Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A series of phenylated pyrazoloalkanoic acid derivatives were synthesized and evaluated as inhibitors of ADP-induced human platelet aggregation. 3,4,5-Triphenyl-1H-pyrazole-1-nonanoic acid (8d), with an IC50 of 0.4 microM, was the most potent inhibitor identified in this study. Biochemical studies determined that 8d increased intraplatelet cAMP accumulation and stimulated platelet membrane-bound adenylate cyclase in a concentration-dependent fashion. Displacement of [3H]iloprost by 8d from platelet membranes indicated that the platelet prostacyclin (PGI2) receptor is the locus of biological action. Structure-activity studies demonstrated that the minimum structural requirements for binding to the platelet PGI2 receptor and inhibition of ADP-induced platelet aggregation within this series are a vicinally diphenylated pyrazole substituted with an omega-alkanoic acid side chain eight or nine atoms long. Potency depended upon both side-chain length and its topological relationship with the two phenyl rings.
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PMID:Structure-activity relationships associated with 3,4,5-triphenyl-1H-pyrazole-1-nonanoic acid, a nonprostanoid prostacyclin mimetic. 137 Jun 96

N:NIH mice were vaccinated according to the WHO recommendations for the potency test with the Second International Standard for Pertussis Vaccine (ISPV). Blood for serological investigation was taken from the animals on day 14 post immunization before intracerebral challenge with Bordetella pertussis 18323 was done. The relationship between anti-pertussis toxin, anti-filamentous hemagglutinin and anti-adenylate cyclase antibody levels as measured by ELISA and protection from intracerebral challenge was studied. The proportion of surviving mice increased in correlation with increasing anti-PT titres; a protective level of 4 ELISA units/ml was found. Such relationship between protection against intracerebral challenge and antibody titres was not found for anti-FHA nor for anti-AC antibodies, thus suggesting that these antibodies do not play an important role in protection in this model. The excellent correlation between anti-PT antibody titres and protection suggests that the measure of anti-PT response could be a useful tool for estimating the potency of whole-cell vaccines. The development of an alternative method for testing the potency of pertussis whole-cell vaccines based on the anti-PT response should be considered.
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PMID:Pertussis whole cell vaccine: relation between intracerebral protection in mice and antibody response to pertussis toxin, filamentous hemagglutinin and adenylate cyclase. 152 Sep 70

Severe magnesium depletion leading to hypocalcaemia has been described in a variety of clinical settings. Inadequately low concentrations of parathyroid hormone (PTH) are a constant feature of hypomagnesaemic hypocalcaemia (HMHC), while target organ resistance to PHT in kidneys and bone may be demonstrated in the majority of these patients. The failure of membrane-bound adenylate cyclase in the parathyroids, kidneys and bone, thought to be the most important molecular mechanism in HMHC, cannot explain the concomitant resistance to vitamin D and its metabolites. In recent years, information has accumulated on further magnesium-dependent intracellular events and alternative pathways of transcellular signalling. This may eventually allow the identification of one or more further biochemical mechanisms leading to hypocalcaemia in severe magnesium deficiency.
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PMID:Mechanisms of hypocalcaemia in the clinical form of severe magnesium deficit in the human. 159 Nov 42

