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 ADP-ribosylation factor (ARF) is the small (21 kb) GTP-binding protein required for the efficient cholera toxin-catalyzed ADP-ribosylation of purified Gs, the stimulating regulatory component of adenylate cyclase. Human ARF cDNA clones were obtained from a human cDNA library by cross-species hybridization with bovine ARF1, and the nucleotide and deduced amino acid sequences were determined. Comparison of the sequences of human and bovine ARF1 showed 90% identity at the nucleotide level and 100% identity at the amino acid level, demonstrating the highly conserved nature of the ARF protein. Using human ARF cDNA as the probe, we have detected ARF messenger RNA (approximately 2.2-2.3 kb) in a wide variety of human tissues and tumor cell lines.
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PMID:Molecular cloning, sequence analysis and mRNA expression of human ADP-ribosylation factor. 253 13

The aim of the present study has been to characterize the regulation by opiates of 45Ca2+ influx in rat spinal cord-dorsal root ganglion cocultures. We have demonstrated that K+-induced depolarization, in the presence of the Ca2+ channel agonist Bay K8644, stimulated Ca2+ influx (3-4-fold) via the dihydropyridine class of voltage-dependent Ca2+ channels. While mu and delta opiates had no effect, kappa opiate agonists (e.g. U50488, dynorphin) profoundly depressed the stimulated Ca2+ influx (86% inhibition at 100 microM U50488). The kappa agonist action was stereospecific and could be reversed by the opiate antagonist naloxone. The inhibition produced by kappa agonists was greatly diminished following pertussis toxin treatment, and this effect was accompanied by toxin-induced ADP-ribosylation of a 40-41-kDa protein. This suggests that kappa opiate receptors are negatively coupled to voltage-dependent Ca2+ channels, via a pertussis toxin-sensitive GTP-binding protein. Basal 45Ca2+ uptake, stimulated by adenylate cyclase activators (forskolin and cholera toxin), was potently inhibited by kappa opiates suggesting that, under conditions of neurohormonal stimulation of adenylate cyclase, kappa receptors are coupled to Ca2+ channels indirectly via the adenylate cyclase complex. In addition, cAMP-independent coupling pathways may also be involved.
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PMID:Kappa opiate agonists inhibit Ca2+ influx in rat spinal cord-dorsal root ganglion cocultures. Involvement of a GTP-binding protein. 253 41

Prostaglandin E (PGE) receptor is coupled to a pertussis toxin-insensitive GTP-binding protein in bovine adrenal medulla, but PGE receptor partially purified from bovine adrenal medulla was functionally reconstituted with Gi into phospholipid vesicles (Negishi, M., Ito, S., Yokohama, H., Hayashi, H., Katada, T., Ui, M., and Hayaishi, O. (1988) J. Biol. Chem. 263, 6893-6900). We demonstrate here that PGE2 inhibited forskolin-induced accumulation of cAMP in cultured bovine chromaffin cells. In plasma membranes prepared from bovine adrenal medulla, PGE2 inhibited forskolin-stimulated adenylate cyclase activity in a GTP-dependent manner. This inhibitory action of PGE2 was abolished by treatment of the membrane with pertussis toxin. Reconstitution of the membranes ADP-ribosylated by pertussis toxin with Gi purified from bovine brain restored the potency of PGE2 to inhibit the adenylate cyclase activity. Inhibition of forskolin-induced cAMP accumulation by PGE2 was also abolished by exposure to the toxin in the cells, indicating that PGE receptors are coupled to Gi. In contrast, PGE2 stimulated the formation of inositol phosphates in chromaffin cells, but this effect was not affected by treatment of the cells with pertussis toxin, suggesting that the PGE receptors are coupled to phosphoinositide metabolism via a pertussis toxin-insensitive G-protein. Both the inhibitory action of cAMP accumulation and stimulation of phosphoinositide metabolism were specific for PGE1 and PGE2, and the Scatchard plot analysis of PGE2 binding to the membrane showed a single high-affinity binding site (Kd = 2 nM). In bovine adrenal chromaffin cells PGE2 enhanced catecholamine release in the presence of ouabain by stimulation of phosphoinositide metabolism (Yokohama, H., Tanaka, T., Ito, S., Negishi, M., Hayashi, H., and Hayaishi, O. (1988) J. Biol. Chem. 263, 1119-1122). We further examined the modulation of catecholamine release by PGE2 through its inhibitory coupling to the adenylate cyclase system. Prior exposure of chromaffin cells to forskolin or dibutyryl-cAMP reduced nicotine-stimulated catecholamine release, and PGE2 attenuated forskolin-induced inhibition of catecholamine release stimulated by nicotine, but not dibutyryl-cAMP-induced inhibition. In the absence of evidence that PGE receptor subtypes exist, these results suggest that the PGE receptor is coupled to two signal transduction systems leading to inhibition of cAMP accumulation via Gi and to production of inositol phosphates via a pertussis toxin-insensitive G-protein, both of which may modulate catecholamine release from bovine chromaffin cells.
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PMID:Prostaglandin E receptors in bovine adrenal medulla are coupled to adenylate cyclase via Gi and to phosphoinositide metabolism in a pertussis toxin-insensitive manner. 253 96

