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 transfected the COS-7 cells with cDNAs encoding different human somatostatin receptor (hSSTR) subtypes, and found that hSSTR subtypes mediate not only the inhibition of forskolin-induced cAMP accumulation but also the stimulation of phospholipase C (PLC) and Ca2+ mobilization. Activation of PLC by 1 microM somatostatin (SRIF) was in the order of: hSSTR5 > hSSTR2 > hSSTR3 > hSSTR4 >> hSSTR1. Pertussis toxin (PTX) treatment completely or partially reversed the PLC activation. 1 nM SRIF was equally effective for adenylate cyclase (AC) inhibition in a PTX-sensitive manner, in all the cells expressing different hSSTRs, except for hSSTR1. Nevertheless, SRIF stimulated AC even in the presence of forskolin at higher doses of SRIF in PTX-treated hSSTR5-expressing cells. We conclude that the cloned hSSTRs differentially couple to PTX-sensitive and -insensitive G-proteins to modulate PLC, Ca2+ mobilization and AC.
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PMID:Phospholipase C activation and Ca2+ mobilization by cloned human somatostatin receptor subtypes 1-5, in transfected COS-7 cells. 803 40

To elucidate the signaling events mediated by specific somatostatin receptor (SSTR) subtypes, we expressed SSTR1 and SSTR2 individually in rat pituitary GH12C1 and F4C1 cells, which lack endogenous somatostatin receptors. In transfected GH12C1 cells, both SSTR1 and SSTR2 coupled to inhibition of Ca2+ influx and hyperpolarization of membrane potential via a pertussis toxin (PTx)-sensitive mechanism. These effects reflected modulation of ion channel activities which are important for regulation of hormone secretion. Somatostatin analogs MK678 and CH275 acted as subtype selective agonists as expected. In transfected F4C1 cells, both SSTR1 and SSTR2 mediated somatostatin-induced inhibition of adenylyl cyclase via a PTx-sensitive pathway. In addition, activation of SSTR2 in F4C1 cells, but not SSTR1, stimulated phospholipase C (PLC) activity and an increase in [Ca2+]i due to release of Ca2+ from intracellular stores. Unlike adenylyl cyclase inhibition, the PLC-mediated response was only partially sensitive to PTx. To determine the structural determinants in SSTR2 necessary for activation of PLC, we constructed chimeric receptors in which domains of SSTR2 were introduced into SSTR1. Chimeric receptors containing only the third intracellular loop, or all three intracellular loops from SSTR2, mediated inhibition of adenylyl cyclase, but failed to stimulate PLC activity as did wild-type SSTR2. Furthermore, the C-terminal tail of SSTR2 was not required for coupling to PLC. Thus, by expressing individual somatostatin receptor subtypes in pituitary cells, we have identified both overlapping and distinct signaling pathways for SSTR1 and SSTR2, and have shown that sequences other than simply the intracellular domains are required for SSTR2 to couple to the PLC signaling pathway.
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PMID:Both overlapping and distinct signaling pathways for somatostatin receptor subtypes SSTR1 and SSTR2 in pituitary cells. 922 36