alpha 2-Adrenergic receptors (alpha 2-AR) exist as subtypes that are expressed in a tissue-specific manner and differ in 1) their ligand recognition properties, 2) their extent of receptor protein glycosylation, and possible 3) their mechanism of signal transduction. Genomic or cDNA clones encoding three receptor subtypes have been characterized; however, both functional and radioligand binding studies in rodents suggest the existence of a fourth receptor subtype. To isolate the rat genes encoding receptor subtypes we screened a rat genomic library with an oligonucleotide probe encompassing the third membrane span of the human C-4 alpha 2-AR. Two intronless rat genes were isolated that encode distinct receptor subtypes (RG10, RG20). RG10 and RG20 encode proteins of 458 and 450 amino acids, respectively, that are 56% homologous and possess the structural features expected of this class of membrane-bound receptors. RG10 identifies a mRNA species of approximately 2500 nucleotides that is found primarily in brain, whereas RG20 identifies a larger mRNA species (approximately 4000 nucleotides) that is found in several tissues including brain, kidney, and salivary gland. RG10 is 88% homologous to the human C-4 alpha 2-AR and exhibits similar binding properties ( [3H]rauwolscine KD = 0.7 +/- 0.3 nM) as determined following transient expression of the receptor in COS-1 cells. RG20 exhibits ligand binding properties distinct from the three receptor subtypes identified by molecular cloning. Saturation binding studies indicate an affinity constant of 15 +/- 1.2 nM for the alpha 2-AR antagonist [3H]rauwolscine, a value 6-20 times higher than that observed for the three cloned receptor subtypes. In competition binding studies the potency order of competing ligands for RG20 is phentolamine greater than idazoxan greater than yohimbine greater than rauwolscine greater than prazosin. Of the three previously cloned alpha 2-AR, RG20 is most closely related to the human C-10 alpha 2-AR (89% homology) and is also capable of mediating adenylylcyclase inhibition as determined following its stable expression in NIH-3T3 fibroblasts. However, in contrast to RG20, [3H] rauwolscine exhibits a KD of 2 nM for the C-10 receptor, and the potency order for competing ligands is rauwolscine greater than or equal to yohimbine greater than idazoxan greater than phentolamine greater than prazosin. RG20 and C-10 are also distinguished by their affinity for SKF-10478 (RG20 Ki = 531 nM, C-10 Ki = 101 nM), a compound that may functionally distinguish pre- and postsynaptic alpha 2-AR. These data suggest that RG20 represents a fourth alpha 2-AR subtype distinct from the known alpha 2A-C receptor subtypes.
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PMID:Isolation of rat genomic clones encoding subtypes of the alpha 2-adrenergic receptor. Identification of a unique receptor subtype. 164 50

We have examined the effects of xamoterol, a partial beta 1-adrenoceptor agonist, on cardiac beta-adrenoceptors using isolated myocytes and cell-free preparations. Xamoterol was considerably less effective than isoproterenol in stimulating adenylate cyclase activity but the difference was narrowed by 1 microM forskolin, presumably by inducing more efficient coupling to the catalytic subunit of the enzyme. Xamoterol mediated a time- and concentration-dependent loss of beta-adrenoceptors from the cell surface of cardiac myocytes through a process of internalization sensitive to the cytoskeleton inhibitors, colchicine and cytochalasine. In cell-free preparations, loss of membrane-bound beta-adrenoceptors induced by xamoterol, but not that induced by 1 microM isoproterenol, was prevented by the inhibitor of protein kinase A. In contrast, 100 nM heparin (an inhibitor of beta-receptor kinase) prevented the isoproterenol-but not the xamoterol-mediated decline of beta-receptors. In addition, 1 microM xamoterol attenuated the isoproterenol-mediated internalization of beta-adrenoceptors in cardiac myocytes over a wide range of isoproterenol concentrations. This attenuation required activation of protein kinase A. These results suggest that the influence of xamoterol on the cycling of cardiac beta-adrenoceptors involves different pathways than those utilized by isoproterenol.
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PMID:Effects of xamoterol on the reversible cycling of cardiac beta-adrenoceptors. 170 88

Effect of protein deficient diet on hepatic plasma membrane fluidity has been studied in rats using (i) steady state fluorescence polarization and anisotropy, (ii) phospholipid and cholesterol contents, (iii) phospholipid fatty acid composition, (iv) turnover of phosphatidyl choline (PC), and (v) activities of membrane-bound enzymes as parameters and rats fed casein (20%) diet as standard group. A significant increase in steady state fluorescence and anisotropy values was registered in the deficient group, indicating increased resistance and hence decrease in fluidity of the plasma membrane. Supplementation of the diet with lysine and threonine improved these values, thereby suggesting the significance of diet for membrane fluidity. Simultaneous significant alterations in other parameters, viz. (i) decrease in PC, PE and free cholesterol and increase in esterified cholesterol contents, (ii) decrease in unsaturation of fatty acids of PC, (iii) decrease in incorporation of NaH2 32PO4, [CH3-14C]choline and [CH3-14C]methionine into plasma membrane PC, and (iv) decrease in activities of plasma membrane 5'-nucleotidase and phosphodiesterase along with increase of (Na(+)-K+)ATPase and adenyl cyclase, were observed in the deficient group which on supplementation with lysine and threonine showed improvement over alterations.
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PMID:Hepatic plasma membrane fluidity and dietary proteins. 175 32

