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)

1. Adenylate cyclase (EC 4.6.1.1) activity has been determined in the parotid and sublingual glands of the mouse. Optimal activity of the enzyme was obtained at a Mg2+-concentration of 8 mM at pH 8.2, using AMP-PNP as the substrate. 2. Cyclic AMP degradation during the adenylate cyclase assay was relatively high in both the homogenate and the 40,000 g pellet-fraction of the glands. Theophylline was effective in inhibiting this degradation only in the parotid hemogenate, whereas isobutylmethylxanthine inhibited the cyclic AMP degradation in both salivary glands. Using the latter phosphodiesterase inhibitor, we observed a higher adenylate cyclase activity in the sublingual glands than in the parotid glands. 3. Various receptor-selective sympathetic and parasympathetic agonists and antagonists have been tested for their capacity to influence the adenylate cyclase activity and the glycoprotein secretion in the parotid and sublingual glands of the mouse, in vitro. (a) The parotid glycoprotein secretion was increased by beta-adrenergic agonists, which stimulate adenylate cyclase, and by cholinergic muscarinic drugs, which do not activate this enzyme. The adrenergic alpha-agonist phenylephrine appeared to be involved neither in the glycoprotein secretion nor in the direct regulation of the adenylate cyclase activity. (b) The sublingual protein and mucin secretion was increased by cholinergic muscarinic agents. The over-all protein secretion was stimulated also by phenylephrine, but this effect could be blocked by propranolol. The adenylate cyclase activity in membrane preparations was not stimulated by these secretogogues.
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PMID:Comparison of adenylate cyclase activity and in vitro secretion in the parotid and sublingual glands of the mouse. 3 65

Retro-orbital tissue membranes have been shown to have adenylate cyclase activity which can be stimulated by thyrotropin and by an exophthalmogenic factor derived from the thyrotropin molecule by partial pepsin digestion. This stimulable activity is maximal after 15 min and is optimal in the presence of 3 mM magnesium and 1.5 mM ATP. Calcium salts are exquisitely inhibitory to the hormonal stimulation; sodium, lithium, and ammonium salts are significantly less inhibitory. Thyrotropin and the exophthalmogenic factor induce similar maximal levels of stimulation but a 4- to 5-fold higher concentration of exophthalmogenic factor is required to achieve this level. Fluoride stimulates adenylate cyclase activity 2- to 3-fold higher than either thyrotropin or the exophthalmogenic factor; thyrotropin, luteinizing hormone, the beta subunit of thyrotropin, and the alpha subunit of thyrotropin have relative activities for stimulation of cyclase activity of 100:2:2 less than 0.5. Several other polypeptide and glycoprotein hormones have no effect. The gamma-globulin from patients with malignant exophthalmos has no significant effect on cyclase activity either alone or in the presence of maximal levels of thyrotropin or the exophthalmogenic factor; this gamma-globulin does, however, stimulate cyclase activity at submaximal hormone levels. Trypsin not only destroys the hormone-stimulable adenylate cyclase activity on retro-orbital tissue plasma membranes, but also destroys it on the 15,000 to 30,000 molecular weight receptor fragment released from the membranes by the tryptic action.
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PMID:Stimulation of adenylate cyclase activity in retro-orbital tissue membranes by thyrotropin and an exophthalmogenic factor derived from thyrotropin. 5 Oct 22

