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 effects of forskolin, a potent activator of adenylate cyclase, were examined on the frog neuromuscular junction. The depolarization elicited by ionophoretically applied acetylcholine was markedly reduced in amplitude and its time course was speeded up after treatment with 20-100 microM forskolin. The amplitude of extracellularly recorded miniature endplate potentials was decreased by the same factor as that of ionophoretically evoked responses and their decay time constant became shorter. All these changes, but not the shortening of spontaneous responses, were produced by 3-isobutyl-1-methylxantine and by N6-2'-O-dibutyryl cyclic AMP, both known to elevate intracellular cAMP. Forskolin-induced actions can be thus ascribed to the activation of cAMP-dependent protein kinase and to a direct effect on acetylcholine receptor channel.
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PMID:The effect of forskolin on the response of acetylcholine receptors in frog sartorius endplate. 169 69

In the adult motor endplate the acetylcholine receptor protein (AChR) is strictly localized under the motor nerve ending, whereas in the noninnervated myotube it is distributed all over the surface of the cell. The genesis of this anisotropic distribution involves a differential regulation of AChR gene transcription. In situ hybridization with AChR subunit probes discloses high levels of unspliced and mature mRNA all over differentiating myotubes. After the entry of the exploratory motor axons, the mRNA clusters located outside the endplate decrease in number and become restricted to the subneural "fundamental" nuclei. Denervation causes a reappearance of unspliced and mature mRNA in extrajunctional areas. A compartmentalized expression of AChR genes take place during endplate formation. Chronic paralysis of the embryo interferes with the disappearance of extrajunctional AChR that, thus, represents an electrical activity-dependent repression of AChR genes. The entry of Ca2+ ions through the sarcolemmal membrane during electrical activity and the activation of protein kinase C plausibly contribute to this membrane-to-gene regulation. The maintenance and late increase in AChR number at the endplate requires the intervention of an anterograde signal or signals, of neural origin. Several factors have been suggested to play a role in this process, such as an acetylcholine receptor-inducing activity (ARIA), ascorbic acid, or calcitonin gene-related peptide (CGRP), a peptide known to coexist with acetylcholine in spinal cord motoneurons. In cultured chick muscle cells, CGRP increases the concentration of surface AChR and alpha-subunit unspliced and mature mRNA and stimulates membrane-bound adenylate cyclase, suggesting that distinct second messengers are involved in the regulation of AChR biosynthesis by electrical activity and by CGRP. The data are interpreted in terms of a model in which it is assumed that (i) in the adult muscle fiber, different stages of gene expression occur in the nuclei in subneural and extrajunctional areas, and (ii) different second messengers elicited by neural factors or electrical activity regulate the state of transcription of these nuclei via trans-acting allosteric proteins binding to cis-acting DNA regulatory elements. The upstream flanking regions of several of the AChR subunit genes reveal ubiquitous DNA elements such as TATA and CAAT boxes, Sp1 binding sites and SV40 core enhancer sites, and muscle-specific MyoD (CANNTG) elements. The contribution of some of these elements to the differential regulation of the multiple AChR subunits is discussed.
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PMID:Compartmentalized transcription of acetylcholine receptor genes during motor endplate epigenesis. 188 10

Incubating skeletal muscle fibers with forskolin, an activator of adenylate cyclase, increases the rate at which nicotinic acetylcholine receptors (AChRs) desensitize when exposed to ACh. Several reports indicate that this is due to the phosphorylation of AChRs by cAMP-dependent protein kinase, but other studies suggest that forskolin interacts with AChRs directly and that second-messenger systems are not required. To help clarify this issue, we studied the effects of forskolin and several other drugs on AChR function in embryonic rat myotubes. AChR function was studied by recording ACh-induced membrane depolarizations and ACh-induced single-channel currents. Our results indicate that forskolin at low concentrations enhances AChR desensitization through the action of a second messenger, most likely cAMP. An analog of forskolin that is much less effective in activating adenylate cyclase (1,9-dideoxyforskolin) is also much less potent in enhancing desensitization. Forskolin at low concentrations does not alter single-channel conductance or mean channel open time. However, when used at concentrations above 20 microM, forskolin may also exert direct drug effects on AChRs.
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PMID:Desensitization of acetylcholine receptors in rat myotubes is enhanced by agents that elevate intracellular cAMP. 245 25

