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:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vasoactive intestinal peptide (VIP) and secretin are two related peptides that activate adenylate cyclase on membranes of striatal neurons and glial cells from embryonic mouse brain grown in primary culture. On the two cell types, the maximal activation that could be induced by secretin was only 40% above basal activity, which represented less than 15% of the maximal effect obtainable with VIP. From competition experiments performed on glial cells and the neuroblastoma X glioma hybrid, NG 108-15, a cell line known to possess both VIP and secretin sensitive-adenylate cyclase, we demonstrate that secretin does not activate VIP receptors. Furthermore, secretin has an apparent high affinity (EC50 10(-8) M) for its receptors on striatal neurons and NG 108-15 whereas an apparent low affinity (EC50 7 X 10(-6) M) was found on striatal glial cells. This suggests the existence of either two distinct secretin receptors or a desensitized form.
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PMID:Do secretin and vasoactive intestinal peptide have independent receptors on striatal neurons and glial cells in primary cultures? 301 77

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 measured 125I-secretin binding to membranes prepared from rat fundic glands and compared the abilities of natural and synthetic secretin (SN) analogs to inhibit 125I-secretin binding and to activate the cAMP generating system in glandular and subcellular preparations from the fundus and antrum. The natural peptides structurally related to porcine secretin (pSN) included: chicken secretin (cSN), vasoactive intestinal peptide (VIP), porcine peptide with N-terminal histidine and C-terminal isoleucine amide (PHI), helodermin, growth hormone releasing factors isolated from the rat hypothalamus (rhGRF-43, rhGRF-29) or from a human pancreatic tumour (hpGRF-40). These peptides inhibited the binding of 125I-secretin to rat fundic membranes: pSN greater than cSN greater than PHI, VIP and activated the cAMP generating system in fundic glands, according to the following order of potency; pSN greater than cSN greater than PHI, VIP greater than rhGRF-29 greater than rhGRF-43. Porcine peptide with N-terminal tyrosine and C-terminal tyrosine (PYY), GIP, SOM and hpGRF-40 were inactive. Structural requirements for secretin receptor activity were evaluated with four synthetic secretin analogs corresponding to porcine secretin substituted at the N-terminal end by sequence portion of VIP, GIP, GLU and SOM: Ala4-Val5-SN(VIP-SN); Tyr1-Ala2-Glu3-SN (GIP-SN); Gln3-SN (GLU-SN) and Phe1-Phe1-Trp3-Lys4-SN (SOM-SN). The relative potencies of the analogs in fundic and antral preparations were: pSN greater than VIP-SN greater than VIP, GIP-SN greater than GLU-SN greater than SOM-SN for 125I-secretin displacement and cAMP production (glandular cAMP generation and adenylate cyclase activation).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Secretin receptor activity in rat gastric glands. Binding studies, cAMP generation and pharmacology. 301 94

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

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

In an effort to find analogs of glucagon that would bind to the glucagon receptor of the rat liver membrane but would not activate membrane-bound adenyl cyclase, several hybrid molecules were synthesized which contained sequences from both glucagon and secretin. [Asp3, Glu9]Glucagon and [Asp3, Glu9, Arg12]glucagon were inactive in the adenyl cyclase assay even at high concentrations but retained some binding affinity for the receptor. They were able to displace 125I-glucagon completely from its receptor and could completely inhibit the activation of adenyl cyclase by natural or synthetic glucagon. The inhibition index [I/A]50 was approximately 110 for both analogs. [Asp3]Glucagon, [Glu3]glucagon and [Asp3, Lys17, 18, Glu21]glucagon were weak partial agonists, while [Asp3, Glu21]glucagon was inactive and a poor inhibitor. The peptides were synthesized by solid-phase methods and purified to homogeneity by reverse-phase high-performance liquid chromatography on C18 silica columns. These are the first fully synthetic competitive glucagon antagonists to be reported.
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PMID:Glucagon antagonists. Synthesis and inhibitory properties of Asp3-containing glucagon analogs. 303 23

Several glucagon analogs were synthesized in an effort to find derivatives that would bind with high affinity to the glucagon receptor of rat liver membranes but would not activate membrane-bound adenylate cyclase and, therefore, would serve as antagonists of the hormone. Measurements on a series of glucagon/secretin hybrids indicated that replacement of Asp9 in glucagon by Glu9, found in secretin, was the important sequence difference in the N terminus of the two hormones. Further deletion of His1 and introduction of a C-terminal amide resulted in des-His1-[Glu9]glucagon amide, which had a 40% binding affinity relative to that of native glucagon but caused no detectable adenylate cyclase activation in the rat liver membrane. This antagonist completely inhibited the effect of a concentration of glucagon that alone gave a full agonist response. It had an inhibition index of 12. The pA2 was 7.2. An attempt was made to relate conformation with receptor binding. The peptides were synthesized by solid-phase methods and purified to homogeneity by reverse-phase high-performance liquid chromatography on C18-silica columns.
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PMID:Synthetic peptide antagonists of glucagon. 303 68

