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)

Both chloroadenosine (EC50 = 3 X 10(-7) M) and cholera toxin, like nerve growth factor, increase the specific activity of choline acetyltransferase in PC12 cells over a period of several days. The increase in choline acetyltransferase activity in response to chloroadenosine appears to be caused by the ability of chloroadenosine to increase adenosine 3':5'-phosphate synthesis by binding to an adenosine receptor that activates adenylate cyclase. To test this hypothesis we determined if chloroadenosine can cause an increase in choline acetyltransferase activity in adenosine kinase-deficient PC12 cells. We have previously shown that adenosine analogues are significantly less effective at regulating adenosine 3':5'-phosphate in adenosine kinase-deficient PC12 cells than in wild type cells [Erny and Wagner (1984) Proc. natn. Acad. Sci. U.S.A. 81, 4974-4978]. Adenosine kinase-deficient PC12 cells are resistant to the induction of choline acetyltransferase in response to chloroadenosine, but not cholera toxin, supporting the role of adenosine 3':5'-phosphate in mediating the effects of chloroadenosine. The increase in choline acetyltransferase activity in wild type cells was accompanied by an increase in acetylcholine levels, demonstrating that chloroadenosine also regulates storage of acetylcholine. Acetylcholine levels were quantitated using an assay based on the ability of acetylcholine to compete with [125I]bungarotoxin for binding to the acetylcholine receptor.
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PMID:Genetic evidence that chloroadenosine increases the specific activity of choline acetyltransferase in PC12 cells via modulation of an adenosine-dependent adenylate cyclase. 652 95

ACh regulates the gene encoding phenylethanolamine N-methyltransferase (PNMT) in bovine adrenal chromaffin cells. In addition to stimulating catecholamine release from these cells, cholinergic agents elevate transcription of the PNMT gene. Carbachol, which activates both nicotinic and muscarinic receptors, produces 12-19-fold increases in PNMT mRNA and a 22-fold increase in epinephrine release. Selective nicotinic and muscarinic antagonists (hexamethonium and atropine) each partially reduce carbachol-stimulated increases in PNMT mRNA while a combination of both eliminates > 90% of the carbachol response, thus indicating that separable nicotinic and muscarinic components contribute to the cholinergic increase in PNMT mRNA. Muscarine alone produces a dose-dependent increase (mean sixfold) in steady state PNMT mRNA levels and stimulates the rate of transcription fivefold. Only atropine and the m3-m4-selective muscarinic antagonist 4-diphenylacetoxy-4-methyl-piperidine (4-DAMP) reduce the response to muscarine, strongly suggesting that the m4 receptor is crucial for PNMT mRNA activation. In these chromaffin cells, muscarine inhibits adenylate cyclase, antagonist bind with affinities characteristic of m4 receptors, and cDNA hybridization detects only m4 mRNAs (Fernando et al., 1991). Nicotine also induces a dose-dependent increase (mean of 8.5-fold) in PNMT mRNA levels. The importance of voltage-gated Ca2+ channels in the nicotine effect is demonstrated by the stimulatory effects of calcium ionophores on PNMT mRNA levels (two-to fivefold increase) and the ability of the L- and N-type channel blockers nifedipine and omega-conotoxin to decrease the nicotine response (by 60% and 40%, respectively). Nuclear "run-on" assays further reveal that nicotine enhances transcription of the PNMT gene (approximately fourfold). Thus, this study provides the first demonstration that both nicotinic and muscarinic stimulation modify genomic responses of bovine adrenergic chromaffin cells and identifies possible mechanisms.
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PMID:A single transmitter regulates gene expression through two separate mechanisms: cholinergic regulation of phenylethanolamine N-methyltransferase mRNA via nicotinic and muscarinic pathways. 751 33