1. Six rat liver plasma-membrane subfractions of different density and morphological, enzymic and chemical properties were prepared from homogenates by a combination of differential, rate-zonal and density-gradient centrifugation. They consisted of three vesicular 'light' subfractions of density 1.12-1.13 and three 'heavy' subfractions of density 1.16-1.18 containing membrane strips and intercellular junctions. 2. All six subfractions contained a basal adenylate cyclase activity. One of the 'light' subfractions that showed the highest glucagon-stimulated adenylate cyclase activity was identified as deriving form the blood-sinusoidal face of the hepatocyte. This subfraction, unlike the others, was contaminated by Golgi components, as indicated by its morphological properties and the presence of galactosyl- and sialyl-transferase activities. 3. All the six subfractions showed high activities of the following plasma-membrane marker enzymes: 5'-nucleotidase, alkaline phosphodiesterase (nucleotide pyrophosphatase), alkaline phosphatase, leucine naphthylamidase and Mg2+-activated adenosine triphosphatase. A 'light' subfraction that showed the highest specific activities of all the above marker enzymes, but lacked a glucagon-stimulated adenylate cyclase activity, was identified as deriving from the bile-canalicular face of the hepatocyte. 4. The 'heavy' subfractions, which showed generally the lowest activities of the above plasma-membrane enzyme markers, and were characterized by the presence of desmosomes and gap junctions, were taken to originate from the contiguous faces of the hepatocyte. 5. The protein composition of the six subfractions was generally similar, as shown by polyacrylamide-gel electrophoresis. Differences in the amounts of various protein and glycoprotein bands among the subfractions correlated with their morphology, enzymic composition and sialic acid content. 6. Hormonal and histochemical evidence supporting the identification of a bile-canalicular subfraction, a blood-sinusoidal subfraction and contiguous-face subfractions is discussed.
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PMID:Functional polarity of the rat hepatocyte surface membrane. Isolation and characterization of plasma-membrane subfractions from the blood-sinusoidal, bile-Canalicular and contiguous surfaces of the hepatocyte. 12 84

Insulin action is discussed with emphasis on events that occur at the plasma membrane. A summary is presented of previous studies which indicate that the insulin receptor of fat and liver cells is a large glycoprotein, partially buried in the outer surface of the plasma membrane, with a high (K-D approximately 10-10 M) and specific affinity for insulin. The participation of membrane phospholipids in the binding of insulin and the role of sialic acid residues in the transmission of the insulin binding signal are discussed. The relation of insulin action to its effects on cyclic nucleotide levels is explored. On the one hand, insulin action (glucose transport) is inhibited by compounds (cholera toxin, ACTH, glucagon and L-norepinephrine) that stimulate adenylate cyclase; conversely, insulin both inhibits the lipolytic action of these compounds, and raises cellular levels of cyclic GMP. An hypothesis is presented whereby a single cyclase species may be responsible for the formation of either cyclic AMP or cyclic GMP, depending on the nature of the hormone stimulus. The role of membrane phosphorylation in the action of insulin is discussed in the context of experiments demonstrating a specific inhibition by ATP of insulin-mediated glucose transport, in association with the phosphorylation of two specific membrane proteins. The ability of insulin to modulate cyclic nucleotide levels in cultured cells and to act as a growth factor is discussed. Insulin stimulates DNA synthesis and the uptake of alpha-aminoisobutyric acid in human fibroblasts, which effects are also mediated by epidermal growth factor. Insulin acts at concentrations much higher than those obtained in vivo, whereas epidermal growth factor acts at concentrations thought to be physiological. The insulin binding sites (K-D is approximately equal to 10-9 M) related to growth, and observed both in human fibroblasts and in lectin-stimulated and leukemic human lymphocytes would not be appreciably occupied at physiological insulin concentrations. The implications of such 'low affinity' binding sites for insulin are discussed in relation to the action of other growth factors.
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PMID:Insulin: interaction with membrane receprots and relationship to cyclic purine nucleotides and cell growth. 16 82

The author first considers the general conditions of reversibility, saturability, specificity and affinity which should be filled by all receptors, but emphasizes certain special difficulties on analysis of TSH receptors. TSH is a glycoprotein of molecular weight 28,000, composed of 2 alpha and beta sub-units; the role of each of these with regard to the receptor, is discussed. The TSH receptor is mainly localised in the outer part of the plasma membrane of the thyroid cells. An important point concerns the biological significance of the link between TSH and receptors and the activation of the adenylate cyclase AMPc system. One may experimentally dissociate with lecithinase these two cell events: treatment of thyroid tissue with this enzyme abolishes the biological response but does not affect the bond. The notion of hormone dependency of thyroid carcinoma is still classical but should be reconsidered in the light of new data concerning TSH receptors. Finally, the notion of variable receptivity of the thyroid tissue to TSH permits one to imagine another regulatory mechanism for which the receptors are responsible.
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PMID:[Thyroid gland TSH receptors]. 18 42