Despite the availability of efficient transcription and translation signals, some heterologous gene products are not adequately expressed when introduced into prokaryotes and eukaryotes. An expression system has been established in Escherichia coli to increase the yield of cloned gene products, where the C terminus of ubiquitin was fused to the N terminus of unstable or poorly expressed proteins. Fusion of ubiquitin to yeast metallothionein or to the alpha subunit of the adenylate cyclase-stimulatory GTP-binding protein increased the yield from undetectable to 20% of the total cellular protein. A ubiquitin-N alpha-protein hydrolase has been partially purified from rabbit reticulocytes; this enzyme faithfully cleaves the junction peptide bound between the C-terminal Gly-76 of ubiquitin and the fusion protein. The increased yield of cloned gene products is very likely due to increased stability and/or more efficient translation of the fusion proteins. Possible mechanisms for the augmentation of ubiquitin fusion-protein expression in prokaryotes and eukaryotes are discussed.
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PMID:Ubiquitin fusion augments the yield of cloned gene products in Escherichia coli. 253 93

The beta 1- and beta 2-adrenergic receptor subtypes are biochemically and functionally similar, because both receptors mediate the catecholamine-dependent activation of adenylate cyclase through the GTP-binding protein, Gs. Pharmacologically, the two receptors can be distinguished on the basis of their relative affinities for the agonists epinephrine and norepinephrine as well as their affinities for several selective antagonists. The primary structures of the human beta 1- and beta 2-adrenergic receptors have recently been deduced from the cloning of their genes and (or) cDNAs, revealing high sequence homology and a membrane topography of seven putative transmembrane regions similar to that of rhodopsin. Chimeric beta 1/beta 2-adrenergic receptor cDNAs have been constructed by site-directed mutagenesis and the chimeric RNA transcripts expressed in Xenopus laevis oocytes. The pharmacological properties of the expressed chimeric receptor proteins were assessed by radioligand binding utilizing subtype-selective agonists and antagonists. Apparently, several of the putative transmembrane regions contribute significantly to the determination of subtype selectivity, presumably by formation of a ligand-binding pocket, with determinants for agonist and antagonist binding being distinguishable.
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PMID:Properties of the beta 1- and beta 2-adrenergic receptor subtypes revealed by molecular cloning. 254 47

Incubation of human platelets with protein kinase C activator 4 beta-phorbol-12 beta-myristate-13 alpha-acetate (PMA) abolished stimulation of membrane high-affinity GTPase by platelet-activating factor (PAF). GTPase stimulation by epinephrine decreased by 30%, while the prostaglandin E1 (PGE1) effect was unchanged. Basal GTPase activity (22.4 +/- 1.1 pmol Pi/min per mg protein) was not affected by PMA. Therefore, a study was performed of the effect of endogenous protein kinase C activation on adenylate cyclase regulation by agonists. PMA pretreatment completely suppressed PAF inhibition of basal adenylate cyclase activity but hardly influenced the inhibition by PAF of forskolin-stimulated activity. Adenylate cyclase inhibition by epinephrine in the presence of propranolol was not suppressed completely after platelet incubation with PMA. Epinephrine effects on basal and forskolin-stimulated activities decreased equally. Platelet pretreatment with PMA increased PGE1-stimulated activity by abolishing the inhibitory effect of high GTP concentrations. These studies indicate that protein kinase C selectively inhibits PAF effects, presumably by inactivating a GTP-binding protein coupled with PAF receptors.
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PMID:Selective inactivation by endogenous protein kinase C of human platelet high-affinity GTPase coupled with PAF receptors. 254 23

