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)

In view of the evidence that vasoactive intestinal peptide (VIP) may modulate acute inflammatory injury in the lung, we investigated the presence and characteristics of VIP receptors on alveolar macrophages (AMs). We examined the binding of monoiodinated [Tyr(125I)10]-labeled VIP (125I-VIP) to rat AMs (> 96% pure), obtained from Sprague-Dawley rats by bronchoalveolar lavage (BAL). At 23 degrees C, the interaction of 125I-VIP with AMs was rapid, reversible, saturable, and linearly proportional to the number of cells. At equilibrium, the binding was competitively inhibited by 10(-11)-10(-6) M of native peptide [half-maximal inhibition (IC50) = 0.53 +/- 0.34 nM, n = 8], with evidence for two classes of binding sites: one with a high affinity (Kd = 0.20 +/- 0.09 nM) and a low capacity (1,190 +/- 640 sites/cell) and another with a low affinity (Kd = 43.2 +/- 13.8 nM) and a high capacity (51,700 +/- 14,000 sites/cell). VIP-related peptides inhibited the binding with the order of potency: VIP > peptide histidine isoleucine > helodermin >> secretin; glucagon was ineffective. In the presence of 3-isobutyl-1-methylxanthine, VIP dose dependently stimulated adenosine 3',5'-cyclic monophosphate accumulation in intact AMs, with maximal stimulation (6.3 times basal level) at 1 nM, and half-maximal accumulation at 0.23 +/- 0.11 nM VIP (Kd for high-affinity sites). For determination of the mass of the VIP receptor, 125I-VIP was covalently bound to AMs with the cross-linking agent dithiobis succinimidyl propionate. Autoradiographic studies after sodium dodecyl sulfate/polyacrylamide gel electrophoresis of solubilized affinity-labeled cells revealed a single major band of M(r) 76,400. We conclude that VIP binds to specific receptors on rat AMs that are coupled to adenylate cyclase, through which VIP may modulate inflammatory responses within the lung.
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PMID:Characterization of vasoactive intestinal peptide receptors on rat alveolar macrophages. 794 52

We investigated the receptor mechanisms by which vasoactive intestinal polypeptide (VIP) and related peptides exert their effects on tyrosine hydroxylase (TH) gene expression. VIP, secretin, and peptide histidine isoleucine (PHI) each produced increases in TH gene expression, as measured by increases in TH mRNA levels and TH activity. The concentrations at which the effects of these peptides were maximal differed for TH activity and TH mRNA. Moreover, maximal increases in TH activity were 130-140% of control, whereas maximal increases in TH mRNA were 250% of control. The concentration dependence of the increases in TH mRNA in response to the three peptides was analyzed by fitting the data to nonlinear regression models that assume either one or two components to the response. The data for secretin fit best to a model that assumes a single component to the increase in TH mRNA levels. The data derived for PHI and VIP fit best to models that assumed two components to the TH mRNA response. These data suggested that there may be more than one receptor or signal transduction mechanism involved in the response to the various peptides. We examined whether the peptides exerted their effects through common or multiple second messenger systems. The ability of maximally active concentrations of these peptides to stimulate increases in TH mRNA was not additive, indicating that the peptides work through a common receptor or signal transduction pathway. Each peptide stimulated increases in protein kinase A (PKA) activity. Secretin and VIP were ineffective in increasing TH mRNA levels in a PKA-deficient mutant PC12 cell line (A126-1B2). Moreover, the adenylate cyclase antagonist 2',5'-dideoxyadenosine prevented the increase in TH mRNA produced by each peptide. Thus, each peptide requires an intact cyclic AMP second messenger pathway to produce changes in TH gene expression, suggesting that the complex pattern of response to VIP and PHI revealed by concentration-response analysis was due to the actions of these peptides at multiple receptors. To evaluate this possibility, we examined the effect of several peptide receptor antagonists on the increase in TH gene expression elicited by VIP, PHI, and secretin. The secretin antagonist secretin (5-27) (20 microM) had no significant effect on VIP or PHI stimulation of TH gene expression, but reduced the effect of secretin. The VIP antagonist VIP (10-28) (20 microM) reduced the effect of VIP on increasing TH mRNA, but had no significant effect on the response of TH mRNA to secretin or PHI.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Vasoactive intestinal polypeptide-related peptides modulate tyrosine hydroxylase gene expression in PC12 cells through multiple adenylate cyclase-coupled receptors. 809 40