The Calcitonin-Gene Related Peptide (CGRP), a neuropeptide present in chick spinal cord motoneurons, increases the levels of surface acetylcholine receptor (AChR) and of the AChR alpha-subunit mRNA in cultured chick myotubes. Cholera toxin (CT), an activator of adenylate cyclase, produces a similar effect which does not add up with that of CGRP. Consistent with this observation, CGRP increases the content of cyclic AMP in chick muscle cells in culture. Tetrodotoxin (TTX), a blocker of voltage-sensitive Na+ channels, elevates the levels of AChR and of AChR alpha-subunit mRNA. This effect is additive with that of CGRP or CT. TPA (12-O-tetradecanoyl phorbol-13-acetate), an activator of protein kinase C, decreases the level of AChR but has no effect on the level of AChR alpha-subunit mRNA. Interestingly, TPA inhibits the increase of AChR alpha-subunit mRNA caused by TTX without affecting that produced by CGRP or CT. These data suggest that CGRP, which coexists with acetylcholine in spinal cord motoneurons, could be one of the anterograde factors (or a model of such factor) responsible for the enhanced expression of the genes coding for AChR subunits in subneural nuclei, via the activation of adenylate cyclase. Muscle electrical activity would then inhibit the expression of the same genes in extrajunctional nuclei, via another intracellular pathway.
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PMID:[Possible trophic role on the neuromuscular junction of a neuropeptide co-existing with acetylcholine in motor neurons of the spinal cord]. 254 40

Sertoli cells cultured from immature hamsters respond to FSH with a dose-related increase in cAMP accumulation. Pertussis toxin acts synergistically with FSH to stimulate cAMP accumulation. This effect of pertussis toxin indicates that Sertoli cell adenylate cyclase is under tonic inhibition due to the activity of the Ni inhibitory transducer. The acetylcholine receptor antagonists atropine or tubocurarine, or the opioid antagonist naltrexone, have no effect on the FSH-induced stimulation of cAMP accumulation, suggesting that neither acetylcholine nor opioids are responsible for the inhibition of Sertoli cell cyclase. While exogenous adenosine is inhibitory, adenosine deaminase augments the ability of FSH to stimulate cAMP accumulation, but not to the level of pertussis toxin. This indicates that the Sertoli cells produce endogenous adenosine that is at least partially responsible for the tonic inhibition of adenylate cyclase. Other possibilities for the tonic inhibition of cyclase include other Sertoli cell products, germ cell products, peritubular cell products or an action of FSH itself through both stimulatory and inhibitory transducers.
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PMID:Tonic inhibition of adenylate cyclase in cultured hamster Sertoli cells. 282 41

The role of prostanoids in the regulation of chick myoblast differentiation has been investigated. At 3 X 10(-6) M, indomethacin and chloroquine specifically inhibit cell fusion. They do not affect cell proliferation, alignment, or the expression of two muscle-specific proteins, namely, the acetylcholine receptor and the muscle-specific form of creatine phosphokinase. The results demonstrate that it is indomethacin's activity as an inhibitor of prostaglandin synthesis at the cyclooxygenase step that causes the block of cell fusion, whereas chloroquine probably acts at the earlier step of phospholipase A. Prostaglandin E1 (PGE1), but not prostaglandin E2 (PGE2), rapidly reverses the inhibition of fusion imposed by indomethacin or chloroquine. The dose response of the myoblasts to PGE1 is a bell-shaped curve with a 100% reversal of fusion at approximately 10(-9) M. Eicosatrienoate and linoleate reverse the inhibition of fusion with similar kinetics, whereas arachidonate is completely ineffective. The ability of PGE1 and eicosatrienoate but not PGE2 and arachidonate to restore fusion to control levels implies that fusion is specifically regulated by a prostanoid of the one series. The reversal of the fusion-block by linoleate further suggests that this fatty acid provides the necessary source of eicosatrienoate in the myoblast plasma membrane. At 10(-8) M and above, PGE1 and PGE2 stimulate adenylate cyclase and depress control fusion as does 10(-5) M isoproterenol. The beta-adrenergic blocker propranolol abolishes both isoproterenol's inhibition of myoblast fusion and its activation of adenylate cyclase. The similar depressions imposed on cell fusion by 10(-8)-10(-6) M prostanoid and 10(-5) M isoproterenol suggest that in both cases the depressive effects are mediated by cyclic AMP. It is concluded that a prostanoid of the one series regulates fusion by a cyclic AMP-independent mechanisms.
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PMID:Myoblast fusion is regulated by a prostanoid of the one series independently of a rise in cyclic AMP. 301 99