GTP-binding proteins have been implicated as transducers of a variety of biological signaling processes. These proteins share considerable structural as well as functional homology. Due to these similarities, it was thought that a monoclonal antibody that inhibits the light activation of the rod outer segment GTP-binding protein, tranducin (Gt), might exert some functional effect upon the G proteins that regulate the adenylate cyclase system. Antibody 4A, raised against the alpha subunit of Gt, cross-reacted (by hybridization on nitrocellulose) with purified alpha subunits of other G proteins (Gi and Gs, regulatory guanyl nucleotide-binding proteins that mediate inhibition and stimulation of adenylate cyclase, respectively) as long as they were not denatured. This antibody, which interferes with rod outer segment cGMP phosphodiesterase activation by blocking interaction between rhodopsin and Gt, also interfered with actions of both the stimulatory and inhibitory G proteins of adenylate cyclase from rat cerebral cortex membranes. Effects of monoclonal antibody (mAb) 4A were dose-dependent and not reversed by washing. mAb 4A also blocked the Gi-mediated inhibition of adenylate cyclase in the cyc- variant of S49 lymphoma and in doing so raised the level of adenylate cyclase activity in both the cyc- variant and the S49 wild type. There was no effect of mAb 4A on adenylate cyclase activity of the resolved catalytic subunit. These results suggest that the well known sequence homologies among the G proteins involved in cellular signal transduction may extend to the sites that interact with other members of signal-transducing cascades (receptors and effector molecules). Therefore, antibody 4A may serve as a useful tool to probe the similarities and differences among the various systems.
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PMID:A monoclonal antibody against the rod outer segment guanyl nucleotide-binding protein, transducin, blocks the stimulatory and inhibitory G proteins of adenylate cyclase. 254 96

Forskolin and vasoactive intestinal polypeptide (VIP) were shown to increase cyclic AMP accumulation in a human neuroblastoma cell line, SK-N-SH cells. The alpha 2-adrenergic agonist UK 14304 decreased forskolin-stimulated cyclic AMP levels by 40 +/- 2%, with an EC50 of 83 +/- 20 nM. This response was blocked by pretreatment with pertussis toxin (PT) (EC50 = 1 ng/ml) or by the alpha 2-antagonists yohimbine, idazoxan, and phentolamine. Antagonist IC50 values were 0.3 +/- 0.1, 2.2 +/- 0.3, and 1.4 +/- 0.1 microM, respectively. This finding suggests the presence of normal inhibitory coupling of SK-N-SH cell alpha 2-adrenergic receptors to adenylate cyclase via the inhibitory GTP-binding protein species, Gi. Muscarinic receptors in many target cell types are coupled to inhibition of adenylate cyclase. However, in SK-N-SH cells, muscarinic agonists synergistically increased (67-95%) the level of cyclic AMP accumulation elicited by forskolin or VIP. EC50 values for carbamylcholine (CCh) and oxotremorine facilitation of the forskolin response were 1.2 +/- 0.2 and 0.3 +/- 0.1 microM, respectively. Pharmacological studies using the muscarinic receptor subtype-preferring antagonists 4-diphenylacetoxy-N-methylpiperidine, pirenzepine, and AF-DX 116 indicated mediation of this response by the M3 subtype. IC50 values were 14 +/- 1, 16,857 +/- 757, and 148,043 +/- 16,209 nM, respectively. CCh-elicited responses were unaffected by PT pretreatment. Muscarinic agonist binding affinity was indirectly measured by the ability of CCh to compete for [3H]quinuclidinyl benzilate binding sites on SK-N-SH cell membranes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Alpha 2-adrenergic and muscarinic cholinergic receptors have opposing actions on cyclic AMP levels in SK-N-SH human neuroblastoma cells. 254 24

The negative regulation of the beta-adrenoreceptor affinity by guanine nucleotides in the sarcolemmal fraction of chicken skeletal muscle at different stages of ontogenesis was studied. It was found that the negative regulation is absent in the embryonic period; the effect of GTP is manifested only before hatching, whereas that of Gpp(NH)p--at later periods, i.e., in 1-month-old chickens. Similar age-dependent dynamics was revealed with respect to the GTP effect on the dissociation rate of the [3H]DHA-beta-adrenoreceptor complex. An addition to the system containing embryonic muscle membranes of the GTP-binding protein isolated from skeletal muscle and liver of chickens whose age exceeds 20 days led to earlier manifestations of the above effects (on the 13th-15th embryonic days). The data obtained testify to the limiting role of GTP-binding proteins in the negative control of the hormone-receptor interaction and support the authors' hypothesis on the absence in the embryonic muscle of the 42 kD GTP-binding protein responsible for the functional coupling of the hormone-sensitive adenylate cyclase components.
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PMID:[Lack of negative regulation of beta-adrenoreceptor affinity by guanine nucleotides in embryonic membranes and its induction by the GTP-binding protein from mature protein]. 254 13

According to present-day concepts an important and, presumably, a key role in signal transmission in photoreceptor cells is ascribed to a system containing the photosensitive protein rhodopsin, GTP-binding protein transducin and cyclic GMP phosphodiesterase which in many features is similar to the adenylate cyclase system from other eukaryotic cells. The experimental and literary data concerning the already established and hypothetical mechanisms of transmission, enhancement and switch-off of the signal in the rhodopsin----transducin----phosphodiesterase chain are reviewed.
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PMID:[The enzymology of visual reception: phosphodiesterase cascade of signal amplification]. 254 57


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