The two-microelectrode voltage-clamp technique was used to monitor K+ channel activity in Xenopus oocyte follicular cells, which are electrically coupled to the oocyte itself by gap junctions. Endogenous vasodilators such as calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP), prostaglandin E2 (PGE2) and adenosine activate glibenclamide-ATP-sensitive K+ (KATP) channels in Xenopus oocyte follicular cells. The mechanism of action of CGRP was studied in detail. CGRP effects undergo a rapid desensitization. CGRP acts via CGRPI receptors. Its effects are antagonised by the amino-truncated CGRP analog hCGRP(8-37). The second messenger for CGRP activation of KATP channels is cAMP. Phosphodiesterase inhibition by 3-isobutyl-1-methylxanthine enhances the CGRP response while adenyl cyclase inhibition by either 2',5'-dideoxyadenosine or progesterone nearly completely depresses the CGRP response. Vasoconstrictors such as ACh and angiotensin II also have receptors in follicular cells. ACh strongly inhibits the CGRP activation of K+ channels as it inhibits the activation of KATP channels by P1060, but angiotensin II does not. It is concluded that as in vascular smooth muscle cells, CGRP and probably other hyperpolarizing vasodilators open KATP channels in follicular cells by protein kinase A activation.
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PMID:CGRP-induced activation of KATP channels in follicular Xenopus oocytes. 753 Aug 40

The experiments were done to investigate the presence and subtype of functionally presynaptic muscarinic receptors in cholinergic nerves of the guinea pig urinary bladder. Bladder strips were incubated with 3H-choline and superfused with Tyrode's solution containing eserine. Secreted 3H-acetylcholine was separated from 3H-choline. The electrically evoked 3H-acetylcholine secretion increased with the stimulation frequency. 3H-Acetylcholine secretion was enhanced by muscarinic antagonists, was depressed by carbachol and by alpha adrenoceptor agonists but was not influenced by drugs acting at beta adrenoceptors or purinoceptors. The rank order for the enhancing effect of muscarinic antagonist EC50 values was propantheline < atropine < methylatropine < N-desethyloxybutynin < UH-AH 37 < benzhexol < AQ-RA 741 < 4-DAMP < procyclidine < emepronium < secoverine < oxybutynin < tropicamide < promethazine < himbacine < hexahydrosiladifenidol < methoctramine = pirenzepine < dicyclomine < AF-DX 116, and the EC50 values correlated best with constants for the M4/m4 muscarinic receptor subtype. The enhancing effect of atropine was counteracted by carbachol; the effects of atropine and emepronium were not additive. The 3H-acetylcholine secretion was also enhanced by forskolin, 3-isobutyl-1-methylxanthine, 8-bromo cyclic AMP and dibutyryl cyclic AMP. The combined effects of atropine and forskolin were additive. These results suggest that the 3H-acetylcholine secretion in the guinea pig urinary bladder is regulated by a presynaptic muscarinic autoreceptor of the M4 subtype that is not coupled to adenylate cyclase.
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PMID:Classification of the presynaptic muscarinic receptor subtype that regulates 3H-acetylcholine secretion in the guinea pig urinary bladder in vitro. 761 31

The action of the A2a-adenosine analogue, CGS 21680C, on electrically evoked [3H]acetylcholine ([3H]-ACh) release, and its interaction with forskolin (an activator of adenylate cyclase), MDL 12,330A (an irreversible inhibitor of adenylate cyclase), rolipram (an inhibitor of cyclic AMP specific phosphodiesterase), dibutyryl- (db-cAMP) and 8-bromo- (8-Br-cAMP) cyclic AMP analogues (substances that mimic intracellular actions of cyclic AMP), were investigated using rat phrenic nerve-hemidiaphragm preparations. CGS 21680C facilitated [3H]-ACh release. Forskolin (but not 1,9-dideoxy forskolin), rolipram, db-cAMP and 8-Br-cAMP also increased evoked neurotransmitter release in a concentration-dependent manner. When the evoked [3H]-ACh release that is dependent on stimulation of the adenylate cyclase/cyclic AMP transduction system was supramaximally stimulated by these compounds, CGS 21680C (3 nmol/l) could not further increase [3H]-ACh release. Phosphodiesterase inhibition with low concentrations (< or = 30 mumol/l) of rolipram significantly potentiated the augmenting effect of CGS 21680C (1 nmol/l) on evoked [3H]-ACh release. MDL 12,330A (an irreversible inhibitor of adenylate cyclase) decreased evoked [3H]-ACh release. The irreversible blocking action of MDL 12,330A on [3H]-ACh release was overcome by by-passing cyclase activation with db-cAMP and 8-Br-cAMP, but could not be overcome with FSK or CGS 21680C. The inhibitory effect of MDL 12,330A on evoked [3H]-ACh release was not mimicked by nifedipine. It is concluded that the increase in [3H]-ACh release caused by CGS 21680C results from activation of an A2a-adenosine receptor positively linked to the adenylate cyclase/cyclic AMP system.
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PMID:Evidence that the presynaptic A2a-adenosine receptor of the rat motor nerve endings is positively coupled to adenylate cyclase. 787 Jan 91

