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)

Injection of tranylcypromine and L-tryptophan results in rats displaying behavioural changes including hyperactivity, probably due to stimulation of post-synaptic 5-hydroxytryptamine (5-HT) receptors. Increased locomotor activity of a different type is elicited by injection of tranylcypromine and L-dopa, a procedure which increased dopaminergic function in the brain. It has now been demonstrated that the neuroleptic drugs, chlorpromazine, alpha-flupenthixol, haloperidol and spiroperidol block both syndromes. The inhibition produced by these drugs on 5-HT-induced hyperactivity is probably because a dopaminergic system is involved in the behavioural expression of the 5-HT induced hyperactivity. The structurally related drugs with no neuroleptic activity (ethopropazine, promethazine and beta-flupenthixol)are without effect on thses hyperactivity syndromes. Also ineffective were the neuroleptics pimozide and clozapine. Striatal dopamine sensitive adenylate cyclase activity in vitro was inhibited by the administration of chlorpromazine (100 mg/kg) in vivo. Rats treated for 4 or more days with chlorpromazine, alpha-flupenthixol, spiroperidol and haloperidol subsequently showed enhanced locomotor activity in response to tranylcypromine and L-Dopa. Administration of those drugs which did not block hyperactivity acutely did not result in enhancement. Only chlorpromazine, when given for 4 days, enhanced the hyperactivity response following tranylcypromine and L-tryptophan, probably because the drug also blocks 5-HT receptors. In rats displaying enhanced behavioural responses no evidence was found for enhanced sensitivity of striatal adenylate cyclase to dopamine.
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PMID:Single and repeated administration of neuroleptic drugs to rats: effects on striatal dopamine-sensitive adenylate cyclase and locomotor activity produced by tranylcypromine and L-tryptophan or L-Dopa. 1 27

The ability of three analogs of ACTH1-24 ([Gln5, Phe9] ACTH1-24, [Gln5, Ala9[Acth1-24, and [Gln5, Lys8, Phe9[ ACTH1-24) embodying tryptophan substitutions to activate the adenylate cyclase system of a bovine adrenal plasma membrane preparation was compared to the effect of the analogs on adenosine 3':5'-monophosphate (cyclic AMP) accumulation and steroidogenesis in viable bovine adrenocortical cells. The results were not comparable. Whereas the analogs antagonized the ACTH1-24-activated membrane cyclase they stimulated cyclic AMP accumulation as well as steroid production of the cells. None of the analogs inhibited steroidogenesis of ACTH1-24-stimulated cells, but two of them, at very high dose levels, inhibited cyclic AMP production. The ability of the analogs to stimulate steroidogenesis of the adrenal cells half-maximally decreased in the order tryptophan greater than phenylalanine greater than alanine, indicating that the aromaticity of the indole ring of tryptophan is necessary for maximal interaction between hormone and receptor. Both the absolute and relative steroidogenic potencies were the same for several analogs when assayed with rat adrenal cells. Although only a small fraction of the cell's potential to produce cyclic AMP was necessary to induce maximum steroid production, the relative activities of a series of analogs were the same for steroidogenesis as for cyclic AMP accumulation. Furthermore, the concentration of cyclic AMP necessary for full steroidogenesis was practically identical for a series of peptides that differed widely in potency. These findings support the postulate that cyclic AMP accumulation and steroidogenesis in adrenocortical cells are coupled processes. The differential behavior of bovine adrenal plasma membranes and bovine adrenocortical cells toward ACTH analogs indicates that structure-function studies using cyclase assays may not reflect events that take place in the intact adrenal or in cell preparations derived therefrom.
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PMID:Differential response to adrenocorticotropic hormone analogs of bovine adrenal plasma membranes and cells. 18

The ability of ACTH fragments and of an ACTH analogue [9-tryptophan(o-nitrophenylsulfenyl)] corticotropin-(1-24)-tetracosapeptide[Trp-(Nps)9 ACTH1-24] to stimulate adenylate cyclase in bovine adrenal cortex membranes and a crude membrane fraction from rat adrenals has been determined. Partial agonists like Trp (Nps)9 ACTH1-24 displayed intrinsic activity in the rat adrenal preparation only if tested in the presence of 5'-guanylylimidodiphosphate [Gpp(NH)p]. On the other hand, no addition of Gpp(NH)p was necessary to demonstrate intrinsic activity of Trp(Nps)9 ACTH1-24 for bovine adrenal cortex adenylate cyclase. A large decrease (15-fold) of the apparent Km values for ACTH1-24, ACTH1-23 and ACTH1-17 was observed with the rat adrenal preparation when Gpp(NH)p was added. The shift in apparent Km values for ACTH1-24 and ACTH1-23 for the bovine adrenal cortex adenylate cyclase system was small or insignificant when Gpp(NH)p was added. The observations suggest that the hormone receptor facilitates the action of guanylnucleotide sites in the membrane. When guanylnucleotide sites are occupied by Gpp(NH)p even weak interactions of the hormone receptor with e.g. partial agonists are propagated to the catalytic subunits of the adenylate cyclase complex resulting in enhanced activity. The differences in adenylate cyclase activation with hormone fragments or analogues and different target tissues may rather reflect the state of the coupling process involving guanylnucleotide binding sites of the isolated membrane fraction than differences in the receptor itself.
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PMID:Adrenal cortex adenylate cyclase. In vitro acitivity of ACTH fragments and analogues. 18 24

