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

---

Query: EC:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multiple mechanisms seem to be involved in regulating the responsiveness of hormone receptor-coupled adenylate cyclase systems. These mechanisms at least involve the receptors and nucleotide regulatory proteins. With the recent development of methods for purifying the catalytic unit of the enzyme it will be possible to assess whether it is also a locus for such regulatory phenomena. At least two major pathways of receptor regulation have been uncovered. Homologous desensitization (Fig. 9) involves the uncoupling and translocation of the receptors out of their normal plasma membrane environment. This process sequesters the receptors away from their effector, the regulatory and catalytic components of adenylate cyclase. The site of receptor sequestration is unclear and might lie within the plasma membrane or within the cell. The sequestered receptors can recycle to the cell surface or become down-regulated, perhaps being destroyed within the cell. Phosphorylation of the receptors through a beta-adrenergic receptor kinase appears to be associated with homologous desensitization. This phosphorylation event may serve either to uncouple functionally the receptors or to trigger their sequestration from the cell surface or both. In heterologous desensitization (Fig. 10), receptor function is regulated by phosphorylation in the absence of receptor sequestration or down-regulation. This covalent modification serves to functionally uncouple the receptors, that is, to impair their interactions with the guanine nucleotide regulatory proteins. Several protein kinases seem to be capable of promoting phosphorylation of the receptors including the cAMP-dependent kinase and protein kinase C. In addition to the receptor modification, heterologous desensitization seems to be associated with functional modifications (phosphorylation?) at the level of nucleotide regulatory proteins (Ns and Ni), (Fig. 10). Further studies of the mechanisms of desensitization of adenylate cyclase-coupled receptors are thus likely to help elucidate modes of regulation of a wide variety of receptor-coupled functions in diverse types of cells.
...
PMID:Molecular mechanisms of beta-adrenergic receptor desensitization. 282 83

Phosphorylation of the beta-adrenergic receptor (beta AR) is closely associated with homologous desensitization of the beta-adrenergic receptor-coupled adenylate cyclase system. Homologous desensitization and receptor phosphorylation also occur in cell mutants which are deficient in their cAMP-dependent protein kinase (kin- mutant of S49 lymphoma cells). beta AR phosphorylation is mediated by a cAMP-independent protein kinase which phosphorylates the receptor only when it is occupied by a beta-agonist. During the time course of desensitization the beta AR kinase (beta ARK) activity is translocated from a cytoplasmic to a plasma membrane location. beta ARK translocation can also be effected by prostaglandin E1 (PGE1) suggesting that this beta ARK may represent a more general enzyme capable of phosphorylating other adenylate cyclase-coupled receptors. Thus, beta ARK may play a key role in the process of homologous desensitization of adenylate cyclase coupled receptors. Extracellular hormones interact with specific receptors at the outer surface of the plasma membrane and thus initiate a cellular response. One of the best studied transmembrane signalling systems known to be coupled to the occupancy of cell surface receptors is adenylate cyclase. The adenylate cyclase system is composed of various components all of which have been purified to homogeneity (Shorr et al., 1982; Homcy et al., 1983; Benovic et al., 1984; Codina et al., 1984; Northup et al., 1980; Sternweis et al., 1981; Bokoch et al., 1984; Pfeuffer et al., 1985). Initially, agonist binding to the receptor promotes coupling of the occupied receptor to one of the guanine nucleotide binding regulatory proteins. These proteins are members of a family of heterotrimeric proteins consisting of alpha, beta and gamma subunits. Stimulatory receptors like the beta-adrenergic (Cerione et al., 1984) or glucagon (Iyengar et al., 1979) receptors couple to the stimulatory regulatory protein Ns (or Gs) whereas inhibitory receptors like the alpha 2-adrenergic (Jacobs et al., 1976) or M2-muscarinic (Harden et al., 1982) receptors couple to the inhibitory regulatory protein Ni (or Gi). Prolonged exposure to agonist hormones, either stimulatory or inhibitory, results in an attenuation of the response to the hormonal activation, a phenomenon called tachyphylaxis or desensitization (Harden, 1983; Sibley and Lefkowitz, 1985; Sharma et al., 1975). One of the best studied models for desensitization is the beta-adrenergic receptor-coupled adenylate cyclase system. In this system two different forms of desensitization have been characterized.(ABSTRACT TRUNCATED AT 400 WORDS)
...
PMID:The beta-adrenergic receptor kinase: role in homologous desensitization in S49 lymphoma cells. 284 12

