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)

Many hormones interact with receptors which stimulate the enzyme adenylate cyclase. Less well characterized ar those receptors which mediate an inhibition of adenylate cyclase activity. However, guanine nucleotides are clearly important in the regulation of both stimulatory and inhibitory receptors. Monovalent cations, notably Na+, regulate many inhibitory receptor systems but apparently not stimulatory receptors. We investigate here the effects of Na+ and guanine nucleotides on the adenylate cyclase-coupled inhibitory alpha 2-adrenergic receptor of the rabbit platelet. Computer modelling of adrenaline competition curves with 3H-dihydroergocryptine (3H-DHE) indicates that adrenaline induces two distinct affinity states of the alpha 2 receptor--one of higher (alpha 2H) and the other of lower (alpha 2L) affinity. Guanyl-5'-yl-imidodiphosphate (Gpp(NH)p) seems to reduce adrenaline affinity to converting the high-affinity state into the low-affinity form of the receptor. In contrast, Na+ reduces adrenaline affinity at both the high- and low-affinity states of the alpha 2 receptor while preserving receptor heterogeneity. Thus, guanine nucleotides and Na+ differ in the manner by which each reduces agonist affinity for the alpha 2-adrenergic receptor.
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PMID:Differential regulation of the alpha 2-adrenergic receptor by Na+ and guanine nucleotides. 625 38

The binding of a radiolabeled "mu receptor" prototype opiate, dihydromorphine (H2morphine), and the binding of a "delta receptor" prototype, [D-Ala2,D-Leu5]enkephalin (D-Enk), to slide-mounted rat caudate slices were simultaneously compared quantitatively and visualized by autoradiography. Generally, D-Enk bound to opiate receptors distributed evenly throughout the entire striatum (type 2 pattern), whereas H2morphine labeled discrete islands or patches of receptors (type 1 pattern). In the presence of Mn2+ (3 mM) or other divalent cations, however, Na+ and GTP at 25 degrees C caused an increase in D-Enk binding at the expense of H2morphine binding at striatal opiate receptor patches. Thus, these conditions shifted D-Enk binding from an even pattern to one that included both an even and patchy distribution. These incubation conditions not only promoted D-Enk binding to striatal patches but also enabled the opiate receptor to regulate adenylate cyclase with the same (P less than 0.01) ligand selectivity pattern as that obtained by the displacement of D-Enk binding. The relative affinity of opiate receptors in striatal patches for opiate peptides, naloxone, and morphine appears to be a function of incubation conditions and coupling to adenylate cyclase and is not indicative of distinctly different opiate receptors. We postulate a three-state allosteric model consisting of mu agonist-, mu antagonists-, and adenylate cyclase-coupled delta-agonist-preferring states, whose equilibrium may be regulated by a sulfhydryl group mechanism.
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PMID:Interconverting mu and delta forms of the opiate receptor in rat striatal patches. 627 75

(--)-N6-(Phenylisopropyl)adenosine (PIA, 10 microM) and 5'-N-(ethylcarboxamide)adenosine (NECA, 50 microM), potent agonists at the adenylate cyclase-coupled R-site adenosine receptor, were investigated for adenylate cyclase inhibition in a guinea pig ventricular membrane preparation by means of the dATP assay method. Neither compound influenced basal or isoproterenol-stimulated cyclase activity, irrespective of whether Na ions were present or not. These data suggest that R-site receptors may not be involved in the cardiac adenylate cyclase system of the guinea pig.
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PMID:Evidence against adenylate cyclase-coupled adenosine receptors in the guinea pig heart. 627 47