The Bordetella pertussis P.69 protein is an immunogen with vaccine potential. The role of this protein in pathogenesis is unclear; it has been associated with the toxic adenylate cyclase and adhesion to eukaryotic cells. For further analysis of the role of P.69 in the biology of B. pertussis, we have constructed strains which specifically lack P.69. The cloned P.69 (prn) gene of B. pertussis was insertionally inactivated with a kanamycin-resistance cassette. This inactivated gene was used to construct P.69- mutants of B. pertussis by allelic exchange using plasmid pRTP1. B. pertussis P.69- strains produced normal levels of other vir-regulated factors, including adenylate cyclase. The serotype of B. pertussis, determined by Eldering and Preston typing sera and monoclonal antibodies, was also unaffected by the presence or absence of P.69. The ability of a prn mutant to adhere to and invade HEp2 cells was not significantly different from that of its parent strain. A strain containing a mutation in fhaB was significantly less adhesive and invasive than its parent, and a prn fhaB double mutant exhibited an even greater reduction in adhesiveness and invasiveness down to levels comparable with a Vir- strain. However, strains harbouring mutations in FHA and/or P.69 were able to colonize or multiply in the murine respiratory tract, although a Vir- strain was unable to survive and proliferate in the same infection model.
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PMID:Construction and characterization of Bordetella pertussis mutants lacking the vir-regulated P.69 outer membrane protein. 178 93

In order to quantitate the role of the kidneys in the clearance and degradation of calcitonin, a trapped-label procedure was used to label human calcitonin. In contrast to conventional [125I]calcitonin, the trapped-label preparation allows quantitative measurements of the extent of uptake as well as of degradation in vivo because the final degradation products do not leave the cells. Trapped-label calcitonin activated adenylate cyclase of bone cells and kidney, as did the native hormone. Ten minutes after intravenous injection into rats, 16% of a trace dose was found in the kidneys. Renal recovery increased to 20% after one hour; in addition, 14% of the injected dose was found in the urine. Eighty per cent of the radioactivity in the urine was in high-molecular weight material. After 90 min, the sum of the accumulated radioactivities in the kidneys and the urine reached 40% of the dose. More than 80% of the radioactivity was sedimentable by centrifuging in a density gradient, indicating that intact calcitonin, as well as the degradation products in the cells, were enclosed within membrane-bound vesicles. Two minutes after injection of trapped-label calcitonin, the peak of radioactivity was found in light gradient fractions associated with cell membrane marker enzymes. Between 5 and 15 min, the peak migrated from light fractions to heavy fractions containing lysosomal marker enzymes. After just 2.5 min, 61% of the renal radioactivity was in low-molecular weight degradation products, as determined by gel filtration. The kinetics of renal degradation of calcitonin indicate that substantial amounts of endocytosed calcitonin is degraded before the hormone reaches the lysosomes.
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PMID:Renal uptake and degradation of trapped-label calcitonin. 184 83

The activity of membrane-bound platelet adenylate cyclase, when stimulated in vitro by several compounds (including fluoride), is significantly reduced in alcoholics compared with control subjects. We have begun a study of the genetics of this enzyme activity. Complex segregation analysis of basal (unstimulated) platelet adenylate cyclase activity in families reveals a mode of inheritance that cannot be accounted for by a simple mixed model of transmission. By contrast, adenylate cyclase activity stimulated by fluoride ion reveals a single major locus effect with a modest multifactorial background. These results suggest that a single factor in the second-messenger pathway may (a) account for the majority of individual differences in stimulation of adenylate cyclase of fluoride and (b) help explain the reduced activities previously observed in alcoholics.
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PMID:A genetic study of platelet adenylate cyclase activity: evidence for a single major locus effect in fluoride-stimulated activity. 186 96

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


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