The capacity of vasoactive intestinal peptide (VIP), peptide histidine-isoleucinamide (PHI), secretin, and a series of analogs to discriminate between VIP-preferring and secretin-preferring receptors that coexist in rat pancreatic plasma membranes was evaluated by their ability to inhibit [125I]iodo-VIP and [125I]iodo-secretin binding and to activate adenylate cyclase. VIP, the VIP analogs [D-His1]VIP, [D-Ser2]VIP, [D-Asp3]VIP and [D-Ala4]VIP, PHI, [D-Phe4]PHI, and secretin inhibited the binding of both ligands in a concentration range of 10(-11) M to 10(-5) M and with a selectivity factor varying from 18,000 to 0.1. The only exception was [D-Phe4]PHI that inhibited 125I-VIP binding only, with an IC50 of 7 nM, and with no inhibition of 125I-secretin binding at 10 microM. The peptides tested stimulated adenylate cyclase in the same membranes and the slope of the dose-effect curves indicated that all peptides, except [D-Phe4]PHI, interacted with at least two classes of receptors: VIP-preferring and secretin-preferring receptors. By contrast, the dose-effect curve of [D-Phe4]PHI activation of adenylate cyclase was monophasic and competitively modified by [D-Phe2]VIP (a VIP antagonist) but not by secretin(7-27) (a secretin antagonist), indicating an interaction with VIP-preferring receptors only. Thus, [D-Phe4]PHI appears to be a highly selective tool to characterize these receptors.
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PMID:[D-Phe4]peptide histidine-isoleucinamide ([D-Phe4]PHI), a highly selective vasoactive-intestinal-peptide (VIP) agonist, discriminates VIP-preferring from secretin-preferring receptors in rat pancreatic membranes. 303 4

The effect of vasoactive intestinal peptide (VIP) upon adenylate cyclase (AC) activity has been determined in defined microdissected renal tubules isolated from collagenase-treated rabbit kidneys. In the presence of 10 microM GTP, 1 microM VIP gave marked stimulations of AC over basal values in the bright portion of the distal convoluted tubule (DCTb) (10.1-fold), and in the collecting tubule isolated from the inner stripe of the outer medulla (OMCTi, 7.8-fold). Less pronounced effects of VIP were found in the medullary collecting tubule isolated from the outer stripe (2.5-fold) and in the granular portion of the distal convoluted tubule (2.0-fold). VIP stimulation of AC activity in these segments amounted to 25 to 40% of the effect elicited by other agonists (arginine vasopressin, calcitonin or parathyroid hormone) in their respective target segments. A low response to VIP was observed in the cortical thick ascending limb (1.8-fold) which represented less than 5% of the calcitonin-stimulated AC activity. In the thin descending limb VIP produced a slight and variable stimulation of AC. VIP was without effect upon AC in the convoluted and straight portions of the proximal tubule, the medullary thick ascending limb and the cortical collecting tubule. Half-maximal stimulation of AC by VIP was observed at 26 +/- 10 nM (n = 3) in OMCTi and at 19 nM (n = 2) in DCTb. Related peptides glucagon, secretin and PHI gave lower stimulations of AC compared to VIP in OMCTi. Conversely for rat OMCTi, under identical conditions, glucagon was much more effective than VIP.
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PMID:Distribution of vasoactive intestinal peptide-sensitive adenylate cyclase activity along the rabbit nephron. 317 93

Crude membranes (27,000 g pellets) from five normal human pancreases were prepared. In the presence of GTP, the peptides of the secretin family stimulated adenylate cyclase activity, their order of potency being: secretin greater than helodermin greater than peptide histidine isoleucinamide (PHI) greater than or equal to vasoactive intestinal peptide (VIP) greater than growth hormone releasing factor (GRF) (1-29)-NH2. In addition, helodermin and PHI were more efficient than secretin. Secretin (3-27) inhibited fully the secretin stimulation and partially only the helodermin and PHI stimulation of the enzyme. Secretin receptors were investigated by the ability of secretin and related peptides to inhibit tracer binding. [125I]Secretin binding was fully inhibited by secretin (Kd 0.8 nM), helodermin (Kd 200 nM), and PHI (Kd 250 nM). VIP and GRF(1-29)-NH2 induced partial (20%) inhibition at a high 10 microM concentration. The fragments secretin (2-27), (3-27), (4-27), and (7-27) showed the same low potency and efficacy based on their ability to stimulate adenylate cyclase and to occupy secretin receptors. The analogues [Val5]secretin and [Ala2]secretin had a higher potency than secretin. Based on this comparison of adenylate cyclase stimulation and [125I]secretin binding inhibition, it is tempting to conclude that the human pancreas: (a) possesses highly specific secretin receptors and (b) such receptors could not fully account for the whole pattern of adenylate cyclase activation by related peptides, so that the presence of an added type of "helodermin-PHI-preferring" receptors is suggested.
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PMID:Secretin receptors in human pancreatic membranes. 318 83


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