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)

The ability of secretin, PACAP-(1-27)-peptide, and ten hybrid peptides to recognize and activate the rat secretin and vasoactive intestinal polypeptide (PACAP type II VIP1) receptors was tested on recombinant Chinese hamster ovary (CHO) cell lines. PACAP had a 2500-fold lower affinity than secretin for the secretin receptor, and secretin had a 300-fold lower affinity than PACAP for the VIP1 receptor. Amino acids 8, 13, and 15 of the PACAP molecule contributed significantly to the low affinity of PACAP for the secretin receptor. The amino acids at positions 5, 9, 10, 15, 16, and unidentified amino acid(s) between positions 17-20 made limited contributions to the low affinity of secretin for the VIP1 receptor. To identify the receptor region that interacts with these amino acids, we constructed chimeric receptors, which consist either of the N-terminal extracellular part of the secretin receptor and the core of the VIP1 receptor (N-Sn/VIP1r) or the N-terminal extracellular part of the VIP1 receptor and the core of the secretin receptor (N-VIP1/Snr), and tested the ability of the hybrid ligands to activate the adenylate cyclase of CHO cells expressing these chimeric receptors. The N-Sn/VIP1 receptors had a higher affinity for secretin than for PACAP. The hybrid peptide 6 that consists of the PACAP-(1-8)-Sn-(9-15)-PACAP-(16-27)-peptide sequence had a 30-fold to 200-fold higher potency than either parent peptide for the chimeric receptor, which suggests that while the N- and/or C-terminal part of the peptide interact with the transmembrane domain of the receptor, the discriminator region 9-15 recognizes the extracellular N-terminal domain of the receptor. This was confirmed by the observation that, out of all the peptides tested, hybrid 6 had the weakest potency for activation of the N-VIP1/Sn chimeric receptors.
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PMID:Interaction of amino acid residues at positions 8-15 of secretin with the N-terminal domain of the secretin receptor. 870 39

The two forms of pituitary adenylate cyclase-activating polypeptide, PACAP27,and PACAP38, are novel members of the vasoactive intestinal peptide (VIP)/secretin/glucagon family of peptides. PACAP receptors that are positively coupled to adenylate cyclase and phospholipase C have been recently identified. We examined the expression of PACAP receptors in the rat cortex, hippocampus, cerebellum and hypothalamus during postnatal development. Functional studies revealed PACAP stimulation of cAMP formation in all the brain areas examined and [3H]inositol monophosphate ([3H]InsP) accumulation only in the cerebellum and hypothalamus. Throughout development, the efficacy or PACAP in stimulating cAMP formation slightly increased in the cortex and hypothalamus and decreased in the hippocampus and cerebellum; PACAP stimulation of [3H]InsP formation decreased in the cerebellum and remained steady in the hypothalamus. The effects of PACAP27 and PACAP38 on cAMP levels and inositol phospholipid hydrolysis were dose-dependent between 1 and 100 nM. In the same brain areas, treatment with VIP increased cAMP formation at doses greater than 100nM and failed to affect [3H]InsP content, thus suggesting the existence of type-1 PACAP receptors. The reverse transcription polymerase chain reaction (RT-PCR) was used to analyse the mRNA expression of type-1 PACAP receptor splice variants. PACAP receptor gene expression in the central nervous system was regulated in a developmental- and tissue-specific manner. The PACAP-R transcript was detected in all the brain areas examined whereas PACAP-R-hop mRNA ocurred only in the cerebellum and hypothalamus. The different expression profiles and functional properties of PACAP receptors in the developing rat brain suggest an involvement of PACAP in histogenesis, maturation and neurotransmission.
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PMID:Tissue-specific and developmental expression of pituitary adenylate cyclase-activating polypeptide (PACAP) receptors in rat brain. 871 2