The hormone serotonin (5-hydroxytryptamine) has been implicated as the cause of the diarrhea seen in many patients with the carcinoid syndrome. To determine whether serotonin is an intestinal secretagogue, the effect of serotonin on intestinal water and electrolyte transport was evaluated in the rabbit. Two weeks of daily subcutaneous injection of serotonin suspended in oil resulted in a blood serotonin level elevated to twice that of controls. Intestinal transport was studied in vivo by a perfusion technique. Serotonin treatment resulted in ileal secretion and decreased mid-jejunal absorption of water and electrolytes but did not effect water absorption in the proximal jejunum or colon. Intestinal absorption of D-glucose and the amino acid L-tryptophan and glucose-dependent water and electrolyte absorption were normal in serotonin-treated animals. Serotonin-induced ileal secretion was reversed by methysergide, a peripheral antagonist of serotonin action. No alterations in intestinal histology or permeability occurred in serotonin-treated animals. Serotonin-induced intestinal secretion was not associated with alterations in the activities of intestinal mucosal adenylate cyclase, cyclic nucleotide phosphodiesterase, or Na-K-ATPase.
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PMID:Effect of serotonin treatment on intestinal transport in the rabbit. 83 7

Electrolytic raphe lesion was performed in 4-6-day-old rats and the resulting changes of 5HT metabolism within the central nervous system were analyzed up to 9 months later. As soon as the 2nd day following the selective destruction of B7 and B8 nuclei, forebrain 5HT levels were decreased by more than 75%. This reduction persisted for at least 9 months with no sign of recovery. The time course of 5-HIAA decrease was parallel to that of the indoleamine so that the ratio of 5-HIAA over 5-HT levels in the forebrain of lesioned rats was similar to that estimated in controls, whatever their age. This result would suggest that the remaining serotoninergic neurons in the lesioned rats did not develop a compensatory hyperactivity. The raphe lesion induced no change in MAO activity and synaptosomal tryptophan uptake but a pronounce decrease in the Vmax of synaptosomal KHT uptake process in various forebrain areas occurred. The serotonin sensitive adenylate cyclase activity in colliculi homogenate was not altered by the lesion suggesting that this enzyme was probably located in postsynaptic membranes. In addition, this observation would indicate that 5-HT receptors which are linked to this adenylate cyclase did not become supersensitive following the selective degeneration of serotoninergic neurons. Animals without forebrain serotoninergic innervation might be of great interest to analyse the role of serotoninergic neurons in various functions (sleep, analgesia, thermoregulation).
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PMID:Midbrain raphe lesion in the newborn rat: II. Biochemical alterations in serotoninergic innervation. 86 45

The tryptophan residue of glucagon was modified by reaction with a mono-functional sulfenyl chloride (2-nitrophenylsulfenyl chloride) and with a bifunctional sulfenyl chloride (2,4-dinitro-1,5-phenyldisulfenyl chloride) to produce a monomeric form of glucagon with a modified tryptophan, glucagon-nitrophenylsulfenyl and a dimeric form (glucagon)2-dinitrophenyldisulfenyl respectively. The dimeric form was isolated by chromatography on Sephadex G-50. The circular dichroism spectra of pH and low temperature. The derivatives activated adenylate cyclase from rat liver to an extent comparable to that of the native hormone, indicating that a glucagon dimer is capable of biological activity and that an intact tryptophan residue is not essential for biological response.
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PMID:Conformational and biological properties of a covalently linked dimer of glucagon. Reaction of mono- and bifunctional sulfenyl halides. 99 94

We have constructed mutants of the alpha subunit of Gs in an attempt to identify sites in the protein that are important for its interaction with adenylylcyclase. Some residues specific for those G proteins that activate adenylylcyclase were replaced with residues characteristic of Gi alpha. Mutant proteins were expressed in Escherichia coli, and two of these were purified to homogeneity and characterized in detail. Mutation of trp263, leu268, or arg269 caused a significant loss of the capacity of Gs alpha to stimulate adenylylcyclase, and the triple mutant had less than 1% of the ability of wild type Gs alpha to activate the enzyme. Guanine nucleotide binding and GTP hydrolysis by the mutant proteins were unaltered, as was guanosine 5'-3-O-(thio)triphosphate-induced enhancement of intrinsic tryptophan fluorescence. Mutant proteins also appeared to have a reduced affinity for the G protein beta gamma subunit complex. Secondary structure analysis and comparison with the structure of p21ras suggests that the region of Gs alpha that we have identified is part of a loop that may be involved in interaction of the protein with adenylylcyclase. Although these residues are essential for activation of adenylylcyclase, they are not sufficient to do this when placed in the context of another G protein alpha subunit.
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PMID:Expression and analysis of Gs alpha mutants with decreased ability to activate adenylylcyclase. 165 37

