Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Three separate sets of receptors sensitive to VIP, GIP and pancreatic/entero-glucagons, have been characterized in HGT-1 cells. The order of relative potencies of VIP receptor agonists was VIP greater than rh GRF-43, rh GRF-29 greater than PHI greater than hp GRF-40, secretin. G-37 was about 4 times less potent than G-29 in HGT-1 cells (G-29 greater than G-37), whereas it was about 20 times more potent than G-29 in rat fundic glands (G-37 greater than G-29). Adenylate cyclase in HGT-1 cells was stimulated by VIP, G-29, G-37 and GIP, over a concentration from 3.16 X 10(-9) to 3.16 X 10(-7) M GIP. The experimental data: (1) support the enterogastrone activity of GIP, via adenylate cyclase activation and somatostatin release by gastric D cells; (2) demonstrate that HGT-1 cells originating from a human fundic tumor are sensitive to the glucagon-like peptides G-29 and -37, as rat fundic glands; (3) indicate that the pharmacological properties of the VIP receptor in this human gastric cell line are similar to those characterized in normal human gastric glands.
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PMID:Functional receptors for VIP, GIP, glucagon-29 and -37 in the HGT-1 human gastric cancer cell line. 301 90

We have examined the effects of hGRF on cyclic AMP and glycogen levels in mouse cerebral cortical slices. hGRF-44-NH2 and hGRF-28-OH did not stimulate cyclic AMP formation nor glycogenolysis and did not antagonize the stimulatory effects of VIP on cyclic AMP formation and glycogenolysis. These observations indicate that despite the structural homologies with VIP, hGRF does not interact with VIP receptors coupled to adenylate cyclase in mouse cerebral cortex. This is in contrast with observations in other tissues and species, such as rat and human intestinal epithelial membranes and rat pancreas. We have also compared the effects of hGRF, VIP, PHI and secretin on Growth Hormone (GH) release and cyclic AMP levels in anterior pituitary cells in vitro. VIP and PHI, but not secretin, promote at a high concentration (10(-6) M) a small but significant release of GH. This GH release is accompanied by increases in cyclic AMP levels. The concentration of VIP and PHI required to elicit these effects is high and suggests that VIP and PHI act as low affinity pharmacological analogs of hGRF on hGRF pituitary receptors.
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PMID:Actions of VIP, hGRF, PHI and secretin: comparative studies in cerebral cortex and adenohypophysis. 301 95

The ability of 30 synthetic GRF(1-29)-NH2 analogs to stimulate adenylate cyclase activity was investigated in membranes from rat adenopituitary, rat liver and rat pancreas. In adenopituitary membranes, GRF and GRF analogs interacted with specific GRF receptors, whereas in liver and pancreatic membranes, they interacted with VIP receptors. The C-terminal moiety of GRF was responsible for GRF receptor recognition as the hybrid analog (His1, D-Ala2)-GRF(1-9), VIP(10-28) stimulated pituitary adenylate cyclase through the occupancy of VIP receptors only. When GRF or VIP receptors were occupied by GRF analogs, the N-terminal part of the ligand appeared critical for adenylate cyclase activation. This was established by testing 30 GRF analogs mono-, bi- or tri-substituted in positions 1 to 10. Major observations included: (a) the characterization of (N-Ac-Tyr1, D-Arg2)-GRF(1-29)-NH2 as an antagonist of GRF-stimulated pituitary adenylate cyclase; (b) the discovery of the (N-Ac-Tyr1, D-Phe2)-, (His1, D-Ala2, D-Ser3, NLeu27)-, and (His1, D-Ala2, D-Thr7, NLeu27)-derivatives of GRF(1-29)-NH2 as specific antagonists of VIP receptors in rat pancreatic membranes; (c) the importance of the free NH2 function of amino acid residue 1 for pancreatic adenylate cyclase activation, and (d) the decreased efficiency of iodinated (Tyr1)-GRF(1-29)-NH2 as opposed to the non iodinated form, in all systems tested.
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PMID:Comparative structural requirements of thirty GRF analogs for interaction with GRF- and VIP receptors and coupling to adenylate cyclase in rat adenopituitary, liver and pancreas. 301 3

