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)

To evaluate the identity of the guanosine triphosphate--binding proteins coupling arginine vasopressin receptor occupancy with activation of phospholipase C, leading to Ca2+ mobilization, and activation of phospholipase A2, leading to arachidonate release and prostanoid formation, we used intact cells, saponin-permeabilized cells, and membranes of the rat mesangial cell. Arginine vasopressin 10(-7) mol/L produced a dose-dependent increase in cytosolic Ca2+ to maximal levels of 500 nmol/L with peak responses occurring within 10 seconds of addition of arginine vasopressin to cells in suspension. Arginine vasopressin 10(-7) mol/L elicited a maximal response. These increases were associated temporarily with a fourfold increase in tritiated D-myo-inositol 1,4,5-trisphosphate formation in prelabeled cells. Pertussis toxin (200 ng/ml) did not inhibit the Ca2+ increase nor did it inhibit the increase in tritiated D-myo-inositol 1,4,5-trisphosphate formation, suggesting a pertussis toxin--insensitive signaling pathway for phospholipase C hydrolysis in response to vasopressin. Membranes prepared from mesangial cells increased D-myo-inositol 1,4,5-trisphosphate formation in vitro in response to arginine vasopressin and guanosine-5'-0(3- thiotrisphosphate), and this stimulation was inhibited by guanosine-5'-0(2-thiodiphosphate), confirming the involvement of a guanosine triphosphate--binding protein. In contrast arginine vasopressin stimulated arachidonate release from intact mesangial cells, and this effect was blocked by pretreating cells with pertussis toxin. To demonstrate that this was through a pertussis toxin--sensitive guanosine triphosphate--binding protein, we permeabilized cells with saponin and determined that arginine vasopressin and guanosine-5'-0(3-thiotriphosphate) stimulated the release of arachidonic acid and the stimulation of guanosine-5'-0(3-thiotriphosphate) was inhibited by guanosine-5'-0(2-thiodiphosphate). Finally, pertussis toxin was able to stimulate adenosine diphosphate ribosylation in vivo of a substrate protein in mesangial cell membranes of 41 kd, and this ribosylation was inhibited by pretreating cells with pertussis toxin. These data suggest that the release of arachidonic acid by vasopressin in glomerular mesangial cells is linked to a pertussis toxin--sensitive guanosine triphosphate--binding protein and that this activation of phospholipase C in vasopressin is linked to a pertussis toxin--insensitive guanosine triphosphate--binding protein.
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PMID:Different guanosine triphosphate-binding proteins couple vasopressin receptor to phospholipase C and phospholipase A2 in glomerular mesangial cells. 133 Dec 76

Arginine vasopressin (AVP) interacts with V1 and V2 receptors to stimulate hydrolysis of phosphoinositides (PI) and formation of cAMP, respectively. The effects of AVP on V2 receptors in the kidney are well characterized. In order to determine whether V1 receptors, coupled to phospholipase C for hydrolysis of PI, are also present in the kidney, we investigated the effects of AVP on PI hydrolysis in tissue slices from the cortex, outer medulla, and inner medulla of the rabbit kidney. We found that 10(-6) M AVP produced a significant increase in PI hydrolysis in the inner and outer medulla but not in the cortex. In the inner medulla, AVP (10(-10) M) produced a greater than 50% increase in PI hydrolysis; the effect was much greater at higher concentrations. AVP-stimulated PI hydrolysis was blocked by a V1 antagonist but not by a V2 antagonist. Increasing the osmolality of the incubation to 600 mosmol/kg water also abolished the effect of AVP on PI hydrolysis in the inner medulla. Furthermore, AVP did not stimulate PI hydrolysis (even in isoosmotic media) in isolated inner medullary collecting duct cells which make a major portion of the inner medulla. Our results indicate: 1) V1 receptors linked to PI system are not present in the inner medullary collecting duct cells but are probably present in blood vessels and/or interstitial cells of the renal medulla; and 2) AVP-stimulated PI hydrolysis in the inner medulla is modulated by the osmolality of the extracellular fluid.
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PMID:Stimulation of phosphoinositide hydrolysis in renal medulla by vasopressin. 216 2