Cultured thyroid cells accumulate the lipophilic cation triphenylmethylphosphonium, indicating that there is an electrical potential (interior negative) across the plasma membrane. Thyrotropin stimulates the uptake of the lipophilic cation 3-fold, and the proton conductor carbonylcyanide-m-chlorophenylhydrazone causes efflux of triphenylmethylphosphonium accumulated in the presence or absence of thyrotropin. The stimulatory effect of thyrotropin on triphenylmethylphosphonium accumulation is not mimicked by human chorionic gonadotropin, a glycoprotein hormone with a similar structure whose target organ is not the thyroid, and the effect is abolished if the thyrotropin-receptor activity of the cells is destroyed by treatment with trypsin. Analogous effects are observed with thyroid plasma membrane vesicles which are essentially devoid of mitochondrial and soluble enzyme activities. Triphenylmethylphosphonium uptake and stimulation by thyrotropin occurs when NaCl, KCl, or Tris.HCl concentration gradients are artifically imposed across the vesicle membrane ([salt](out) > [salt](in)). It seems likely, therefore, that triphenylmethylphosphonium uptake is driven by a chloride diffusion potential (interior negative) and that thyrotropin either increases the permeability of the membrane to anions or decreases its permeability to cations. Thyrotropin-stimulated triphenylmethylphosphonium uptake in the vesicle preparations reaches a quasi steady-state within 3 min; in contrast, thyrotropin-stimulated adenylate cyclase activity is negligible during this period of time, becomes measurable after about 4 min, and is optimal after 12-15 min. Thus, a primary mode of action of thyrotropin on the thyroid cell may be an alteration in the electrical potential across the plasma membrane. The relevance of this observation to the mechanism of action of other glycoprotein hormones, certain bacterial toxins, and interferon is discussed.
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PMID:Effects of thyrotropin on the thyroid cell membrane: hyperpolarization induced by hormone-receptor interaction. 19 88

The properties of follitropin receptors in immature porcine testis were determined using highly purified porcine follitropin. 1. The characteristics of follitropin binding to a subcellular fraction rich in plasma membranes were studied using a 125I-labelled follitropin with high specific activity (75-100 Ci/g) and high binding activity. The binding is dependent on time, temperature and pH. It is specific to follitropin as demonstrated by the very low binding activity of the follitropin alpha and beta subunits and of the other glycoprotein hormones. Scatchard analysis of binding data indicated an equilibrium association constant of 2 x 10(10) M-1 and a concentration of high affinity binding sites of 500 fmol/mg membrane proteins. 2. A sensitive radio-ligand receptor assay was developed. Fifty percent inhibition of binding was obtained with as little as 2 ng of porcine follitropin. Ovine and bovine follitropins and pregnant mare serum gonadotropin gave binding inhibition curves parallel to that given by porcine follitropin. With equine and human follitropin, significantly different slopes were recorded. 3. Kinetics of dissociation of labelled follitropin from its testis receptors showed the presence of at least two compartments with fast and slow dissociation rate constants. The ratio between the sizes of the slow and fast compartments appeared dependent upon preincubation time. 4. A temporal correlation was observed between binding of follitropin to testis receptors and activation of membrane bound adenylate cyclase.
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PMID:Study of follitropin receptors in testis using a homologous system. Binding of porcine follitropin to plasma membranes from immature porcine testis and correlation with adenylate cyclase stimulation. 20 14