Synthetic helodermin was more potent than natural helodermin (purified from the venom of Gila monster) in activating adenylate cyclase in rat liver membranes. Two possible reasons for this discrepancy were discussed. Comparing adenylate cyclase activation to the binding of 125I-natural helodermin and 125I-VIP in the presence of six synthetic helodermin fragments (1-27, 7-35, 13-35, 17-35, 18-35 and 22-35), we conclude that the effects of both synthetic and natural helodermin were mediated through an interaction with VIP receptors. The C-terminal (28-35) extension of these peptides favored VIP receptor recognition. Their N-terminal extremity was not necessary for binding and for ensuing adenylate cyclase activation, illustrating again the atypical coupling of VIP receptors with the effector enzymatic system, in rat liver membranes.
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PMID:Interaction of synthetic N- and C-terminal fragments of helodermin with rat liver VIP receptors. 301 6

A model is proposed for the receptors of the VIP family peptides including a ligand and a cellular domain. Specificities of the receptors are due to different ligand binding sites. Three subgroups of the family can be distinguished accordingly: glucagon and oxyntomodulin; GIP; VIP, secretin r and hGRF, PHI and PHM. In the same species, the expression of these different sites is cell-specific resulting in a stoichiometry of the ligand-receptor interaction which is compatible with physiological regulation of cell function. Specificities of the interaction as studied by native and synthetic analogs is supported both by restricted sequences of amino acids (such as that including the N-terminal histidine residue), and membrane-induced configuration of the ligand. Identity of the receptors is related to their interactions with subunits of the adenylate cyclase system. Arguments are put forward indicating that the alpha subunit of the guanyl regulatory protein is a reasonable candidate for directly transducing to the adenylyl cyclase the information contained in the activated ligand-binding site subunits. Evidence of functional and molecular heterogeneity of the recognizing site and of the alpha subunits leads to the supposition that some types of specific complementarity is retained at this level of interaction, further enhancing the possibility of species and cell differences. On the other hand, the identities found in other sequences of the alpha and ras oncogene products extend to the receptor of the VIP family peptides a pattern of organization which is similar to that recently described for the insulin family of receptors. The role of ligand specific receptor mediated regulation in homologous or heterologous desensitization is reviewed in brief for the peptides of the VIP family as well as the appearance of the specific receptor during the ontogenesis or the cell differentiation. The co-distribution of plasma membrane receptors from other families further adds to the cell specificity resulting for each differentiated cell in unique patterns of recognizing site. Some examples of receptor-receptor interaction are given, indicating that the integration of the different signals by cells might occur at an early step through the transmembranair domain of the receptor.
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PMID:The receptors of the VIP family peptides (VIP, secretin, GRF, PHI, PHM, GIP, glucagon and oxyntomodulin). Specificities and identity. 301 7

Bovine thymic peptide extract (1-100 micrograms/ml) is shown to completely inhibit the binding of [125I]VIP to rat blood mononuclear cells, lymphoid cells of spleen, and liver plasma membranes. In the three models, the bovine thymic peptide extract inhibits [125I]VIP binding with a potency that is 4000-7000 times lower than that of the native VIP, on a weight basis. In rat liver plasma membranes, the bovine thymic peptide extract stimulates adenylate cyclase with a maximal efficiency that is similar to that of VIP. At maximal doses, VIP and thymic peptide extract do not exert an additive effect on adenylate cyclase, suggesting that the activation of the enzyme by the bovine thymic peptide extract occurs through VIP receptors. Finally, no VIP-like immunoreactivity was detected in the thymic peptide extract using an antiserum raised against mammalian VIP. All these data suggest the presence in the bovine thymic peptide extract of a new substance which behaves as a VIP agonist in rat.
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PMID:Interaction of a bovine thymic peptide extract with vasoactive intestinal peptide (VIP) receptors. 302 Dec 53