Desensitization of adenylate cyclase-coupled beta-adrenergic receptors in avian erythrocytes results in a 40-65% decrease in agonist-stimulated adenylate cyclase activity and correlates with increased phosphorylation of beta-adrenergic receptors. To assess the role of phosphorylation in desensitization, membranes from isoprenaline- and dibutyryl cyclic AMP-desensitized turkey erythrocytes were incubated with alkaline phosphatase for 30 min at 37 degrees C, pH 8.0. In both preparations alkaline phosphatase treatment significantly decreased desensitization of agonist-stimulated adenylate cyclase activity by 40-75% (P less than 0.05). Similar results were obtained after alkaline phosphatase treatment of membranes from isoprenaline- and dibutyryl cyclic AMP-desensitized duck erythrocytes. Moreover, alkaline phosphatase treatment of membranes from duck erythrocytes desensitized with 12-O-tetradecanoylphorbol 13-acetate returned agonist-stimulated adenylate cyclase activity to near control values. In all experiments, inclusion of 20 mM-sodium phosphate to inhibit alkaline phosphatase during treatment of membranes attenuated the enzyme's effect on agonist-stimulated adenylate cyclase activity. In addition, alkaline phosphatase treatment of membranes from control and isoprenaline-desensitized turkey erythrocytes increased the mobility of beta-adrenergic-receptor proteins, specifically photoaffinity-labelled with [125I]iodocyanopindolol-diazirine, on SDS/polyacrylamide-gel electrophoresis. The increased mobility of the beta-adrenergic-receptor proteins after alkaline phosphatase treatment of membranes was again inhibited by 20 mM-phosphate. These results provide additional evidence for a direct role for phosphorylation in desensitization of adenylate cyclase-coupled beta-adrenergic receptors in avian erythrocytes.
...
PMID:Alkaline phosphatase relieves desensitization of adenylate cyclase-coupled beta-adrenergic receptors in avian erythrocyte membranes. 284 55

In both man and rat, urinary cAMP (U cAMP) level increases in response to PTH. The increased cAMP arises largely by secretion from the proximal tubule where cAMP synthesis is stimulated by PTH through adenylate cyclase-coupled receptors. We have previously demonstrated alpha 2-adrenergic receptors which inhibit PTH-stimulated adenylate cyclase in rat renal cortex membranes in vitro. In the present study, the effects of alpha-adrenergic agonists and antagonists on the U cAMP response to PTH were investigated in anesthetized rats in vivo. Injection of PTH (15 U/kg iv) produced an increase in U cAMP from 1.7 +/- 0.3 to 7.4 +/- 0.7 nmol cAMP/mumol creatinine (n = 6), (P less than 0.001). This rise was largely due to an increase in nephrogenous cAMP which increased 10-fold. Infusion of the alpha 2-adrenergic agonist clonidine at 1 microgram/kg X min caused a decrease in the cAMP response to PTH to 3.6 +/- 0.5 nmol cAMP/mumol creatinine (n = 12) (P less than 0.001). Infusion of the alpha 2-selective catecholamine alpha-methylnorepinephrine (1 microgram/kg X min) caused a similar reduction in U cAMP response to that observed with clonidine. The alpha-adrenergic antagonist phentolamine (100 micrograms/kg X min) reversed the effects of clonidine and, when administered in the absence of alpha-agonists, caused an increased cAMP response to PTH. These results demonstrate the presence of alpha-receptors in the rat proximal convoluted tubule which oppose the actions of PTH in vivo.
...
PMID:Renal proximal tubular alpha-adrenergic receptors oppose urinary 3,5'-cyclic adenosine monophosphate response to parathyroid hormone in vivo. 285 38

We recently demonstrated that heterologous desensitization of adenylate cyclase in turkey erythrocytes is highly correlated with phosphorylation of the beta-adrenergic receptor. In contrast, little is known of the biochemical mechanisms underlying the homologous form of beta-adrenergic receptor desensitization, which is agonist-specific and not cAMP-mediated. Accordingly, the present studies were undertaken to examine if phosphorylation of the beta-adrenergic receptor is also associated with this form of desensitization in a well studied model system, the frog erythrocyte. Preincubation of these cells with the beta-adrenergic agonist isoproterenol leads to a 45% decline in isoproterenol-stimulated adenylate cyclase activity without significant changes in basal, prostaglandin E1-, NaF-, guanyl-5'-yl-imidodiphosphate-, forskolin-, or MnCl2-stimulated enzyme activities. There is also a 48% decline in [125I]iodocyanopindolol membrane binding sites. Conversely, preincubation of the cells with prostaglandin E1 attenuates only the prostaglandin E1-stimulated enzyme activity and does not affect [125I]iodocyanopindolol binding. Phosphorylation of the beta-adrenergic receptor was assessed by preincubating the cells with 32Pi and desensitizing them, and subsequently purifying the receptors by affinity chromatography. Under basal conditions there is about 0.62 mol of phosphate/mol of receptor whereas after desensitization with isoproterenol this increases to 1.9 mol/mol. This isoproterenol-induced receptor phosphorylation exhibits stereospecificity and is blocked by the beta-adrenergic antagonist propranolol. In addition, preincubation with prostaglandin E1 does not promote beta-adrenergic receptor phosphorylation. These data suggest that receptor phosphorylation is involved in homologous as well as heterologous forms of desensitization and may provide a unifying mechanism for desensitization of adenylate cyclase-coupled hormone receptors.
...
PMID:Homologous desensitization of adenylate cyclase is associated with phosphorylation of the beta-adrenergic receptor. 285 84