Arginine vasopressin (AVP)-induced formation of inositol phosphates and increased calcium efflux in smooth muscle cells (A-10) were inhibited by short term treatment with phorbol 12,13-dibutyrate (PDBu), an activator of protein kinase C (Ca2+/phospholipid-dependent protein kinase) (Aiyar, N., Nambi, P., Whitman, M., Stassen, F. L., and Crooke, S. T. (1987) Mol. Pharmacol. 31, 180-184). Here we report that prolonged treatment of A-10 cells (48 h) with PDBu markedly enhanced AVP-induced calcium mobilization but inhibited ATP- and thrombin-induced calcium mobilization. PDBu (400 nM) doubled [Ca2+]i induced with 3 nM AVP, while the basal calcium concentrations before and after AVP were not different from those of untreated cells. The EC50 for a 24-h exposure was 2.3 nM PDBu. Phorbol 12-myristate 13-acetate was also effective, while 4-alpha-phorbol 12,13-didecanoate (48 h at 400 nM) was without effect. 4-alpha-phorbol 12,13-didecanoate also did not affect inositol phosphate formation. PDBu markedly enhanced inositol phosphate formation induced by AVP but not by NaF. PDBu did not affect basal inositol phosphate and polyphosphoinositide levels, and cytosolic and membrane-associated phospholipase C activity. PDBu treatment (48 h, 400 nM) decreased membrane-associated and cytosolic protein kinase C activity by 80 and 90%, respectively. However, the dose response and time course of changes in protein kinase C activity did not correlate with the same curves for PDBu enhancement of AVP-induced calcium mobilization. We conclude that prolonged PDBu treatment selectively enhanced AVP-induced calcium mobilization and polyphosphoinositide hydrolysis. These effects were not caused by an increase in vasopressin receptor number and apparent affinity, an increase in phospholipase C activity, G-protein-phospholipase C coupling, formation of polyphosphoinositide, or inhibition of inositol phosphate metabolizing enzymes. Enhancement of the AVP responses did not correlate with desensitization or activation of protein kinase C. We suggest that prolonged PDBu treatment might sensitize a putative V1 receptor-G-protein-phospholipase C complex.
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PMID:Prolonged incubation with phorbol esters enhanced vasopressin-induced calcium mobilization and polyphosphatidylinositol hydrolysis of vascular smooth muscle cells. 252 48

Arginine vasopressin (VP) activates phospholipase C (PLC) and stimulates insulin secretion and inositol phosphate (insP) production in mouse islets and clonal hamster beta cells (HIT). The insulin response to VP is reportedly dependent on extracellular glucose and there is evidence that glucose also activates PLC. The interactions of VP and glucose have been further examined in HIT cells. Glucose stimulated insulin secretion but not insP production and VP stimulated both insulin secretion and insP production in the absence of extracellular glucose. However, in the presence of glucose the insulin and insP responses to VP were potentiated. The phorbol ester, tetradecanoylphorbol acetate (TPA), which activates protein kinase C (PKC), stimulated basal insulin secretion but inhibited insP production. In the presence of submaximal concentrations of VP, 100 nmol/l TPA inhibited VP-stimulated inositol monophosphate production and there was no additivity of stimulated insulin secretion. With a maximal (10 nmol/l) concentration of VP, TPA caused additive insulin secretion and insP levels were stimulated above baseline. Twenty-four hour preincubation with TPA to down-regulate PKC did not inhibit the insulin response to VP. We conclude that extracellular glucose does not activate PLC and is not required for VP-stimulated insulin secretion although it potentiates VP-stimulated insulin secretion and insP production.
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PMID:Vasopressin-stimulated insulin secretion and inositol phosphate production: interactions with glucose and phorbol esters. 761 55

Arginine vasopressin mediates its effects through vasopressin receptor activation and second messenger production. Recent cloning of the V1a receptor provided the opportunity to investigate the possible signal transduction pathways associated with this single vasopressin receptor subtype. When stably expressed in CHO cells, vasopressin stimulated several signal transduction pathways simultaneously including calcium influx, phospholipase A2, phospholipase C, and phospholipase D. Vasopressin-stimulated release of arachidonic acid, IP3 formation, and phosphatidylethanol formation (in the presence of 1% ethanol) were used as indexes of phospholipase A2, phospholipase C, and phospholipase D activation, respectively. V1a receptor-activation stimulated a peak followed by a sustained plateau phase of intracellular calcium. The plateau phase was dependent on extracellular calcium, insensitive to blockers of voltage sensitive calcium channels, blocked by heavy metals, and quenched when MnCl2 was present in the extracellular media. Removal of extracellular calcium blunted the release of IP3, and blocked the release of arachidonic acid and phosphatidylethanol indicating that these responses were at least in part regulated by receptor-operated calcium influx. Vasopressin-stimulated release of arachidonic acid and phosphatidylethanol were augmented with the phorbol ester PMA, and this augmentation was blocked by inhibitors of protein kinase C and absent with long-term PMA treatment. Vasopressin-stimulated IP3 release was inhibited with PMA and the inhibition reversed with protein kinase C inhibitors.
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PMID:The cloned vasopressin V1a receptor stimulates phospholipase A2, phospholipase C, and phospholipase D through activation of receptor-operated calcium channels. 796 20