The expression of the pituitary adenylate cyclase-activating polypeptide/vasoactive intestinal polypeptide (PACAP/VIP) receptor subtypes was evaluated in the normal rat pituitary gland and in different rat spontaneous transplantable SMtTW tumours (SMtTW2 which expresses prolactin (PRL), SMtTW10 which expresses GH and SMtTW3 which expresses both PRL and GH) by measurement of PACAP/VIP-stimulated adenylate cyclase activity and detection of the presence of mRNA coding for the different receptor forms. In normal glands, the order of potency of the peptides suggested that adenylate cyclase activity was mediated through interaction with PACAP selective receptors (PACAP I receptors); mRNAs coding for the PACAP I receptor, but also for the PACAP II VIP2 receptor, were detected. In SMtTW2 tumours, the functional response was close to that observed in the presence of PACAP II VIP2 receptors; mRNAs coding for PACAP I and PACAP II VIP1 and PACAP II VIP2 receptors were detected. In the SMtTW10 tumours, the functional response was complex but compatible with the involvement of PACAP I and PACAP II receptors; mRNAs coding for the PACAP I and PACAP II VIP1 receptors were detected. In the SMtTW3 tumour, the profile was similar to that of the normal pituitary gland and the mRNA coding for the PACAP I receptor only was detected. Thus, while the control of normal pituitary gland adenylate cyclase activity by PACAP and VIP was mediated by PACAP-selective receptors, in spontaneous transplantable tumours a variable profile was observed and PACAP, as well as VIP1 and VIP2 receptors, may contribute to the responses.
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PMID:Pituitary adenylate cyclase-activating polypeptide/vasoactive intestinal polypeptide receptor subtypes are differently expressed in rat transplanted pituitary tumours (SMtTW) and in the normal gland. 878 82

1. Inhibitory junction potentials (IJPs) and relaxations evoked in response to field stimulation (supramaximal voltage, 0.1 ms, single stimulus and 5 stimuli at 5-40 Hz) of non-adrenergic non-cholinergic (NANC) nerves with atropine and phentolamine (each 1 microM) were measured in the guinea-pig internal anal sphincter (gpIAS). The mean resting membrane potential was -44.2 +/- 0.2 mV (n = 1119 cells from 260 preparations). 2. NANC nerve stimulation evoked frequency-dependent IJPs (19.7 +/- 1.1 mV, n = 165, 33 tissues to a single stimulus) and relaxations. IJPs consisted of two tetrodotoxin (1 microM)-sensitive components: one was abolished by apamin (0.3 microM) and the P2-purinoceptor antagonist suramin (100 microM); the other, smaller in amplitude, was sensitive to inhibitors of nitric oxide synthase (NOS, e.g. L-NAME, 100 microM) and the nitric oxide (NO) scavenger oxyhaemoglobin (HbO, 10 microM). 3. ATP (1 mM), vasoactive intestinal polypeptide (VIP, 0.01-0.25 microM) and pituitary adenylate cyclase-activating peptide (PACAP(1-27), 0.84 microM) each hyperpolarized and relaxed the gpIAS; only ATP responses resembled the evoked IJPs in time course. 4. The guanylyl cyclase inhibitor LY83583 (10 microM) abolished apamin-insensitive IJPs and relaxations. The cGMP phosphodiesterase inhibitor M&B 22948 (30 microM) and 8-Br-cGMP (100 microM) each hyperpolarized the gpIAS. 5. Two components comprise the IJP and relaxation evoked in response to NANC nerve stimulation in the gpIAS. One, sensitive to apamin, resembles the response to ATP and is modulated by purinoceptor antagonists; the other, apamin and suramin insensitive, is inhibited by NO antagonists.
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PMID:Neuronal mediators of inhibitory junction potentials and relaxation in the guinea-pig internal anal sphincter. 878 13