Desensitization of beta-adrenergic receptors means loss of receptor activity due to overstimulation by beta-mimetic drugs. Desensitization has been demonstrated in experimental studies using cell cultures, isolated organs and in vivo models. It generally evolves in two steps: uncoupling between the receptor and adenylate cyclase is followed by a decrease of the number (or down-regulation) of receptors. Desensitization can be either specific or non specific. In the first case, the phenomenon is related to the occupation of the receptor by an agonist and the occupied receptor only is altered (homologous desensitization). In the second case, the phenomenon is related to production in excess of cyclic AMP and other adenylate cyclase-coupled receptors are altered (heterologous desensitization). Studies performed on cellular models have shown that beta-receptor desensitization can be related to phosphorylation of the receptor by a cyclic AMP-dependent protein-kinase and that down-regulation corresponds to the incorporation of the beta-receptors in cytoplasmic vesicles. Desensitization has also been related to the activation of membrane phospholipid metabolism and the production of prostaglandins. Studies of bronchial beta-adrenergic receptors, mostly performed on isolated organs, have shown that beta-mimetic and, in some cases, phosphodiesterase inhibitor drugs can induce desensitization of beta-receptors. The possibility of beta-adrenergic receptor activity and desensitization independent of adenylate cyclase and cyclic AMP has also been evoked. In clinical practice, the reality of beta-adrenergic desensitization is still controversial. The existence of a variable proportion of "spare" receptors could explain the variability of patient responses to the long-term treatment of asthma by beta-mimetic drugs.
...
PMID:[Mechanisms of desensitization of beta-adrenergic receptors]. 286 91

The binding of novel dibenzodioxazocine derivatives to rat striatal dopamine receptors was studied in vitro, using 3H-spiperone as radioligand. The biochemical-pharmacological characteristics of the effect of a selected representative, EGYT-2509 are discussed in details. The parameters of specific spiperone binding to rat striatal membrane preparation (KD = 0.550 nM, Bmax = 465 fmole/mg protein) as well as the displacing potencies of known dopamine receptor ligands matched closely the corresponding values in the literature. Using 0.4 nM radioligand, a Ki value of 404 nM was obtained for EGYT-2509; the binding of the drug had a minor serotonergic component. EGYT-2509 behaved as a dopamine receptor antagonist in all functional in vitro biochemical-pharmacological tests (striatal adenylate cyclase, striatal dopamine release, prolactin release from pituitary) performed previously. The drug exhibited a marked preference for adenylate cyclase-coupled (D1) dopamine receptors, followed by the 3H-spiperone displacing potency at striatal receptors. It was a rather weak antagonist both at striatal dopamine autoreceptors and at the receptors controlling prolactin release. Finally, when comparing the structure-activity relationships obtained with dibenzo-dioxazocines in the dopamine receptor binding assay with the relative pharmacological potencies of a structurally related neuroleptic group, i.e. of phenothiazines, a definite parallelism could be demonstrated.
...
PMID:Dopamine receptor binding of a novel dibenzodioxazocine derivative, EGYT-2509. 286 98

The beta-adrenergic receptor kinase is a cytosolic enzyme that specifically phosphorylates the agonist-occupied form of the beta-adrenergic receptor (beta AR). Beta AR kinase appears to be translocated from the cytosol to the plasma membrane when kin- S49 lymphoma cells are incubated with either beta-adrenergic agonists or prostaglandin E1, both of which act through receptors which stimulate adenylate cyclase. We report here that brief (approximately 20 min) exposure of wild type S49 lymphoma cells to somatostatin (which inhibits adenylate cyclase) promotes the translocation of beta AR kinase to an extent comparable to that observed in the presence of the beta agonist isoproterenol or prostaglandin E1. Beta AR kinase activity can be measured using either beta AR or rhodopsin, the retinal receptor for light, as a substrate. The translocation process triggered by somatostatin is rapid, reversible, and is associated with somatostatin receptor desensitization. The latter is apparent as an attenuation of the inhibition by somatostatin of forskolin-stimulated adenylate cyclase activity in membranes of S49 cells preincubated in the presence of the peptide. These results strongly suggest that beta AR kinase is able to phosphorylate and desensitize both stimulatory and inhibitory adenylate cyclase-coupled receptors, thus emerging as a general kinase that regulates the function of different receptors in an agonist-specific fashion.
...
PMID:Somatostatin induces translocation of the beta-adrenergic receptor kinase and desensitizes somatostatin receptors in S49 lymphoma cells. 288 86