Arginine vasopressin (AVP) acts in the pituitary gland, in synergy with corticotrophin-releasing factor, to induce ACTH release in response to stressful stimuli. Pituitary AVP receptors in the rat are coupled to phospholipase C, as are the so-called V1-type AVP receptors. The present study examined [3H]AVP binding in membranes prepared from the anterior lobe of the pituitary gland of the pig. [3H]AVP, alone or in competition with analogues, bound to sites in the pig anterior lobe which are pharmacologically similar to those described previously by others in the rat pituitary gland. For comparison, the same competition studies were performed on membrane preparations from the rat liver which contain the classic V1-type AVP receptor. Pituitary and liver AVP-binding sites were dissimilar; both cyclic and linear V1 antagonists had, in general, a much lower affinity for pituitary AVP-binding sites than for those in the liver. Thus, Phaa-D-Tyr(Et)-Phe-Gln-Asn-Lys-Pro-Arg-NH2 (Phaa = phenylacetyl) has a 2500-fold greater affinity for the latter (negative logarithm of inhibition constant (pKi) = 9.64) than for the former (pKi = 6.22). One linear antagonist, Pa-D-Tyr-Phe-Val-Asn-Arg-Pro-Arg-Arg-NH2 (Pa = propionyl) had about equal affinities for liver and pituitary membranes (pKi = 6.39 and 6.53 respectively). Another compound, Phaa-D-Tyr-Phe-Val-Asn-Arg-Pro-Arg-Arg-NH2 had the highest affinity found to date for binding to AVP sites in the pituitary (pKi = 7.43). These findings suggest some ideas for the design of more potent and/or selective AVP analogues acting in the pituitary gland.
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PMID:Vasopressin-binding sites in the pig pituitary gland: competition by novel vasopressin antagonists suggests the existence of an unusual receptor subtype in the anterior lobe. 807 38

Arginine vasopressin (AVP) has been shown to stimulate tyrosine phosphorylation and activation of p42 mitogen-activated protein (MAP) kinase (p42MAPK) in vascular smooth muscle cells (VSMC). In VSMC, AVP increases free intracellular Ca2+ concentration ([Ca2+]i) and activates protein kinase C (PKC) through activation of phospholipase C. The contribution of PKC and [Ca2+]i in p42MAPK regulation was therefore determined. Activation of PKC by phorbol 12-myristate 13-acetate (PMA) stimulated tyrosine phosphorylation and activation of p42MAPK to the same extent as AVP. Inhibition of PKC by staurosporine or downregulation of PKC by PMA pretreatment abolished AVP-induced stimulation of p42MAPK. When [Ca2+]i was elevated to the same level as with AVP, using either ionomycin (0.1 microM) or thapsigargin (0.1 microM), MAP kinase was only partially activated. Elevation of [Ca2+]i to supraphysiological levels by 1 microM ionomycin stimulated MAP kinase activity to the same extent as AVP. This effect was blocked by downregulation of PKC. The intracellular Ca2+ chelator BAPTA [1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid] blocked AVP-induced [Ca2+]i increase but did not affect AVP stimulation of p42MAPK. Thus AVP-induced activation of p42MAPK requires only the activation of PKC but not an increase in [Ca2+]i.
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PMID:AVP-induced activation of MAP kinase in vascular smooth muscle cells is mediated through protein kinase C. 823 19