We have cloned and sequenced a cDNA (RPR4) encoding a new member of the secretin/calcitonin/parathyroid hormone (PTH) receptor family. RPR4 was identified by PCR of rat pituitary cDNA, and a full-length clone was isolated from a rat olfactory bulb cDNA library. When RPR4 was functionally expressed in COS 7 cells, cyclic adenosine monophosphate (cAMP) production was stimulated by vasoactive intestinal peptide (VIP), pituitary adenylate cyclase activating peptides (PACAP-38 and PACAP-27) and helodermin, with equal potency. Peptide histidine isoleucine (PHI) and rat growth hormone releasing hormone (rGHRH) also stimulated cAMP production at lower potency. This suggests that RPR4 encodes a novel VIP receptor which we have designated the VIP2 receptor. In situ hybridisation showed that mRNA for this receptor was present mainly in the thalamus, hippocampus and in the suprachiasmatic nucleus.
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PMID:The VIP2 receptor: molecular characterisation of a cDNA encoding a novel receptor for vasoactive intestinal peptide. 822 21

The binding characteristics of vasoactive intestinal peptide (VIP) in the liver membranes of the dog were examined using radioligand binding assay with 125I-VIP and unlabelled peptides and results were compared with those from the rat. The binding of VIP to canine liver membranes occurred in a reversible, saturable, specific and temperature-dependent manner. Guanine nucleotides dose-dependently inhibited VIP binding. The order of potency in competition experiments with unlabelled peptide was: VIP > pituitary adenylate cyclase activating peptide (PACAP)-27 > PACAP-38 >> peptide histidine isoleucine (PHI) = secretin in the dog, and PACAP-27 > PACAP-38 > VIP > PHI > secretin in the rat. PHI and secretin were about 5000 times less potent than VIP in the dog, but secretin was about 100 times less potent than VIP in the rat. The VIP binding sites in canine liver membranes have recognition sites for VIP which differ from those in rat liver membranes. As most of VIP in the portal vein was removed during its passage through the canine liver, the binding sites of canine liver may play a role in degradation of VIP.
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PMID:Characterization of vasoactive intestinal peptide receptors in canine liver membranes. 830 67

The lower airways of guinea pigs were analysed for helospectin and helodermin using immunocytochemistry. A moderate supply of helospectin/helodermin-like immunoreactive nerve fibers and few nerve fibers displaying helodermin immunoreactivity was seen in the smooth muscle, around seromucous glands and small blood vessels in the trachea and around bronchi and pulmonary blood vessels. Helospectin I-, helospectin II- and helodermin-induced suppression of smooth muscle responses were analysed using isolated circular segments of trachea and pulmonary arteries of guinea pigs. In both airways and arteries the peptides caused a concentration-dependent relaxation of precontracted segments. The maximal relaxant activity observed was more pronounced in the airways than in the arteries. The effects of the helospectins and helodermin were compared to those of vasoactive intestinal peptide (VIP), peptide histidine isoleucine (PHI), pituitary adenylate cyclase activating peptide (PACAP) and acetylcholine (ACh). All peptides, with the exception of PACAP, caused a total or nearly total relaxation of the precontracted tracheal segments. In the trachea PACAP was significantly more potent than the other five peptides whereas only small potency differences were seen in the pulmonary artery. The relaxant responses to helospectin I, helospectin II and helodermin in the trachea and the intrapulmonary arteries were unaffected by pretreatment with atropine, prazosin, yohimbine, propranolol, mepyramine and cimetidine. Conceivably, nerve fibers containing helospectin and helodermin may play a role in the regulation of airway resistance and in the regulation of local pulmonary blood flow.
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PMID:Helospectin/helodermin-like peptides in guinea pig lung: distribution and dilatory effects. 835 7

