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)

Noradrenergic neurons in the locus ceruleus contain neuropeptide Y and galanin, which project to the hypothalamic region. We have investigated the regulatory mechanisms of these peptides on norepinephrine release in rat hypothalamic slices in vitro. Neuropeptide Y and galanin significantly inhibited the stimulation-evoked [3H]norepinephrine release in a dose-dependent manner (1 Hz: S2/S1 ratio (mean +/- SEM), control 0.947 +/- 0.040, n = 11, neuropeptide Y 1 x 10(-8) M 0.509 +/- 0.013, n = 8, p less than 0.01, neuropeptide Y 1 x 10(-7) M 0.283 +/- 0.021, n = 8, p less than 0.01; galanin 1 x 10(-7) M 0.448 +/- 0.026, n = 8, p less than 0.01, galanin 1 x 10(-6) M 0.261 +/- 0.023, n = 8, p less than 0.01). The inhibition of norepinephrine release by the alpha-2 agonist UK 14,304 was potentiated by neuropeptide Y and galanin. The blockade of the alpha 2-adrenergic receptors by RX 781094 diminished the inhibitory effects of neuropeptide Y and galanin on norepinephrine release. Pretreatment of hypothalamic slices with islet activating protein (a toxin that interferes with the coupling of inhibitory receptors to adenylate cyclase) attenuated the suppression of norepinephrine release by UK 14,304, neuropeptide Y, and galanin. These results support the idea that neuropeptide Y and galanin are involved in the regulation of central adrenergic transmission partially mediated by alpha 2-adrenergic receptors and islet-activating protein-sensitive guanosine triphosphate-binding proteins in rat hypothalamus.
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PMID:Neuropeptide Y and galanin in norepinephrine release in hypothalamic slices. 247 59

Several neuropeptides, calcitonin gene-related peptide (CGRP), galanin, neuropeptide Y (NPY), pituitary adenylate cyclase activating peptide (PACAP), substance P (SP), vasoactive intestinal polypeptide (VIP), the noradrenergic marker dopamine beta-hydroxylase (DBH) and the general neuroendocrine marker PGP 9.5 were localized by immunocytochemistry in the parathyroid glands of chicken, rat, guinea-pig, cat, dog and sheep. The general density of innervation varied markedly among the species. Nerve fibers storing CGRP, NPY, PACAP, SP and VIP were present in all species examined. Galanin-containing fibers occurred in all species except guinea-pig and adrenergic (DBH-containing) fibers in all species except chicken and guinea-pig. Generally, the nerve fibers were distributed around blood vessels, in the parenchyma as single scattered fibers, and often also within the capsule. Coexistence studies were performed in cat and sheep. CGRP and SP invariably coexisted in the same nerve fibers. Further, CGRP partially coexisted with PACAP, NPY was observed in the same nerve fibers as DBH. A small population of NPY-containing fibers also seemed to contain galanin (cat only). VIP and NPY coexisted in a population of nerve fibers in the parenchyma. A population of VIP-containing fibers also seemed to contain PACAP. The results indicate the presence of several neuropeptides in the parathyroid glands. As judged by their distribution patterns they may regulate both secretory activity and blood flow, some of them possibly in a cooperative manner.
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PMID:Peptide-containing nerve fibers in the parathyroid glands of different species. 751 98

The ubiquitous neuropeptide galanin controls numerous functions such as endocrine secretions, intestinal motility, and behavioral activities. These regulatory effects of galanin are mediated through the interaction with specific membrane receptors and involve the pertussis toxin-sensitive guanine nucleotide binding proteins Gi/Go as transducing elements. We report here the isolation of a cDNA coding for a human galanin receptor from a Bowes melanoma cell line cDNA expression library, by using a radioligand binding strategy. The nucleotide sequence of the cloned receptor reveals an open reading frame encoding a 349-amino acid protein with seven putative hydrophobic transmembrane domains and significant homology with members of the guanine nucleotide binding protein-coupled neuropeptide receptor family. The cloned receptor expressed in COS cells specifically binds human, porcine, and rat galanin with high affinity (Kd in the nanomolar range) and mediates the galanin inhibition of adenylate cyclase. A 2.8-kb galanin receptor transcript was identified in several human tissues. Cloning of this galanin receptor should enhance our knowledge of its distribution, structure, and function in human physiology and pathophysiology.
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PMID:Molecular cloning of a functional human galanin receptor. 752 88