The effect of chronic lead treatment on pituitary dopamine (DA) D2 receptors was studied by measuring (-)sulpiride-displaceable [3H]spiroperidol-binding and DA-inhibited adenylate cyclase. Receptor number was reduced in lead-exposed animals and bromocriptine was less able to inhibit cyclase activity in pituitary homogenates. In addition, the capacity of DA to inhibit the VIP-stimulated cAMP formation was decreased.
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PMID:Chronic lead exposure alters dopaminergic mechanisms in rat pituitary. 302 29

The biological activities of VIP derivatives as photoaffinity labels are described. The derivatives were obtained by VIP modification with azido phenyl glyoxal at arginyl residues 12 and 14 ([Az Bz Arg12-14]VIP) or only at position 14 ([Az Bz Arg14]VIP). The first derivative exhibited pronounced hydrophobic properties. The level of cAMP produced in HT 29 cells by this derivative represented 15% of that obtained by VIP at equimolar concentration (10(-10) M). The second derivative ([Az Bz Arg14]VIP) was synthesized by a new procedure, in which amino acids of VIP buried in the active site of the receptor were protected from azido phenyl glyoxal. This analog retained a high binding affinity for receptor (Kd, 0.5 nM for [125I-Tyr,Az Bz Arg14]VIP vs. 0.1 nM for [125I] VIP) and was found to be biologically active, as judged by stimulation of adenylate cyclase activity (production of cAMP was 120 pmol/10(6) cells vs. 140 pmol for VIP at 10(-10) M). Photolysis of this analog in the presence of HT 29 cell membranes resulted in a stimulation of adenylate cyclase which persisted in spite of repeated washings. Our findings indicate that [125I-Tyr,Az Bz Arg14] VIP binds covalently to active sites to form an active peptide-receptor complex. When low affinity binding sites were specifically photolabeled using a selective protection of high affinity sites by incubating membranes with 10(-10) M VIP for 5 min, the derivative did not stimulate adenylate cyclase activity. This suggests that VIP acts through a high affinity site to produce the biological activity and that the functional relevance of low affinity sites is unclear.
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PMID:Selective photolabeling of high and low affinity binding sites for vasoactive intestinal peptide (VIP): evidence for two classes of covalent VIP-receptor complexes in intestinal cell membranes. 302 93

Treatment of HT29 cells with the tumor promoting phorbol ester PMA resulted in an attenuation of VIP-stimulated cAMP production in intact cells and VIP-stimulated adenylate cyclase activity in cell membranes. PMA did not decrease the ability of cholera toxin and forskolin to elevate cAMP levels in intact cells. Fluoride-stimulated adenylate cyclase activity in HT29 cells homogenates was not affected by PMA. The maximal VIP binding capacity of homogenates prepared from HT29 cells treated with PMA was decreased by 50%. It is concluded that protein kinase C regulates VIP receptor function possibly through phosphorylation of the VIP receptor.
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PMID:Phorbol ester induces loss of VIP stimulation of adenylate cyclase and VIP-binding sites in HT29 cells. 302 47

Porcine VIP was iodinated by the chloramine-T method. The reaction products, which were separated by high pressure liquid chromatography, included residual native VIP, oxidized VIP and at least two iodinated VIP species. The iodo-VIP derivatives were recognized by antibodies raised against VIP and by VIP receptors. Furthermore, they appear to be approximately equipotent agonists to VIP in activating the adenylate cyclase in membranes from the rat submandibular salivary gland and in the stimulation of pancreatic secretion in vivo.
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PMID:Iodinated derivatives of the vasoactive intestinal polypeptide (VIP) are agonists at the cat pancreas and the rat submandibular salivary gland. 302 65


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