Recent immunocytochemical studies have shown that calcitonin gene-related peptide (CGRP) coexists with the neurotransmitter acetylcholine in spinal motoneurons of the chick. Moreover, CGRP causes an increase in the number of acetylcholine receptors on the surface of cultured chick myotubes. CGRP might thus serve as one of the signals by which motoneurons regulate endplate development. In a search for the second messengers involved, we now demonstrate that CGRP stimulates accumulation of cyclic AMP (cAMP) in cultured chick myotubes. This effect is, at least in part, mediated by an increase in cAMP synthesis, as the peptide also activates adenylate cyclase in chick muscle membranes. Nanomolar concentrations of CGRP elicit significant increases in both cellular cAMP levels and acetylcholine receptor numbers. The present findings suggest that cAMP is one of the second messengers which mediate the increase in acetylcholine receptor number elicited by CGRP. Furthermore, CGRP might be implicated in other trophic actions mediated by cAMP in skeletal muscle cells.
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PMID:Calcitonin gene-related peptide elevates cyclic AMP levels in chick skeletal muscle: possible neurotrophic role for a coexisting neuronal messenger. 303 93

In cultured chicken myotubes, calcitonin gene-related peptide (CGRP), a peptide present in spinal cord motoneurons, increased by 1.5-fold the number of surface acetylcholine receptors (AChRs) and by threefold AChR alpha-subunit mRNA level without affecting the level of muscular alpha-actin mRNA. Cholera toxin (CT), an activator of adenylate cyclase, produced a similar effect, which did not add up with that of CGRP. In contrast, tetrodotoxin, a blocker of voltage-sensitive Na+ channels, elevated the level of AChR alpha-subunit mRNA on top of the increase caused by either CGRP or CT. 12-O-Tetradecanoyl phorbol-13-acetate (TPA), an activator of protein kinase C, markedly decreased the cell surface and total content of [125I]alpha BGT-binding sites and reduced the rate of appearance of AChR at the surface of the myotubes without reducing the level of AChR alpha-subunit mRNA. Moreover, TPA inhibited the increase of AChR alpha-subunit mRNA caused by tetrodotoxin without affecting that produced by CGRP or CT. Under the same conditions, TPA decreased the level of muscular alpha-actin mRNA and increased that of nonmuscular beta- and gamma-actins mRNA. These data suggest that distinct second messengers are involved in the regulation of AChR biosynthesis by CGRP and muscle activity and that these two pathways may contribute to the development of different patterns of AChR gene expression in junctional and extrajunctional areas of the muscle fiber.
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PMID:Calcitonin gene-related peptide and muscle activity regulate acetylcholine receptor alpha-subunit mRNA levels by distinct intracellular pathways. 349 28

The affinities of muscarinic acetylcholine receptor agonist and antagonist compounds have been measured in studies of adenylate cyclase inhibition and phosphatidylinositol turnover in guinea-pig atria and ventricles. The affinities of all compounds tested were similar in atrial and ventricular preparations. However, three antagonists, atropine, pirenzepine and gallamine had different affinities at receptors coupled to adenylate cyclase inhibition compared with those which stimulated turnover of phosphatidylinositols. The neuromuscular blocking agents gallamine and pancuronium, which demonstrate cardioselective acetylcholine receptor antagonist activity, were competitive antagonists at receptors coupled to both second messenger systems. However, their affinities measured in both systems were lower than expected from tissue-response studies. Therefore, the cardioselectivity of these compounds cannot be explained by a simple competitive interaction with receptors coupled to either adenylate cyclase inhibition or phosphatidylinositol turnover.
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PMID:A comparison of muscarinic acetylcholine receptors coupled to phosphatidylinositol turnover and to adenylate cyclase in guinea-pig atria and ventricles. 355 93

Three components of differentiated muscle membrane, the acetylcholine receptor, acetylcholinesterase (EC 3.1.1.7; acetylcholine hydrolase), and adenylate cyclase [EC 4.6.1.1; ATP pyrophosphate-lyase (cyclizing)], appear simultaneously during myogenesis in cultures of embryonic chick muscle, after the main period of rapid cell fusion. However, unlike the cytoplasmic proteins of differentiated muscle, the elaboration of these membrane components is unaltered when fusion is blocked by lowering the calcium concentration in the medium. These results suggest that membrane differentiation and cytoplasmic differentiation are regulated independently during muscle development.
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PMID:Differentiation of cell membranes in cultures of embryonic chick breast muscle. 452 10


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