The regulation of amino acid transport by angiotensin II (AII) and cyclic AMP (cAMP) was assessed in cultured vascular smooth muscle cells, using a nonmetabolizable amino acid, alpha-[3H]aminoisobutyric acid (AIB). An exposure time in excess of 2 h was required for AII to elicit a stimulatory response, the magnitude of which increased in a time-dependent manner for 12 h. AII-induced transport was blocked by [1-sarcosine, 8-isoleucine]AII, a competitive inhibitor of AII binding. The effect of AII was not abolished by downregulation protein kinase C with phorbol 12,13-dibutyrate or by use of a protein kinase C inhibitor, suggesting that transport in response to AII can be mediated by a protein kinase C independent pathway. In contrast, the elimination of calcium from the incubation medium reduced AII-stimulated AIB uptake. The calmodulin inhibitor N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide partially inhibited AIB uptake in response to AII, suggesting that calmodulin may be involved in the modulation of AII-stimulated amino acid transport. AIB transport was also increased by elevating intracellular cAMP levels via beta-adrenergic receptor stimulation, the use of a cAMP analog (N6-monobutyryl cAMP), or a phosphodiesterase inhibitor (3-isobutyl-1-methylxanthine) or by direct stimulation of adenylate cyclase with forskolin. cAMP-induced AIB transport was evident within 10 min and peaked within 1 h. At 1 h AII enhanced cAMP-stimulated AIB transport. A possible mechanism for this effect is suggested by the observation that AII potentiated cAMP production in response to isoproterenol and 3-isobutyl-1-methylxanthine.
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PMID:Interactions between angiotensin II and adenosine 3':5'-cyclic monophosphate in the regulation of amino acid transport by vascular smooth muscle cells. 872 30

1. In the feline lower oesophageal sphincter (LOS), the distribution of the carbon monoxide (CO) producing enzymes haem oxygenase (HO)-1 and -2 was studied by immunohistochemistry and confocal microscopy, the HO activity was measured and the possible role for CO as a mediator of relaxation was investigated. 2. HO-2 immunoreactivity was abundant in nerve cell bodies of the submucosal and myenteric plexus. Approximately 50% of the HO-2-containing myenteric cell bodies were also nitric oxide synthase- and vasoactive intestinal peptide (VIP)-immunoreactive. In addition, HO-2 immunoreactivity was seen in nerve fibres, in non-neuronal cells dispersed in the smooth muscle and in arterial endothelium. HO-1 immunoreactivity was confined to non-neuronal cells in the smooth muscle, similar to those positive for HO-2. 3. Activity of HO, measured as CO production, was observed in LOS homogenates at a rate of 1.00 +/- 0.05 nmol mg-1 protein h-1. This production was inhibited by the HO inhibitor, zinc protoporphyrin-IX (ZnPP). 4. In isolated circular smooth muscle strips of LOS, developing spontaneous tone, exogenously administered CO evoked a concentration-dependent relaxation reaching a maximum of 93 +/- 3%. This relaxation was accompanied by an increase in cyclic GMP, but not cyclic AMP levels. The relaxant response was attenuated by methylene blue, but unaffected by tetrodotoxin. Repeated exposure to CO resulted in a progressive reduction of the relaxant response. 5. ZnPP caused a rightward-shift of the concentration-response curves for the relaxant responses to VIP, peptide histidine isoleucine, and pituitary adenylate cyclase activating peptide 27. 6. ZnPP and tin protoporphyrin-IX (another inhibitor of HO) did not affect nonadrenergic, noncholinergic relaxations induced by electrical field stimulation. Nor did ZnPP affect relaxations induced by 3-morpholino-sydnonimine or forskolin. 7. The present findings, showing localization of HO immunoreactivity to both neuronal and nonneuronal cells of the feline LOS, ability of LOS to produce CO and a relaxant effect of CO in circular LOS muscle, suggest a role for CO as a peripheral messenger.
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PMID:Localization and activity of haem oxygenase and functional effects of carbon monoxide in the feline lower oesophageal sphincter. 873 43