Total [3H]phosphoinositide (IPx) accumulation, a measure of phospholipase C (PLC) activity, induced by somatostatin (somatotropin release-inhibiting factor, SRIF) and cortistatin (CST) analogues was studied at human somatostatin receptor subtypes 1-5 (hsst1-5) recombinantly expressed in CCL39 (Chinese hamster lung fibroblast) cells. SRIF14 (10 microM) stimulated total [3H]-IPx production 200% and 1070% over basal levels, and increased intracellular Ca2+ ([Ca2+]i) 1600% and 2790%, in cells expressing hsst3 and hsst5 receptors, respectively. The SRIF14-stimulated IPx production was partly blocked by 100 ng/ml pertussis toxin (PTX) (30% and 15% inhibition, respectively). At hsst1, hsst2, and hsst4 receptors, only weak or no stimulation of PLC activity was found (Emax = 114%, 122%, and 102%, respectively). Consequently, hsst3 and hsst5 receptors were subjected to more detailed studies to establish pharmacological profiles of PLC stimulation. At hsst3 receptors, the relative efficacies of most ligands were in the same range (maximum response Emax = 218-267%). At hsst5 receptors Emax varied over a broad range, seglitide, CST17, SRIF28 displaying almost full agonism compared to SRIF14, whereas octreotide and BIM 23052 showed very low partial agonism. BIM 23056 behaved as an antagonist on SRIF14-induced total [3H]-IPx accumulation with a pKB (negative logarithm of antagonist binding constant) of 6.74 at hsst3 receptors, and of 6.94 at hsst5 receptors. The putative cycloantagonist SA showed weak antagonist activity on SRIF14-induced total [3H]-IPx levels at hsst3 (pKB = 5.85), but not at hsst5 receptors. The [3H]-IPx accumulation profiles at sst3/sst5 receptors were compared to their respective radioligand binding ([125I]LTT-SRIF28, [125I][Tyr10]CST14, [125I]CGP 23996, [125I][Tyr3]octreotide binding), to [35S]GTPgammaS binding, and to forskolin-stimulated adenylate cyclase (FSAC) inhibition profiles determined previously in CCL39 cells. The different affinity profiles correlated relatively well at both receptor subtypes with PLC activation (sst3: r = 0.90-0.97; sst5: r = 0.80-0.87). However, [35S]GTPgammaS binding correlated only minimally with stimulation of [3H]-IPx levels at sst5 receptors (r = 0.59), but rather well at sst3 receptors (r = 0.80). A moderate correlation was also observed between inhibition of FSAC activity and stimulation of PLC activity for hsst3 and hsst5 receptors with correlation coefficients of 0.85 and 0.70, respectively. In summary, most SRIF analogues behave as full agonists at hsst3 receptors and agonist-induced phosphoinositide turnover correlates well with radioligand binding, [35S]GTPgammaS binding and inhibition of adenylate cyclase activity, all measured in CCL39 cells. By contrast, at hsst5 receptors, most SRIF analogues behave as intermediate or very low partial agonists (although receptor levels are comparatively high, 7000 vs. 400 fmol/mg), and the agonist-induced phosphoinositide turnover correlates rather poorly with radioligand binding, [35S]GTPgammaS binding or inhibition of adenylate cyclase activity, all measured in the same cell line. Agonist-induced phosphoinositide turnover, [35S]GTPgammaS binding and inhibition of adenylate cyclase activity, show differences both in the rank orders of potency and relative efficacy at hsst3 and markedly at hsst5 receptors, suggesting either that PLC activity is functionally irrelevant or, more probably, that agonist-dependent receptor trafficking is taking place in CCL39 cells.
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PMID:Characterisation of human recombinant somatostatin receptors. 4. Modulation of phospholipase C activity. 1059 91

A family of octapeptide derivatives of somatostatin cyclized via a disulfide bridge (des-AA(1,2,4,5,12,13)[d-2Nal(8)]-somatostatin-14, ODN-8) was identified that has high affinity and selectivity for the human sst(3) somatostatin receptor subtype transfected in CCL39 cells. The binding affinity of carbamoyl-des-AA(1,2,4,5,12, 13)[d-Cys(3),Tyr(7),d-Agl(8)(Me,2-naphthoyl)]-somatostatin-14 (sst(3)-ODN-8) is equal to that of somatostatin-28 for sst(3) and less than one-thousandth that for the other four somatostatin receptor subtypes. Compound sst(3)-ODN-8 potently reverses the somatostatin-28-induced inhibition of forskolin-stimulated cAMP production (pK(B) = 9.07) and reverses the somatostatin-28-induced stimulation of phospholipase C activity (pK(i) = 9.22) in sst(3)-transfected CCL39 cells. [(125)I-Tyr(7)]sst(3)-ODN-8 selectively labels sst(3)-expressing cells with subnanomolar binding affinity (K(D) = 0.27 nM). With the use of this radioligand, sst(3)-expressing human tumors, particularly inactive pituitary adenomas, can be identified with receptor autoradiography; moreover, areas of the human lymphoreticular system express sst(3) binding sites selectively displaced by nanomolar concentrations of sst(3)-ODN-8. Based on the structure-activity relationship of selected analogs substituted at positions 3, 7, and 8, we hypothesize that the basis for sst(3) selectivity, high affinity, and possibly antagonism resides in the ring size of the analog and the unique conformational and structural character of the N-methylated amino-2-naphthoyl side chain of aminoglycine at position 8 and not in the Tyr(7) substitution or in the d-configuration at position 3. The family of labeled and unlabeled sst(3)-ODN-8 analogs represents highly innovative, potent, and specific sst(3)-selective antagonist tools for the study of sst(3)-mediated physiological and pathophysiological conditions that may suggest novel clinical applications.
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PMID:SST3-selective potent peptidic somatostatin receptor antagonists. 1109 48

1. The bovine Galpha(14) is a member of the G(q) subfamily of G proteins that can regulate phospholipase Cbeta isoforms but the extent to which Galpha(14) recognizes different receptor classes is not known. 2. Galpha(14) was cotransfected with a variety of receptors in COS-7 cells, and agonist-induced stimulation of phospholipase C was then measured. 3. Activation of the type 2 but not type 1 somatostatin receptor in cells coexpressing Galpha(14) stimulated the accumulation of inositol phosphates; functional expression of both subtypes of somatostatin receptors was determined by the ability of somatostatin to inhibit cyclic AMP accumulation. 4. Among the three opioid receptors (mu, delta, and kappa), only the delta receptor was capable of stimulating IP formation when coexpressed with Galpha(14) in COS-7 cells. 5. A panel of G(i)- and G(s)-linked receptors was screened for their ability to stimulate IP accumulation via Galpha(14). The adenosine A(1), complement C5a, dopamine D(1), D(2) and D(5), formyl peptide, luteinizing hormone, secretin, and the three subtypes of melatonin (mt1, MT2, and Xenopus) receptors were all incapable of activating Galpha(14), while the alpha(2)- and beta(2)-adrenoceptors were able to do so. 6. Galpha(14)-mediated stimulation of phospholipase Cbeta was agonist dose-dependent. These data demonstrate that although Galpha(14) can interact with different classes of receptors, it is much less promiscuous than Galpha(15) or Galpha(16).
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PMID:Galpha(14) links a variety of G(i)- and G(s)-coupled receptors to the stimulation of phospholipase C. 1126 36

