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)

Functional and specific receptors for vasoactive intestinal peptide (VIP) (determined by their capacity to bind 125I-VIP and activate adenylate cyclase) and cyclic AMP-dependent phosphodiesterase activities were characterized in enterocytes of human fetal small intestine between 18 and 23 weeks of gestation. Half-maximal stimulation of the cyclase and inhibition of 125I-VIP binding in membrane preparations were respectively observed at 1.4 and 5 X 10(-10) M VIP. The peptides structurally related to VIP activated the cyclic AMP generating system at pharmacological doses (10(-7) M and above) in the following order of potency: VIP greater than PHI greater than GRF greater than secretin. Other peptides or test substances, including GIP, pancreatic glucagon, somatostatin-14, gastrin, CCK, neurotensin, pancreatic polypeptide, PYY, substance P, histamine and isoproterenol are inactive in this system, while the ubiquitous adenylate cyclase activators NaF, forskolin and prostaglandins were effective. These results, combined with the appearance of intestinal VIP in nerve fibers at 8 weeks and with the morphological and enzymatic maturation at 9-12 weeks of the intestinal mucosa, indicate that this neuropeptide may regulate either the differentiation or function of enterocytes during the early development of human intestinal mucosa.
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PMID:Vasoactive intestinal peptide receptor activity in human fetal enterocytes. 298 18

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

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 the presence of 3-isobutyl-l-methylxanthine, VIP produced a dose-related (3 X 10(-9)-10(-7) M) increase (8-fold) in cAMP production in isolated HEp-2 cells incubated at 15 degrees C in KRP buffer. Among the peptides structurally related to VIP, including secretin (10(-7) M), pancreatic glucagon (10(-6) M), PHI, somatostatin-14 (10(-6) M), hpGRF (10(-8)-4 X 10(-6) M), GIP (2 X 10(-7) M), only PHI (3 X 10(-7) M and above) is able to activate the cAMP-generating system in HEp-2 cells, but at 10(2) times lower potency. Under the same conditions, histamine (10(-3) M) was also ineffective, while PGE2 (10(-7)-10(-4) M) increased (4-fold) basal cAMP levels in HEp-2 cells. The VIP effect is related to the interaction of the peptide on VIP recognition sites (125I-VIP-binding capacity), coupled to the membrane-bound adenylate cyclase. The results indicate that the transformed laryngeal cell line HEp-2 possesses a receptor-cAMP system preferentially activated by VIP (relative potencies: VIP greater than PHI much greater than other peptides of the secretin family), and suggest that this neuropeptide could modulate biological functions in normal laryngeal epithelia in man.
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PMID:Activation of the cAMP-generating system by vasoactive intestinal polypeptide (VIP) in the human laryngeal malignant cell line HEp-2. 608 15

Membrane adenylate cyclase from rat heart was activated by the two gut peptides secretin and vasoactive intestinal peptide (VIP), glucagon, and the beta-adrenergic drug isoproterenol, in the presence of guanosine 5'-triphosphate (GTP). With all the stimuli tested, the optimal magnesium concentration was 5 mM, i.e. in excess over the 0.5 mM ATP substrate concentration and 0.01 mM GTP used as cofactor. Under these conditions, half-maximal adenylate cyclase activation with glucagon, secretin, and VIP was achieved at concentrations of 0.5, 0.5 and 1.0 microM, respectively. Data obtained with the secretin (7--27) fragment, a secretin antagonist, indicate that secretin and VIP acted on the same binding sites, which differed from glucagon binding sites. Structural requirements for secretin activation of cardiac adenylate cyclase were evaluated by comparing the potency and efficacy of parent peptides and synthetic analogs. The gastric inhibitory peptide GIP was inactive. When using 13 mono-or bi-substituted analogs, it appeared that amino acids in positions 1, 2, 3, 4 and 6 were of major importance while those in position 5 and 11 played a relatively minor role.
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PMID:Secretin and VIP-stimulated adenylate cyclase from rat heart. I. General properties and structural requirements for enzyme activation. 719 63

Amylin inhibits glucose-induced insulin secretion in the rat pancreas. To study the mechanism by which amylin acts on the B-cell, we have investigated, in the perfused rat pancreas, the effect of synthetic rat amylin (75 pM) on insulin release elicited by secretagogues acting on the B-cell via the adenylate cyclase/cAMP system, i.e., glucagon (10 nM), gastric inhibitory polypeptide (GIP, 1 nM), forskolin (1 microM) and isobutylmethylxanthine (IBMX, 75 microM). In addition, we examined the effect of amylin on GIP-induced insulin release in pancreata from rats pretreated with pertussis toxin, an agent which inactivates certain Gi proteins coupled to adenylate cyclase. Amylin inhibited the insulin response to glucagon (approx. 70%), GIP (approx. 90%), IBMX (approx. 75%) as well as the early phase of forskolin-induced insulin output (approx. 74%). However, amylin failed to modify GIP-induced insulin release in pancreata obtained from pertussis toxin pretreated rats. These results would indicate that the inhibitory effect of amylin on insulin secretion could be, at least in part, attributed to its interfering with the adenylate cyclase/cAMP system. Furthermore, prevention of the inhibitory effect of amylin on GIP-induced insulin output by pertussis toxin pretreatment, supports the concept that amylin can inhibit insulin release via a pertussis toxin-sensitive Gi protein coupled to the adenylate cyclase system.
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PMID:Amylin (islet amyloid polypeptide) inhibition of insulin release in the perfused rat pancreas: implication of the adenylate cyclase/cAMP system. 751 1