Clonal human neuroblastoma cells SH-IN undergo a very conspicuous phenotypic change in culture. Large substrate-adherent cells with a slow growth rate give rise to small cells emerging in focal aggregates and growing to high cell densities. This is accompanied by a dramatic switch in the expression of receptors for the structurally related neuropeptides VIP (vasoactive intestinal polypeptide) and PACAP (pituitary adenylate cyclase activating polypeptide). Large cells expressed mainly PACAP-specific receptors that triggered stimulation of intracellular cGMP production. On the other hand, polyvalent VIP/PACAP receptors positively coupled to adenylate cyclase were mostly observed in the small cells. Both neuropeptides stimulated cell proliferation in large and small cells. These data, together with the previous demonstration of autocrine/paracrine actions of VIP and PACAP in human neuroblastomas, support the idea that these neuropeptides may participate in the establishment of the apparent phenotype in these cancer cells.
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PMID:Switches in the expression and function of PACAP and VIP receptors during phenotypic interconversion in human neuroblastoma cells. 891 56

Functional VIP/PACAP receptors were identified in the human glioblastoma cell line T98G, based on the relative potency of VIP, PACAP and PACAP-38 to stimulate adenylate cyclase activity. Analysis of the T98G cells mRNA by reverse transcription followed by a polymerase chain reaction (RT-PCR) demonstrated the expression of the mRNA coding for the VIP2 receptor subclass only. VIP, PACAP-27 and PACAP-38 were potent and efficIent inhibitors of cell proliferation, assessed by the colorimetric MTT assay. VIP, PACAP-27 and PACAP-38 also reduced the incorporation of 3H-thymidine in T98G cells, but did not significantly alter the percentage of cells present at each stage of the cell cycle. Thus, VIP and PACAP, probably acting through a VIP2 receptor subtype, decreased cell proliferation.
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PMID:VIP and pituitary adenylate cyclase activating polypeptide (PACAP) have an antiproliferative effect on the T98G human glioblastoma cell line through interaction with VIP2 receptor. 892 13

We analyzed the functional and binding properties of the "normal" pituitary adenylate cyclase-activating polypeptide (N-PACAP) type I, PACAP type II/vasoactive intestinal peptide (VIP)1, and chimeric N-PACAP/VIP1 receptors expressed in Chinese hamster ovary cells. The binding properties of the three receptors were investigated using three radioiodinated tracers: 125I-VIP, 125I-PACAP-27, and 125I-PACAP-29 (125I-PACAP-27-Gly28,Lys29-amide). The three tracers labeled very different receptor densities; 125I-PACAP-29 labeled more receptors than either 125I-VIP or 125I-PACAP-27 in the three cell lines. Analysis of the competition curves suggested that the three tracers labeled in a different manner three PACAP I receptor states, two PACAP II/VIP1 receptor states, and three chimeric N-PACAP/VIP1 receptor states in transfected Chinese hamster ovary cells. The previously described PACAP1A and PACAP1B receptors, which differ by their affinities for PACAP-27 and PACAP-38, actually correspond to different PACAP I receptor states. The three receptors were able to increase adenylate cyclase activity when activated by PACAP-38, PACAP-27, or VIP. In contrast with the two parent receptors, the chimeric N-PACAP/VIP1 receptor was activated by PACAP-38 at lower concentrations than PACAP-27, suggesting that the amino-terminal and core receptor domains influence each other and that the conformation of one or both domains was altered in the chimeric compared with wild-type receptors. Comparison of the binding and functional properties of three clones expressing different chimeric N-PACAP/VIP1 receptors densities indicated that 125I-PACAP-29 was necessary to correctly estimate the receptor number and that 125I-PACAP-27 or 125I-VIP labeled only a fraction of the functional receptors. We suspect (but could not demonstrate) that this might also be true for PACAP I and PACAP II/VIP1 receptors.
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PMID:Properties of the pituitary adenylate cyclase-activating polypeptide I and II receptors, vasoactive intestinal peptide1, and chimeric amino-terminal pituitary adenylate cyclase-activating polypeptide/vasoactive intestinal peptide1 receptors: evidence for multiple receptor states. 896 82