Using tunicamycin, we have investigated the role of glycoproteins in membrane transport. Tunicamycin is a glucosamine-containing antibiotic that specifically inhibits dolichol pyrophosphate-mediated glycosylation of asparaginyl residues of glycoproteins. Inhibition of protein glycosylation in chick embryo fibroblasts by tunicamycin or other inhibitors of glycosylation resulted in defective transport of glucose, uridine, and amino acid analogs (alpha-aminoisobutyrate and cycloleucine). The defect in glucose transport is accompanied by decreased glucose metabolism, as determined by rates of CO2 and lactate production. In contrast, tunicamycin treatment did not affect other membrane-associated processes, such as secretion of fibronectin and procollagen, uptake of glucose by passive diffusion, Na+/K+ ATPase and adenylate cyclase activities, or stimulation of adenylate cyclase by prostaglandin and cholera toxin. Two glucose/glycosylation-regulated membrane proteins with apparent subunit molecular weights of 95,000 and 75,000 were induced by tunicamycin treatment. Our results indicate that glycoprotein glycosylation is required for membrane transport.
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PMID:Evidence for role of glycoprotein carbohydrates in membrane transport: specific inhibition by tunicamycin. 21 20

1. Effects of concanavalin A (Con A) and other lectins on 5-hydroxytryptamine (5-HT) uptake by rabbit blood platelets and on their ultrastructure were studied. 2. Uptake of [3H]-5-HT by platelets was decreased by application of Con A, E-PHA (lectin from Phaseolus vulgaris) and lentil-PHA (lectin from Lens culinaris), but not by wheat germ agglutinin (WGA). Con A induced specific changes in the ultrastructure of platelets, causing (i) a change in external appearance from a discoid to an irregularly spherical shape, (ii) re-arrangement of the canalicular system and formation of a concentric structure. These effects of Con A on platelets were antagonized by pretreatment with alpha-methyl-D-mannoside (alpha-MM), a specific inhibitor of Con A binding to glycoprotein. 3. The inhibition of 5-HT uptake by Con A was antagonized by colchicine, vinblastine and sodium nitroprusside (SNP), but not by cytochalasin B. 4. Theophylline, papaverine and dibutyryl cyclic adenosine 3',5'-monophosphate (db cyclic AMP) antagonized the effect of Con A on 5-HT uptake, but dibutyryl cyclic guanosine 3',5'-monophosphate had no effect. Theophylline and db cyclic AMP did not influence the effect of Con A on the ultrastructure of platelets. 5. It is suggested that binding of Con A to specific receptor glycoproteins can inhibit the 5-HT uptake system of platelets. Microtubules, contractile protein and the membrane adenylate cyclase system of platelets may also be regulatory factors in this mechanism.
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PMID:Effects of concanavalin A on 5-hydroxytryptamine uptake by rabbit blood platelets and on their ultrastructure. 21 26

Cholera toxin, through adenylate cyclase activation reproduced cyclic AMP-mediated effects of thyroid-stimulating hormone (TSH) in dog thyroid slices, i.e. protein iodination, [1-14C]glucose-oxidation and hormone secretion. Iodide and carbamylcholine decreased the cyclic AMP accumulation induced by cholera toxin as well as by TSH, which supports the hypothesis of an action of these agents beyond the steps of hormone-receptor and receptor-adenylate cyclase interaction. Cooling to 20 degrees C did not impair the TSH induced cyclic AMP accumulation in thyroid slices, but completely suppressed the cholera toxin effect. This observation has been extended to other hormones and target tissues, such as the parathyroid hormone (PTH) (kidney cortex), adrenocorticotropic hormone (ACTH) (adrenal cortex) and luteinizing hormone (LH) (ovary systems). As in thyroid, cooling dissociated the cholera toxin and hormonal effects on cyclic AMP accumulation. In homogenate, cooling decreased cyclic AMP generation in the presence of cholera toxin but at 20 degrees C and 16 degrees C a cholera toxin stimulation was still observed. These results bear strongly against the hypothesis that the glycoprotein hormones TSH and LH acetivate adenylate cyclase by a mechanism identical to cholera toxin.
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PMID:Dissociation by cooling of hormone and cholera toxin activation of adenylate cyclase in intact cells. 22 51


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