The binding of ovine pituitary adenylate cyclase-activating peptide (PACAP-38) to rat lung membranes was investigated using [125I]PACAP-38 as radioligand. Binding was rapid at 37 degrees C, reversible, saturable, and time, concentration, and temperature dependent. Kinetic parameters derived from saturation experiments revealed a Kd = 100 +/- 15 pM, Bmax = 310 +/- 36 fmol/mg protein, and a Hill slope factor (nH) of 1.17 +/- 0.12. Various chemically synthesized analogues of PACAP-38, as well as related peptides, were tested for their ability to displace [125I]PACAP-38. Of those that had an IC50 < 0.2 microM, the following order of potency was determined: PACAP-38 (IC50 = 25 nM) > or = [Ile2]PACAP-38 (IC50 = 31 nM) > PACAP-27 (IC50 = 54 nM) > [Tyr1]PACAP-38 (IC50 = 104 nM) > GHRH(1-29)NH2 (IC50 = 108 nM) > PHI (IC50 = 181 nM) > [Ser2]PACAP(2-38) (IC50 = 198 nM). Glucagon, PHM, secretin, and GIP exhibited little affinity in the same binding assay. Vasoactive intestinal peptide (VIP) had an IC50 in excess of 1 microM. When [125I]VIP was used as radioligand, PACAP-27 had an IC50 = 0.2 nM > PACAP-38 (IC50 = 0.5 nM) > VIP (IC50 = 16 nM). A novel analog of PACAP-38, [4-Cl-D-Phe6,Leu17]PACAP-38, was able to displace [125I]VIP very efficiently (IC50 = 1 nM), but had little potency in displacing [125I]PACAP-38 (IC50 = 320 nM).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interaction of ovine pituitary adenylate cyclase-activating peptide (PACAP-38) with rat lung membranes. 839 24

Gastric inhibitory polypeptide, originally isolated from porcine intestine, is a gastrointestinal hormone belonging to the vasoactive intestinal peptide (VIP)/glucagon/secretin family. GIP consists of 42 amino acid residues which is derived by proteolytic processing of a GIP precursor. In vivo and in vitro experiments have indicated that GIP auguments glucose-stimulated insulin secretion, suggesting that GIP plays an important role in the regulation of insulin secretion as an incretin. Thus, GIP now is generally referred to as glucose-dependent insulinotropic polypeptide. It is also suggested that GIP may be involved in the pathogenesis of non insulin-dependent diabetes mellitus (NIDDM). GIP exerts its biological actions by binding to its specific receptors, which appear to be coupled to G proteins. We have isolated a cDNA encoding a GIP receptor from a hamster insulinoma(HIT-T15) cDNA library. The hamster GIP receptor is a 462 amino acid protein having seven transmembrane segments. Expression of recombinant of hamster GIP receptors in Chinese hamster ovary (CHO) cells shows that it binds specifically to GIP with high affinity (IC50 = 9.6 nM) and is positively coupled to adenylate cyclase. RNA blot analysis reveals that a 3.8-kb GIP receptor mRNA is expressed at high levels in rat pancreatic islets as well as in HIT-T15 cells.
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PMID:[Gastric inhibitory polypeptide (GIP) and GIP receptor (GIPR)]. 892 Jun 77

The glucose-dependent insulinotropic peptide receptor (GIP-R) is a member of the G protein-coupled receptors. Recent studies have indicated that elevated serum GIP concentrations in type II diabetic patients might induce desensitization of the GIP-R, and this mechanism could contribute to impaired insulin secretion. The cellular and molecular mechanisms governing GIP desensitization are unknown. Here, we report the results of studies on a new family of proteins known as regulators of G protein signaling (RGS) that have been shown to mediate the desensitization process of other receptors. GIP-R and RGS1, -2, -3, and -4 complementary DNAs were cotransfected into human embryonic kidney cells (L293). GIP-stimulated cAMP generation in control cells and in those coexpressing RGS1, -3, and -4 displayed a dose-dependent increase 10 min after GIP treatment. In contrast, RGS2 expression inhibited the GIP-induced cAMP response by 50%, a response similar to that of cells desensitized by preincubation with 10(-7) M GIP. In betaTC3 cells, preincubation of GIP attenuated GIP-induced insulin release by 45% at 15 min and by 55% at 30 min. Expression of RGS2 in the betaTC3 cells significantly decreased GIP-stimulated insulin secretion, whereas glucose-induced insulin release was not affected. RGS2 messenger RNA was identified by Northern blot analysis to be expressed endogenously in betaTC3 and L293 cells, and its level was significantly induced by GIP treatment in betaTC3 cells. Moreover, RGS2 bound Gs alpha protein in an in vitro system, suggesting that RGS2 attenuated the Gs-adenylate cyclase signaling pathway. These results suggest a potential role for RGS2 in modulating GIP-mediated insulin secretion in pancreatic islet cells.
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PMID:Role of regulator of G protein signaling in desensitization of the glucose-dependent insulinotropic peptide receptor. 979 54


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