Human urotensin II-(1-11) and its N-terminally shortened analogues, human urotensin II-(4-11)-OH and human urotensin II-(4-11)-NH2 are potent vasoconstrictor peptides in isolated rat thoracic aorta. Human urotensin II-induced tonic aorta ring contractions are inhibited by the Ca2+ channel antagonists, verapamil, nitrendipine and diltiazem; D609 (Tricyclodecan-9-yl-xanthogenate, K), selective inhibitor of phosphatidylcholine-specific phospholipase C and partially by phospholipase C inhibitor U-73122 [1-[6-((17ss-3 Methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl]-1H-pyrrole-25-dione] and a selective inhibitor of phosphatidyl-inositol-specific phospholipase C-ET-18-OCH3 (Edelfosine,1-O-octadecyl-2O-methyl-rac-glycero-3-phosphorylcholine); protein kinase C inhibitors, chelerythrine and NPC-15437 [S-2,6-diamino-N-[[1-(1-oxotridecyl)-2-piperidinyl]methyl]-hexanamide dihydrochloride]; tyrosine kinase inhibitors, genistein and tyrphostin B42 and Rho-kinase inhibitor HA-1077 [1-(5-isoquinolinylsulfonyl)-homopiperazine dihydrochloride]. This indicates that human urotensin II-induced tonic contractions of the rat aorta are mediated by phospholipase C, protein kinase C, tyrosine kinases and Rho-kinase related pathways. In the high K+ medium, human urotensin II induces dose-dependent phasic oscillations of aortic rings. These are inhibited by Ca2+ channel antagonists, the phospholipase C inhibitor, U-73122 and protein kinase C inhibitors, chelerythrine and NPC-15437, indicating that human urotensin II-induced phasic oscillations of the rat aorta are mediated by phospholipase C and protein kinase C-dependent pathways. Given their close structural similarity, several somatostatin analogues, importantly containing DCys5 and DTrp7 and expressing different degrees of somatostatin receptor antagonist activity, were tested for possible inhibitory effects on human urotensin II-induced contractions of the rat aorta rings. Pre-incubation of rat aorta rings in the presence of somatostatin analogues, which are preferentially sst2 specific binders: PRL-2882; PRL-2903 and PRL-2915 at micro-molar concentrations significantly blocked the development of human urotensin II-induced tonic contractions. Somatostatin receptor antagonists dose-dependently inhibited human urotensin II-induced Ca2+ transients in rat thoracic aorta rings. These somatostatin receptor antagonists displayed moderate affinities for recombinant rat and human urotensin II receptor binding sites. The data support the suggestion that urotensin II receptor and somatostatin type 2/5 receptors display similar surface topologies and that analogues of somatostatin could provide useful lead compounds for the development of more potent urotensin II receptor antagonists.
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PMID:Human urotensin II-induced aorta ring contractions are mediated by protein kinase C, tyrosine kinases and Rho-kinase: inhibition by somatostatin receptor antagonists. 1190 7

Somatostatin (SST) and somatostatin receptors (SSTR) are widely distributed in lymphoid tissues. Here, we report on the stimulatory effects of SST in Epstein-Barr virus-immortalized B lymphoblasts. By RT-PCR, we demonstrated the exclusive expression of the somatostatin receptor isoform 2A (SSTR2A) in B lymphoblasts. Addition of SST rapidly increased the cytosolic free calcium concentration [Ca(2+)](i) maximally by about 200 nM, with an EC(50) of 1.3 nM, and stimulated the formation of inositol phosphates. Furthermore, SST increased binding of guanosine 5'-O-(3-thiotriphosphate) by 50% above basal. These effects were partly inhibited by pertussis toxin (PTX), which indicates the involvement of PTX-sensitive G proteins. We provide further evidence that Galpha(16,) a PTX-insensitive G protein confined to lymphohematopoietic cells, is involved in the otherwise unusual coupling of SSTR2A to phospholipase C activation. In addition, SST activated extracellular regulated kinases and induced a 3.5-fold stimulation of DNA synthesis and a 4.4-fold stimulation of B lymphoblast proliferation, which was accompanied by an enhanced immunoglobulin formation. Thus SST exerts a growth factor-like activity on human B lymphoblasts.
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PMID:Signal transduction of somatostatin in human B lymphoblasts. 1238 15

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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