Pituitary adenylate cyclase-activating polypeptides (PACAP-27 and PACAP-38) are neuropeptides of the vasoactive intestinal polypeptide (VIP)/secretin/glucagon family. PACAP receptors are expressed in different brain regions, including cerebellum. We used primary culture of rat cerebellar granule neurons to study the effect of PACAP-38 on apoptosis induced by potassium deprivation. We demonstrated that PACAP-38 increased survival of cerebellar neurons in a dose-dependent manner by decreasing the extent of apoptosis estimated by DNA fragmentation. PACAP-38 induced activation of the extracellular signal-regulated kinase (ERK)-type of mitogen-activated protein (MAP) kinase through a cAMP-dependent pathway. PD98059, an inhibitor of MEK (MAP kinase kinase), completely abolished the antiapoptotic effect of PACAP-38, suggesting that MAP kinase pathway activation is necessary for PACAP-38 action.
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PMID:Pituitary adenylate cyclase-activating polypeptide (PACAP-38) protects cerebellar granule neurons from apoptosis by activating the mitogen-activated protein kinase (MAP kinase) pathway. 898 38

RO 25-1553 is a synthetic VIP analogue that induced a long-lasting relaxation of tracheal and bronchial smooth muscles as well as a reduction of edema and eosinophilic mobilization during pulmonary anaphylaxis. In the present study, we tested in vitro the capacity of RO 25-1553 to occupy the different VIP/PACAP receptor subclasses and to stimulate adenylate cyclase activity. The cellular models tested expressed one single receptor subtype: Chinese hamster ovary (CHO) cells transfected with the rat recombinant PACAP I, rat VIP1, and human VIP2 receptors; SUP T1 cells expressing the human VIP2 and HCT 15 and LoVo cells expressing the human VIP1 receptor. RO 25-1553 was threefold more potent than VIP on the human VIP2 receptor, 100- and 600-fold less potent than VIP on the rat and human VIP1 receptors, respectively, and 10-fold less potent than VIP and 3000-fold less potent than PACAP on the PACAP I receptor. RO 25-1553 was a full agonist on the VIP2, the PACAP I, and the rat recombinant VIP1 receptor but a partial agonist only on the human VIP1 receptor. Thus, RO 25-1553 is a highly selective agonist ligand for the VIP2 receptor subclass.
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PMID:The long-acting vasoactive intestinal polypeptide agonist RO 25-1553 is highly selective of the VIP2 receptor subclass. 914 28

Stearyl-Nle17-VIP (SNV) is a novel agonist of vasoactive intestinal peptide (VIP) exhibiting a 100-fold greater potency than the parent molecule and specificity for a receptor associated with neuronal survival. Here, mice deficient in apolipoprotein E (ApoE), a molecule associated with the etiology of Alzheimer's disease, served as a model to investigate the developmental and protective effects of SNV. In comparison to control animals, the deficient mice exhibited (a) reduced amounts of VIP messenger RNA; (b) decreased cholinergic activity (c) significant retardation in the acquisition of developmental milestones: forelimb placing behavior and cliff avoidance behavior; and (d) learning and memory impairments. Daily injections of SNV to ApoE-deficient newborn pups resulted in increased cholinergic activity and marked improvements in the time of acquisition of behavioral milestones, with peptide-treated animals developing as fast as control animals and exhibiting improved cognitive functions after cessation of peptide treatment. Specificity was demonstrated in that treatment with a related peptide (PACAP), pituitary adenylate cyclase-activating peptide, produced only limited amelioration. As certain genotypes of ApoE increase the probability of Alzheimer's disease, early counseling and preventive treatments may now offer an important route for therapeutics design.
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PMID:Protection against developmental retardation in apolipoprotein E-deficient mice by a fatty neuropeptide: implications for early treatment of Alzheimer's disease. 929 69


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