Canine jejunal epithelial cells were isolated and maintained in short-term culture to study cholecystokinin (CCK) release. Sequential digestion of jejunal mucosa with collagenase and ethylenediaminetetraacetic acid was followed by counterflow elutriation to enrich CCK-containing cells. After 40 hours in culture on collagen-coated plates, 8.4% of the initially seeded cells were attached; 8.7% of them stained positive with a C-terminal CCK/gastrin antibody and 2.5% stained positive with a gastrin-specific antibody. Basal release of CCK into the culture medium amounted to 1.3% of total cell content over 105 minutes. Receptor-independent stimulation of protein kinase C by the phorbol ester beta-phorbol-12-myristate-13-acetate caused significant CCK release. The inactive form, 4 alpha-phorbol-12-myristate-13-acetate, had no effect. Activation of adenylate cyclase by 10(-5) mol/L forskolin evoked a 2.5-fold increase in CCK concentrations, which was completely abolished by 10(-8) mol/L somatostatin. L-phenylalanine stimulated CCK release at 20 and 50 mmol/L, whereas D-phenylalanine caused significant hormone output only at 50 mmol/L. L-tryptophan had no effect. Cholecystokinin release stimulated by L-phenylalanine was not influenced by the addition of either somatostatin or somatostatin antibody. In conclusion, a system of isolated canine jejunal epithelial cells was developed in short-term culture. This preparation proved suitable for the study of CCK release on a cellular basis.
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PMID:Cholecystokinin release from isolated canine epithelial cells in short-term culture. 172 60

Adenylylcyclase cannot be activated by hormones or guanine nucleotide analogs in membranes from cells that express the G226A mutant form Gs alpha instead of the wild-type protein. The mutant Gs alpha protein appears incapable of undergoing the conformational change necessary for guanine nucleotide-induced dissociation of the G protein alpha subunit from the beta gamma subunit complex (Miller, R.T., Masters, S.B., Sullivan, K.A., Beiderman, B., and Bourne, H.R. (1988) Nature 334, 712-715). G226A Gs alpha was synthesized in Escherichia coli, purified, and characterized. Examination of the kinetics of dissociation of guanosine 5'-3-O-(thio)triphosphate (GTP gamma S) suggests that G226A Gs alpha is incapable of assuming the conformation necessary for high affinity binding of Mg2+ to the alpha subunit-GTP gamma S complex. Associated changes include the failure of Mg2+ and GTP gamma S to confer resistance to tryptic proteolysis upon the protein, to enhance intrinsic tryptophan fluorescence, or to cause dissociation of alpha from beta gamma. However, the GTPase activity of the mutant protein is near normal (at high Mg2+ concentrations), and the protein is capable of activating adenylylcyclase. A similar defect is present in G49V Gs alpha. Failure of G protein subunit dissociation appears to be the explanation for the phenotypic properties of cells that express G226A Gs alpha, and this mutation thus highlights the crucial nature of this reaction as a component of G protein action.
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PMID:The G226A mutant of Gs alpha highlights the requirement for dissociation of G protein subunits. 173 Jun 44

A truncated, 432 residue long, Bordetella pertussis adenylate cyclase expressed in Escherichia coli was analyzed for intrinsic fluorescence properties. The two tryptophans (Trp69 and Trp242) of adenylate cyclase, each situated in close proximity to residues important for catalysis or binding of calmodulin (CaM), produced overlapping fluorescence emission bands upon excitation at 295 nm. CaM, alone or in association with low concentrations of urea, induced important modifications in the spectra of adenylate cyclase such as shifts of the maxima and change in the shape of the bands. From these changes and from the fluorescence spectrum of a modified form of adenylate cyclase, in which a valine residue was substituted for Trp242, it was deduced that, upon binding of CaM to the wild-type adenylate cyclase, only the environment of Trp242 was affected. The fluorescence maximum of this residue, which is more exposed to the solvent than Trp69 in the absence of CaM, is shifted by 13 nm to shorter wavelength upon interaction of protein with its activator. Trypsin cleaved adenylate cyclase into two fragments, one carrying the catalytic domain, and the second carrying the CaM-binding domain (Ladant et al., 1989). The isolated peptides conserved most of the environment around their single tryptophan residues, as in the intact adenylate cyclase, which suggests that the two domains of truncated B. pertussis adenylate cyclase also conserved most of their three-dimensional structure in the isolated forms.
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PMID:Intrinsic fluorescence of a truncated Bordetella pertussis adenylate cyclase expressed in Escherichia coli. 226 68


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