from a Ca2+ influx mediated by cAMP-protein kinase A (PKA) pathway since preincubation with H-89, a potent PKA inhibitor, inhibits this influx. Moreover, a short preincubation (15 min at 37 degrees C) of cells with AlF4- or ACTH prevents the initial release of Ca2+ from intracellular stores induced by Ang II, but does not affect the amount of InsPs accumulated under Ang II stimulation. This rapid inhibition of Ang II action is mediated by ACTH- or AlF4(-)-stimulated cAMP production since pretreatment with H-89 leads to a complete reversal. cAMP most likely acts at the level of Ins(1,4,5)P3 receptors since an increase in intracellular cAMP blunts the calcium response induced by addition of exogenous Ins(1,4,5)P3 to permeabilized cells. These results point out that, in rat glomerulosa cells, activation of the cAMP pathway can induce a rapid desensitization of the phospholipase C pathway by acting downstream of inositol phosphate accumulation.
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PMID:Dual effects of fluoroaluminate on activation of calcium influx and inhibition of agonist-induced calcium mobilization in rat glomerulosa cells. 865 54

The role of phosphatidylcholine (PC) and phosphatidylinositol (PI) specific phospholipase C (PLC) enzymes in the release of immunoreactive arginine vasopressin (ir-AVP) from rat hypothalami in vitro was examined. PC-PLC (0.05-01 U ml-1) increased ir-AVP release but PI-PLC (0.01-0.5 U ml-1) did not. The response to a submaximal concentration of PC-PLC (0.075 U ml-1) was inhibited by the protei kinase C (PKC) inhibitor Ro 31-8220 (40 microM) and by removal of extracellular Ca2+ but was unaffected by the nitric oxide (NO) precursor L-arginine (1 mM), the NO synthase inhibitor N omega-nitro-L-arginine benzyl ester (1 mM) and the phospholipase A2 (PLA2) inhibitors quinacrine (100 microM) and dexamethasone (1 microM). The results suggest that PC-PLC plays an important role in AVP secretion. The responses to PC-PLC appear to be mediated by PKC but not by changes in NO synthase or PLA2 activity.
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PMID:The role of phospholipase C in arginine vasopressin secretion by rat hypothalami in vitro. 917 29

The vasopressin (AVP) V3 pituitary receptor (V3R) is a G protein-coupled corticotropic phenotypic marker that is overexpressed in ACTH-hypersecreting tumors. Studies of the agonist/antagonist binding profile and signal transduction pathways linked to the human V3R have been limited because of the scarcity of this protein. To define the signals activated by V3Rs and the eventual changes triggered by developmental or pathological receptor regulation, we developed Chinese hamster ovary (CHO)-V3 cells stably expressing low, medium, or high levels of human V3Rs (binding capacity, <10, 10-25, and 25-100 pmol/mg, respectively). The affinity of the V3R for 21 peptide and nonpeptide AVP analogs was clearly distinct from that exhibited by the human V1R and V2R. AVP triggered stimulation of phospholipase C in CHO-V3 cells (partially sensitive to treatment with pertussis toxin) with a potency directly proportional to receptor density. V3R-mediated arachidonic acid release also was also sensitive to pertussis toxin and more efficacious in cells exhibiting medium than in those with high receptor density. AVP also stimulated the pertussis toxin-insensitive uptake of [3H]thymidine in CHO-V3 cells. The concentration-response curves for this effect were monophasic in cells expressing low and medium levels of V3Rs; on the contrary, a biphasic curve was observed in cells with high V3R density. Coupling of V3R to increased production of cAMP was only observed in CHOV3 high cells, suggesting a negative relationship between increased cAMP production and DNA synthesis. Activation of mitogen-activated protein kinases by V3R was pertussis toxin insensitive, but was dependent on activation of phospholipase C and protein kinase C; both the level and duration of activation were a function of the receptor density. Thus, the human V3R has a pharmacological profile clearly distinct from that of the human V1R and V2R and activates several signaling pathways via different G proteins, depending on the level of receptor expression. The increased synthesis of DNA and cAMP levels observed in cells expressing medium and high levels of V3Rs, respectively, may represent important events in the tumorigenesis of corticotroph cells.
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PMID:The human V3 pituitary vasopressin receptor: ligand binding profile and density-dependent signaling pathways. 932 19

A calcium-sensing receptor (CaR) has functionally been described in the cortical thick ascending limb of Henle's loop (CTAL) of rat and mouse. This G protein-coupled receptor activates phospholipase C and increases the intracellular Ca2+ concentration. We observed that in the mouse CTAL cAMP formation, induced by 10(-8) mol/l AVP, was inhibited by more than 90% when the extracellular Ca2+ concentration ([Ca2+]e) was increased from 0.5 to 3 mmol/l. Measurements of transepithelial potential difference (PDte) in rat and mouse CTAL and medullary thick ascending limb (mTAL) segments and of transepithelial ion net fluxes in the mouse CTAL (isotonic perfusion conditions: 150 mmol/l NaCl in the lumen and bath) showed that an increase in the [Ca2+]e had no effect on basal and arginine vasopressin (AVP, 10(-10) mol/l)-stimulated transepithelial PDte, NaCl and Mg2+ transport. However, Ca2+ reabsorption was strongly inhibited by increased [Ca2+]e. Addition of AVP reversed this inhibitory effect of increased [Ca2+]e. Under hypotonic perfusion conditions (lumen 50 mmol/l NaCl; bath 150 mmol/l NaCl), a high [Ca2+]e induced a 50% decrease in Mg2+ reabsorption which was restored by AVP. Under these conditions, the effects on Ca2+ transport described above were still observed. In conclusion, activation of the CaR in the mouse TAL has no effect on basal and AVP-stimulated transepithelial NaCl reabsorption despite its large inhibitory effect on cAMP synthesis. The CaR, however, could play a role in the regulation of transepithelial Ca2+ and Mg2+ reabsorption.
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PMID:Calcium-sensing receptor: regulation of electrolyte transport in the thick ascending limb of Henle's loop. 993 24


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