Elevation of adenosine 3',5'-cyclic monophosphate (cAMP) levels in Necturus gallbladder (NGB) epithelium activates an apical membrane Cl- conductance and decreases transepithelial fluid transport (Jv). Acetylcholine (ACh), which had no effects on Jv by itself, antagonized the electrophysiological effects of forskolin (FSK) and theophylline and the decrease in Jv produced by FSK. By itself, ACh had no effects on basal cAMP levels but antagonized the increases in cAMP induced by FSK and theophylline. ACh had no effect on phosphodiesterase activity and prevented both the electrophysiological response and the elevation in cAMP by theophylline. In conclusion, the effect of ACh is mediated by inhibition of adenylate cyclase. A pertussis toxin (PTX)-sensitive G protein may mediate inhibition of adenylate cyclase because pretreatment with PTX prevented the reversal of the electrophysiological effects of FSK by ACh, and PTX catalyzed the ribosylation of cell membranes from NGB epithelium. ACh could have a physiological role in modulating the effects of secretagogues that act via elevation of cAMP levels.
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PMID:Muscarinic stimulation of gallbladder epithelium. III. Antagonism of cAMP-mediated effects. 797 83

1. The effect of calcitonin gene-related peptide (CGRP) on [3H]-acetylcholine ([3H]-ACh) release from motor nerve endings and its interaction with presynaptic facilitatory A2a-adenosine and nicotinic acetylcholine receptors was studied on rat phrenic nerve-hemidiaphragm preparations loaded with [3H]-choline. 2. CGRP (100-400 nM) increased electrically evoked [3H]-ACh release from phrenic nerve endings in a concentration-dependent manner. 3. The magnitude of CGRP excitation increased with the increase of the stimulation pulse duration from 40 microseconds to 1 ms, keeping the frequency, the amplitude and the train length constants. With 1 ms pulses, the evoked [3H]-ACh release was more intense than with 40 microseconds pulse duration. 4. Both the nicotinic acetylcholine receptor agonist, 1,1-dimethyl-4-phenylpiperazinium, and the A2a adenosine receptor agonist, CGS 21680C, increased evoked [3H]-ACh release, but only CGS 21680C potentiated the facilitatory effect of CGRP. This potentiation was prevented by the A2a adenosine receptor antagonist, PD 115,199. 5. Adenosine deaminase prevented the excitatory effect of CGRP (400 nM) on [3H]-ACh release. This effect was reversed by the non-hydrolysable A2a-adenosine receptor agonist, CGS 21680C. 6. The nicotinic antagonist, tubocurarine, did not significantly change, whereas the A2-adenosine receptor antagonist, PD 115,199, blocked the CGRP facilitation. The A1-adenosine receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine, potentiated the CGRP excitatory effect. 7. The results suggest that the facilitatory effect of CGRP on evoked [3H]-ACh release from rat phrenic motor nerve endings depends on the presence of endogenous adenosine which tonically activates A2a-adenosine receptors. Since both CGRP and A2a-adenosine receptors are positively coupled to the adenylate cyclase/cyclic AMP system, cooperation between these receptors might occur at the second messenger transduction system level.
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PMID:Potentiation by tonic A2a-adenosine receptor activation of CGRP-facilitated [3H]-ACh release from rat motor nerve endings. 800 2

This paper examines the interaction of endotoxin at the nicotinic2 receptor (ACh-Rpost) with the adenylate cyclase signal transduction system in skeletal muscle. It reports the drug-receptor (DR) dissociation constant (K, 0.05020 +/- .0015 mg/kg) for E. coli endotoxin. It expands on a previous report (1) which presented the relevance of skeletal muscle cAMP as a metabolic indicator and second messenger influenced by endotoxicosis. The use of a murine endotoxic model allowed for the measuring of K for the antagonist. DR affinity measures which relied on the constrained-slope Schild plot measured it. This report assessed dose-response relations of the competitive antagonist dTC (AN) and their modification (AN') by advancing endotoxicosis. The presence of endotoxin at a fixed final concentration (i.e., 7.75 mg/kg) within the body at the end of a two week period caused a rightward shift in the dTC dose-response curve. Endotoxin desensitized cAMP and caused the dTC curve to be shifted rightward. This report differs from typical pharmacological applications where standard agonist curves are obtainable in the presence of an antagonist. This in vivo model did not allow for the measurement of agonist ACh concentration. Therefore, the use of a pair of compounds (i.e., antagonistic dTC and agonistic endotoxin) and their effects (i.e., suppression of active tension and cAMP desensitization, respectively) allowed us to quantitate K. In summary, this report supports the hypothesis linking the nicotinic2 receptor to the adenylate cyclase signal transduction system and illustrates that endotoxicosis perturbed both.
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PMID:E. coli endotoxin affinity at the nicotinic2 receptor: receptor theory revisited, ilumina nostros occulae. 804 53