Galanin inhibits adenylate cyclase activity and insulin secretion and modulates ion channels in pancreatic beta-cells through pertussis-toxin-sensitive G-protein(s). Antibodies directed against the C-terminal region of specific G-protein alpha-subunits were used to determine which G-protein(s) couple galanin receptors to inhibition of adenylate cyclase in the rat insulinoma cell line RINm5F. Preincubation of membranes with EC antibody (anti-alpha i3) decreased the inhibition of forskolin-stimulated adenylate cyclase activity by galanin (100 nM) by 45% compared with control IgG (P < 0.05) whereas preincubation with AS (anti-alpha i1, alpha i2) or GO (anti-alpha o) antibodies had no significant effect. To confirm these results, RINm5F cells were exposed intermittently over a 4-day period to phosphorothioate oligodeoxynucleotides that were either sense or antisense to alpha i1, alpha i2, alpha i3 or alpha o. Oligodeoxynucleotides antisense to alpha i2, alpha i3 and alpha o specifically decreased the levels of the targeted alpha-subunit in membranes. alpha i1 was undetectable in these cells. Inhibition of adenylate cyclase activity by galanin was largely abolished in membranes from cells exposed to the oligodeoxynucleotide antisense to alpha i3, whereas all other oligodeoxynucleotides had no significant effect on this pathway. Indirect immunofluorescence and immunoblotting of specific membrane fractions with EC antibody show significant localization of alpha i3 to intracellular membrane compartments. These results suggest that Gi3 is the G protein that couples galanin receptors to inhibition of adenylate cyclase activity in RINm5F cells.
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PMID:Inhibition of adenylate cyclase activity by galanin in rat insulinoma cells is mediated by the G-protein Gi3. 752 40

It is unclear whether the inhibition of insulin release by galanin is entirely explained by an interference with the secretory process at a step distal to the rise of cytoplasmic Ca2+ and to the action of second messengers in pancreatic B-cells. In this study, normal mouse islets were used to assess the functional significance of the effects of galanin on other signalling pathways. In the presence of 15 mM glucose, galanin caused a small repolarization of the B-cell membrane and a sustained decrease in the Ca(2+)-dependent electrical activity. These changes were largely prevented by tolbutamide and by arginine. Under these conditions the concentration-dependence curve of galanin inhibition of insulin release was shifted to the right. The IC50 was increased 4-5-fold from a control value of 1.8 nM in the presence of glucose alone. This was not the case when insulin release was increased by cytochalasin B, an agent that acts on the filamentous cell web. We also evaluated the role of the changes in cAMP. To bypass the inhibition of adenylate cyclase produced by galanin, the islets were provided with exogenous, membrane permeant cAMP. When 10 mM glucose and 0.25 mM dibutyryl cAMP were combined, control insulin release was similar to that produced by 15 mM glucose alone. Neither the repolarization of the membrane nor the inhibition of insulin release by galanin were affected. A higher concentration of dibutyryl cAMP (0.5 mM) depolarized the B-cell membrane in the presence of 15 mM glucose and partially antagonized the effects of galanin on membrane potential and insulin release.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Significance of membrane repolarization and cyclic AMP changes in mouse pancreatic B-cells for the inhibition of insulin release by galanin. 752 34

This study characterizes regional regulation of adenylate cyclase by galanin, neuropeptide Y (NPY), secretin and vasoactive intestinal peptide (VIP) in rat brain frontal cortex, hypothalamus and hippocampus. In our experimental system, galanin caused small detectable activation (10-20%) of basal adenylate cyclase activity in frontal cortex and hippocampus but had no effect on basal adenylate cyclase activity in hypothalamus. Galanin inhibited forskolin-stimulated adenylate cyclase in all three brain regions-hypothalamus, hippocampus and frontal cortex by 54.5%, 44.3% and 25.7%, respectively. NPY reduced basal and forskolin-stimulated enzyme activities by 35% only in frontal cortex, but not in the other two brain areas. Secretin had no effect in frontal cortex but caused similar adenylate cyclase activation in hypothalamus and hippocampus. VIP had a stimulatory effect of 32.8% and 32.4% in frontal cortex and hippocampus, respectively. The results indicate regional differences in adenylate cyclase modulation by the four peptides and reveal interesting relations in comparison with peptide and receptor densities in the three investigated brain regions.
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PMID:Regulation of adenylate cyclase by galanin, neuropeptide Y, secretin and vasoactive intestinal polypeptide in rat frontal cortex, hippocampus and hypothalamus. 753 1