In pancreatic beta-cells, calcium is required for insulin secretion, but can also stimulate gene transcription. High potassium-induced membrane depolarization and calcium influx have previously been shown to activate kinases that phosphorylate and thereby activate the transcription factor cAMP response element (CRE-binding protein (CREB) binding to CREs. It is unknown, however, whether hormones and neurotransmitters can activate this mechanism. Arginine vasopressin (AVP), bombesin, and acetylcholine potentiate glucose-induced insulin secretion and are known to raise cytosolic calcium levels through binding to cell surface receptors that activate phospholipase C. The effect of AVP on CRE-directed transcription was examined in the beta-cell line HIT. AVP (0.1-100 nM) stimulated gene transcription after transient transfection of a reporter gene that was placed under the transcriptional control of a CRE. This effect was inhibited by a vasopressin V1 receptor antagonist and depended on calcium influx and calcineurin phosphatase activity. By immunoblots with antiphospho-CREB antibodies and by using a Gal4-CREB fusion protein, it was shown that AVP induces the phosphorylation and activation of CREB. Like AVP, bombesin (100 nM) and the muscarinic agonist carbachol (200 microM) stimulated CRE-mediated transcription. These results show that calcium-mediating insulin secretagogues can activate CREB/CRE-directed transcription in HIT cells, offering a mechanism by which these secretagogues could produce long term effects on beta-cell function, changing the pattern of gene expression.
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PMID:Calcium-mobilizing insulin secretagogues stimulate transcription that is directed by the cyclic adenosine 3',5'-monophosphate/calcium response element in a pancreatic islet beta-cell line. 853 17

The entire coding region of an ovine endometrial oxytocin receptor (OTR) cDNA was generated by PCR, subcloned into the SV40 major late promoter expression vector pSVLJ and transiently expressed in Cos-7 cells. A specific OTR antagonist, 125I-labelled d(CH2)5 [Tyr(Me)2,Thr4,Tyr-NH2(9)]-vasotocin (OTA), was used to describe the binding kinetics of the expressed receptor which had a Kd of 4.5 nM and Bmax of 2.4 nM/mg protein (6.8 x 10(5) receptor molecules/transfected cell). The functional properties of the expressed OTR were determined by measuring oxytocin-induced phosphoinositide (PI) hydrolysis. Oxytocin increased PI turnover in OTR transfected cells fourfold in excess of residual endogenous activity, and stimulated phospholipase C (PLC) activity in a dose- and time-dependent manner, confirming that the expressed OTR cDNA was functional. Arginine vasopressin also stimulated PI turnover in a dose-dependent manner; thresholds of responses to oxytocin and arginine vasopressin were 10(-9) M and 10(-7) M respectively. OTA did not increase PI turnover and competitively inhibited the oxytocin-induced response. Direct activation of the pathway by aluminium fluoride and guanosine (3'-O-thio)-triphosphate (GTP gamma S) confirmed that the OTR was G-protein linked. Co-incubation of GTP gamma S with oxytocin shifted the PI-response threshold from 10(-7) M to 10(-9) M and significantly increased the level of response, suggesting that maximum PI turnover was agonist-dependent. The G-protein involved in mediating the signal transduction pathway was pertussis toxin-insensitive and, therefore, probably a member of the Gq subfamily. The PLC inhibitor, U73122, had no effect on oxytocin-induced PI turnover, consistent with the response in endometrial tissue. These data suggest that the signalling pathway mediated by expressed OTR is similar to that attributed to OTR occupancy in ovine endometrium.
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PMID:Functional characterisation of an ovine endometrial oxytocin receptor cDNA transiently expressed in Cos-7 cells. 869 Oct 97

The present study was undertaken to determine whether extracellular adenosine 5'-triphosphate (ATP) promotes cellular proliferation of cultured rat renal inner medullary collecting duct cells. Extracellular ATP increased inositol 1,4,5-triphosphate (IP3) production and cellular free calcium concentration - [Ca2+]i - in a dose-dependent manner. ATP also caused a transient cellular acidification. Extracellular ATP activated mitogen-activated protein (MAP) kinase and [3H]thymidine incorporation in a dose-dependent manner. However, such effects were not obtained with adenosine 5'-diphosphate, adenosine monophosphate, and adenosine. In addition, uridine triphosphate, a P(2u) purinergic agonist, increased IP3 production and activated MAP kinase. 2-Methylthio ATP, a P(2y) purinergic agonist, also increased IP3 production, but did not affect the MAP kinase activity. We also examined the effect of arginine vasopressin on cellular growth. Arginine vasopressin did not alter MAP kinase activity and [3H]thymidine incorporation in cultured rat renal inner medullary collecting duct cells. These results indicate that extracellular ATP activates phospholipase C mediated through P(2u) and P(2y) purinergic receptors and promotes cellular proliferation mediated through P(2u) purinergic receptors in renal inner medullary collecting duct cells.
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PMID:Extracellular ATP promotes cellular growth of renal inner medullary collecting duct cells mediated via P2u receptors. 920 Apr 13


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