In aged animals and humans the pulsatile secretion of growth hormone (GH), the mean amounts of GH released over 24 h, and the response of GH to the administration of GH-releasing hormone (GHRH) are lower than in young adults. Pituitary somatotrophic cells in old male and female rats show an impaired responsiveness to GHRH, and the reduced secretion of GH in vitro is linked with a diminished stimulation of adenylate cyclase by GHRH. Pretreatment with GHRH in vivo decreases the high basal adenylate cyclase activity in old male rats. This pretreatment does not affect the rise of adenylate cyclase concentration in these rats that is subsequently induced by GHRH administration in vitro. However, it does induce a small rise in adenylate cyclase concentration in old female rats. In young rats of either sex the same GHRH schedule does not alter adenylate cyclase activity, but it does reduce the effectiveness of subsequent acute exposure to GHRH to stimulate enzymatic activity. Short-term administration of GHRH in some aged subjects increases the response of GH to a subsequent acute challenge with GHRH. However, primary or secondary alterations in somatotrophic cells are also present in aged mammals, such as a reduction in the number of GH-immunoreactive structures or post-receptor alterations. In aged rats, major alterations in brain neurotransmitters and neuropeptides are present in hypothalamic and extrahypothalamic structures, especially in catecholaminergic and acetylcholinergic neurones. These alterations are probably due to defects in neurosecretory GHRH and somatostatin neurones. GHRH synthesis is impaired in the hypothalamus of senescent male rats, as shown by a reduction in GHRH mRNA levels and GHRH-like immunoreactivity. Although the expression of somatostatin seems to decrease with age in the rat hypothalamus, secretion and activity of this hormone is increased, resulting in an altered relationship between GHRH and somatostatin gene expression and secretion. Catecholamines induce GH release in most animal species by stimulating GHRH neurones and inhibiting somatostatin-releasing neurones. Acetylcholine stimulates GH release via muscarinic receptors, and thus inhibits the effect of somatostatin neurones. In male rats of various ages, except very young rats, systemic administration of pilocarpine, an agonist of muscarinic receptors, potentiates the GH response to GHRH during the entire lifespan.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Aspects of the neuroendocrine control of growth hormone secretion in ageing mammals. 810 Feb 77

The purpose of this study was to compare vascular responsiveness in young (12 week old), aging hyperinsulinemic-glucose intolerant (52 weeks old) and diabetic (streptozotocin; 14 weeks old) rats. Aortic rings with and without endothelium were maintained in organ chambers for isometric tension recording. The contractile response to KCl was significantly enhanced in aortae from diabetic animals when compared to the responses obtained in young and old ones. The contractile response to norepinephrine or U46619, was significantly shifted to the right in the aortae from aging animals, however the aortae from these hyperinsulinemic rats were hyperresponsive to serotonin. Acetylcholine and ADP provoked an endothelium-dependent relaxation which was markedly depressed in the aortae from diabetic animals. The relaxation to ADP was selectively inhibited in the aging animals. The effect of sodium-nitroprusside was not significantly different in the three groups. Isoproterenol and forskolin induced endothelium-independent relaxation. Isoproterenol responses were inhibited in aging and diabetic animals, however the forskolin-relaxation was inhibited only in the aortae from aging animals. These results suggest that in two models of diabetes (i.e. Type I insulin-dependent and type II non insulin-dependent) vascular responsiveness is differently affected. Aging hyperinsulinemic animals present a selective hyperresponsiveness to serotonin, a selective dysfunction of ADP-induced endothelium-dependent relaxation and smooth muscle adenylate cyclase deficit. In diabetic animals a beta adrenergic hyporesponsiveness, not linked to adenylate-cyclase dysfunction, and non-selective depression of endothelium-dependent responses can be observed.
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PMID:Vascular responsiveness in young, diabetic, and aging hyperinsulinemic rats. 819 94


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