Rat galanin inhibits basal as well as forskolin-stimulated adenylate cyclase activity in rat ventral and dorsal hippocampus. The inhibition of adenylate cyclase activity, both basal and forskolin-stimulated, is characterised by IC50 values being 250-fold lower in ventral hippocampus (IC50 = 1.1 nM) compared to the dorsal hippocampus (IC50 = 270 nM). The maximal inhibition of basal and forskolin-stimulated adenylate cyclase activity in both ventral and dorsal hippocampus in the presence of 10 microM rat galanin is 34-45%. The analysis of the binding data obtained with 125I-labelled Tyr26-porcine galanin as a tracer reveals similar binding constants for rat galanin in both ventral and dorsal hippocampus with 4.8-fold higher concentration of galanin receptors in the ventral hippocampus. Putative galanin receptor subtype differences between the ventral and dorsal hippocampus have been noted by Hedlund et al. (Eur. J. Pharmacol., 224 (1992) 203-205). This study yields further confirmation for the existence of different galanin receptor subtypes or for differential coupling of galanin receptors to the adenylate cyclase in the dorsal versus ventral hippohampus.
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PMID:Differential regulation of adenylate cyclase activity in rat ventral and dorsal hippocampus by rat galanin. 754 Feb 72

Galanin has numerous effects on gastrointestinal smooth muscle. However, because of the lack of specific inhibitors, it is not known which are physiological and which are pharmacological. This study investigates the ability of two chimeric galanin analogs, [# 1-galantide = (M-15) = [galanin (1-13)-substance P(5-11)] and #2-M-35[galanin(1-13)bradykinin (2-9)], which were recently reported to function as galanin-receptor antagonists in the CNS, to interact with galanin receptors on rat jejunal muscle strips or dispersed smooth muscle cells from guinea pig stomach. In both systems each chimeric analog had agonist activity and was as efficacious as galanin. Cross-desensitization experiments demonstrated that in the jejunal muscle strips, both chimeric analogs were causing muscle contraction by interacting with the galanin receptor. In dispersed smooth muscle cells, galanin, as well as each chimeric analog, caused muscle relaxation, whereas substance P and bradykinin both caused muscle contraction. Each chimeric analog was equipotent to galanin in inhibiting binding of 125I-galanin, and there was close agreement between their abilities to occupy the galanin receptor and cause relaxation. Each chimeric analog also activated adenylate cyclase and increased cAMP characteristic of relaxants. These studies demonstrate these chimeric analogs will not be useful for defining the physiological role of galanin in altering gastrointestinal motility, because they function as full galanin-receptor agonists instead of as galanin-receptor antagonists.
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PMID:Chimeric galanin analogs that function as antagonists in the CNS are full agonists in gastrointestinal smooth muscle. 768 5

Second messenger signaling has been shown to regulate a variety of cellular functions in response to external stimuli. The following study was performed to determine the potential role of second messengers on influencing lipoprotein uptake by the arterial wall. An aortic endothelial cell (EC)-smooth muscle cell (SMC) bilayer was preexposed to various mediators of the cyclic AMP and inositol phosphate pathways for 30 min. The permeability, binding, and cellular uptake of 125I-labeled low-density lipoprotein (LDL) (10 micrograms/ml) added to the upper well media of the bilayer were then measured for each cell type after a 3-h incubation period. Forskolin (100 microM), an activator of adenylate cyclase, resulted in an increase in all measured parameters. 8-Br-cAMP (30 microM), a cAMP analogue, showed a similar effect on EC permeability (P < 0.00005) while galanin (0.1 mg/ml), an adenylate cyclase inhibitor, had no effect. GTP-binding protein inhibition with pertussis toxin (10 mg/ml) led to a marked reduction in SMC uptake (P < 10(-7)) without affecting membrane binding. Protein kinase C activation with phorbol myristate acetate (0.1 mg/ml) also increased EC permeability to LDL but, unlike forskolin, had no effect on LDL binding. This effect was further potentiated by calcium ionophore A23187 (5 x 10(-6) M), indicating a contributing role of intracellular calcium. These results would suggest that LDL uptake can be influenced by several second messenger systems, and that EC and SMC may respond differently to these intracellular signals. Second messenger regulation may allow changes in lipoprotein uptake by the arterial wall in response to external stimuli.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Second messenger regulation of lipoprotein uptake by an arterial wall model. 769 36

Galanin is a widely distributed 29/30 amino acid long neuropeptide with multiple biological effects. It inhibits glucose-induced insulin release, hippocampal acetylcholine release, hippocampal glutamate but not GABA release, and it lowers spinal excitability and firing of locus coeruleus neurons. It stimulates food (fat) intake and growth hormone release upon hypothalamic or i.c.v. injection. Galanin actions are mediated via high affinity Gi/G0 protein-coupled receptors--involving effector systems such as K(+)-, Ca(2+)-channels and adenylate cyclase. Galanin receptor agonists are thought to have therapeutic application in treatment of chronic pain and prevention of ischemic damage; galanin receptor antagonists have therapeutic potential in the treatment of Alzheimer's disease, depression, and feeding disorders.
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PMID:Galanin--a neuroendocrine peptide. 769 57


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