It has been shown previously that typical neuroleptics have higher affinities for 3,4-dihydroxyphenylethylamine (dopamine) D1 receptors as labeled by (R)-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1-N-3-benzazepine- 7-ol ([3H]SCH 23390) than for inhibiting dopamine-stimulated adenylate cyclase. We now report that the atypical neuroleptics, clozapine and fluperlapine, exhibit characteristics opposite to typical neuroleptics, i.e., they have higher affinity for inhibiting dopamine-stimulated adenylate cyclase than [3H]SCH 23390 binding. A variety of compounds, i.e., clozapine, fluperlapine, and dopamine, were tested for their capacity to affect the rate constants of [3H]SCH 23390 binding. Treatment of striatal membranes with phospholipase A2 (PLA2) caused a rapid decrease in the Bmax value of the [3H]SCH 23390 binding with no effect on the KD value. The adenylate cyclase, both the unstimulated, the dopamine-, fluoride-, and forskolin-stimulated activity, was far less sensitive than [3H]SCH 23390 binding to PLA2. Treatment of striatal membranes with filipine and (NH4)2SO4 produced, as did PLA2 treatment, a rapid decline in [3H]SCH 23390 binding. However, opposite to PLA2 treatment, these agents stimulated the adenylate cyclase. In conclusion, a comparison of the pharmacological characteristics of [3H]SCH 23390 binding and dopamine-stimulated adenylate cyclase suggests the existence of two different D1 binding sites. The rate experiments exclude the possibility of allosterically coupled sites. Instead our results favor that the D1 receptor exists in different states/conformations, i.e., both adenylate cyclase-coupled and uncoupled, and further, that the atypical neuroleptics clozapine and fluperlapine may have adenylate cyclase-coupled dopamine D1 receptors as target.
...
PMID:Evidence for different states of the dopamine D1 receptor: clozapine and fluperlapine may preferentially label an adenylate cyclase-coupled state of the D1 receptor. 294 3

We have used a recently developed cell-free system (cell lysate) derived from turkey erythrocytes to explore the potential role of cAMP-activated and other protein kinase systems in desensitizing the adenylate cyclase-coupled beta-adrenergic receptor. Desensitization by the agonist isoproterenol required more than simple occupancy of the receptor by the agonist since under conditions where adenylate cyclase was not activated, no desensitization occurred. As in whole cells, addition of cyclic nucleotides to the cell lysate produced only approximately 50% of the maximal isoproterenol-induced desensitization obtainable. Addition of the purified cAMP-dependent protein kinase holoenzyme plus isoproterenol to isolated turkey erythrocyte plasma membranes mimicked the submaximal desensitization induced in lysates by cAMP. This effect was entirely blocked by the specific inhibitor of the cAMP-dependent protein kinase. By contrast, maximal desensitization induced in lysates by isoproterenol was only approximately 50% attenuated by the protein kinase inhibitor. In the lysate preparations, isoproterenol was also shown to induce, in a stereospecific fashion, phosphorylation of the beta-adrenergic receptor. Phosphorylation promoted by isoproterenol was attenuated by cAMP-dependent protein kinase inhibitor to the same extent as desensitization (i.e. approximately 50%). Phorbol diesters also promoted receptor desensitization and phosphorylation in cell lysates. The desensitization was mimicked by incubation of isolated turkey erythrocyte membranes with partially purified preparations of protein kinase C plus phorbol diesters. In the cell lysate, calmodulin also promoted receptor phosphorylation and desensitization which was blocked by EGTA. Desensitization of adenylate cyclase by isoproterenol, phorbol diesters, and calmodulin was not observed to be additive. These findings suggest that: (a) multiple protein kinase systems, including cAMP-dependent, protein kinase C-dependent, and Ca2+/calmodulin-dependent kinases, are capable of regulating beta-adrenergic receptor function via phosphorylation reactions and that (b) cAMP may not be the sole mediator of isoproterenol-induced phosphorylation and desensitization in these cells.
...
PMID:Desensitization of the turkey erythrocyte beta-adrenergic receptor in a cell-free system. Evidence that multiple protein kinases can phosphorylate and desensitize the receptor. 298 11


<< Previous 1 2 3 4 5 6 Next >>

---