We have examined the binding of radio-iodinated vasoactive intestinal peptide (VIP) to rat platelets. The binding was time- and temperature-dependent and was reversible, saturable and specific. Scatchard analysis of binding data suggested the presence of a single class of binding sites, with Kd = 2.49 +/- 0.76 nM and Bmax = 112.1 +/- 54.6 fmol/10(8) cells. Several VIP-related peptides inhibited 125I-VIP binding to rat platelets with the following order of potency: helodermin > or = VIP > peptide histidine isoleucine. Glucagon, secretin, growth hormone-releasing hormone (GHRH), and gastric inhibitory peptide (GIP) were ineffective. VIP and the other peptides increased cyclic AMP production with the same order of potency as the inhibition of binding, but the stimulation by VIP was less marked than that by prostacyclin (PGI2). We conclude that rat platelets have functional, adenylate cyclase-linked, receptors that bind preferentially to helodermin and VIP.
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PMID:Characterization of VIP-and helodermin-preferring receptors on rat platelets. 883 17

The genes for either the TSH receptor (TSH-R) or the stimulatory guanine nucleotide-binding protein subunit (Gs alpha) can undergo somatic mutations in thyroid cells, leading to constitutive activation of adenylyl cyclase and the formation of clonal hyperfunctioning thyroid adenomas. Autonomously functioning thyroid adenomas are thought not to be common precursors of thyroid cancer. If this is the case, mutations of the TSH-R or Gs alpha would not be expected to be highly prevalent in thyroid carcinomas. In this paper we report the results of a screen for structural defects in exon 10 of the TSH-R (which includes the whole serpentine structure, but not the extracellular domain) and of Gs alpha in 30 thyroid carcinomas. Five of these were from patients with functioning metastasis, as we hypothesized that if mutations of these genes were to play a role in the progression to malignancy, they would be more likely to manifest in thyroid cancers that retain unusual differentiated function (i.e. capable of synthesizing enough thyroid hormone to render patients euthyroid or hyperthyroid after total thyroidectomy). None of the 30 tumors had activating point mutations of Gs alpha. Only 2 of 30 had somatic mutations of the TSH-R (codon 632: ACC to GCC, Thr to Ala; and ACC to ATC, Thr to Ile, respectively), the latter in a patient with a thyroid hormone-producting follicular carcinoma. These results suggest that events leading to constitutive activation of the adenylate cyclase signal transduction cascade are not a frequent event in the progression toward differentiated thyroid carcinomas.
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PMID:Structural studies of the thyrotropin receptor and Gs alpha in human thyroid cancers: low prevalence of mutations predicts infrequent involvement in malignant transformation. 892 35

The mediators of nonadrenergic, noncholinergic (NANC) relaxation in the longitudinal muscle of rat jejunum were studied in vitro. Electrical field stimulation (EFS) of segments of rat jejunum induced a rapid transient relaxation followed by a subsequent contraction in the presence of atropine and guanethidine. NG-Nitro-L-arginine (L-NOARG, 10 microM) inhibited the EFS-induced NANC relaxation by about 25%, and L-arginine (1 mM) completely reversed this inhibition. Exogenously added nitric oxide (0.1-10 microM) induced relaxation of the segment. Treatment of the segment with alpha-chymotrypsin resulted in about 50% inhibition of the EFS-induced relaxation. Several peptide candidates for the mediator of NANC relaxation were examined by using selective antagonists of their receptors or by a receptor-desensitization method. Results indicated that vasoactive intestinal peptide, pituitary adenylate cyclase activating peptide, peptide histidine isoleucine, atrial natriuretic peptide and neurotensin are not associated with NANC relaxation of the segments. On the other hand, apamin at 1 microM inhibited the EFS-induced relaxation by 74%. Inhibitory effects of L-NOARG and, apamin or alpha-chymotrypsin treatment on the EFS-induced relaxation were additive and almost complete. Exogenous nitric oxide-induced relaxation was not affected by apamin. Inhibitory junction potentials (i.j.p.'s) were recorded from longitudinal muscle cells of rat jejunum. Apamin at 200 nM abolished i.j.p.'s induced by two pulses of EFS. These results suggest that NANC relaxation in longitudinal muscle of rat jejunum involves two independent components: one is a nitric oxide-mediated minor component, and the other is an unknown substance-mediated apamin-sensitive major component that is inhibited by alpha-chymotrypsin treatment.
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PMID:Nonadrenergic, noncholinergic relaxation in longitudinal muscle of rat jejunum. 907 49


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