The adenylate cyclase-coupled beta 2-adrenergic receptor of the frog erythrocyte has served as a useful model system for elucidating the mechanisms of catecholamine-induced densensitization. In this system, it has been previously demonstrated that agonist-induced refractoriness is associated with sequestration of the beta-adrenergic receptors in vesicles away from the cell surface and from their effector unit, the adenylate cyclase system (Stadel, J.M., Strulovici, B., Nambi, P., Lavin, T.N., Briggs, M.M., Caron, M.G., and Lefkowitz, R.J. (1983) J. Biol. Chem. 258, 3032-3038). These internalized beta-adrenergic receptors appear to be structurally intact as assessed by photoaffinity labeling, but their functional status has previously been unknown. In the present studies, we sought to assess the functionality of the sequestered vesicular receptors by fusing them to Xenopus laevis erythrocytes. This cell is suitable for such studies, since it has almost no detectable beta-adrenergic receptor or catecholamine-sensitive adenylate cyclase, but contains prostaglandin E1-stimulable adenylate cyclase. Fusion of beta-adrenergic receptor-containing vesicles from desensitized frog erythrocytes with X. laevis erythrocytes results in a 30-fold stimulation of the hybrid adenylate cyclase by the beta-adrenergic agonist isoproterenol. This effect was entirely blocked by the beta-antagonist propranolol. The catecholamine-sensitive adenylate cyclase activity established in the vesicle-Xenopus hybrids showed the characteristic agonist potency series of the donor frog erythrocyte beta 2-adrenergic receptor. Fusion of vesicles from desensitized frog erythrocytes in which the beta-adrenergic receptors had been inactivated with the group specific reagent dicyclohexylcarbodiimide, or of vesicles derived from control frog erythrocytes, which contain low amounts of beta-adrenergic receptor, did not establish catecholamine-sensitive adenylate cyclase activity in the hybrids. These data demonstrate that beta-adrenergic receptors internalized during desensitization retain their functionality when recoupled to an adenylate cyclase system from a different source. The functional uncoupling of these receptors during desensitization is thus more likely due to their sequestration away from the other components of the adenylate cyclase than to any alterations in the receptors themselves.
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PMID:Functional integrity of desensitized beta-adrenergic receptors. 630 39

We have utilized limited in situ trypsinization of the adenylate cyclase-coupled beta-adrenergic receptor of frog erythrocytes to probe the processes of receptor activation, desensitization, and recycling. Treatment of intact erythrocytes with trypsin (1 mg/ml) for 1 h at 20 degrees C converts all the receptor peptides (identified by photoaffinity labeling with p-azido-125I-benzylcarazolol) from a Mr approximately 58,000 to a Mr approximately 40,000 species. Nonetheless, the trypsinized beta-adrenergic receptors bind agonists and antagonists with unaltered affinity and with no change in the number of binding sites. Moreover, the ability of the proteolyzed receptors to interact with the nucleotide regulatory protein to form a high affinity guanine nucleotide-sensitive state and to activate adenylate cyclase were also unaltered. However, upon exposure of intact cells to the agonist isoproterenol, trypsinized beta-adrenergic receptors were more rapidly and more completely cleared from the plasma membranes ("down-regulated") than untrypsinized receptors. Whereas down-regulated receptors from nontrypsinized cells appear to recycle to the cell surface after removal of the agonist, internalized trypsinized beta-adrenergic receptors do not recycle to the plasma membrane and appear to be degraded within the cell. Moreover, when internalized receptors, recovered in a light vesicle fraction, were fused with a heterologous adenylate cyclase system, untreated but not trypsinized receptors reconstituted catecholamine stimulation of the enzyme. These data suggest that the beta-adrenergic receptor contains a trypsin-sensitive site which is exposed on the outer surface of the plasma membrane. Proteolysis at this site releases a fragment which though not critically involved in either ligand binding or "effector coupling" might be important for anchoring the receptors in the plasma membrane. These data also suggest that in situ proteolysis of the receptors might serve as a physiological trigger for their internalization and degradation.
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PMID:Activation, desensitization, and recycling of frog erythrocyte beta-adrenergic receptors. Differential perturbation by in situ trypsinization. 632 69

In cellular systems provided with activatory (Ra-site) receptors for adenosine, such as rat cerebral microvessels and rat liver plasma membranes, the adenosine-receptor antagonist 8-phenyltheophylline (10 microM) significantly decreased adenylate cyclase activity if ATP was the substrate and only if GTP was present. With dATP as substrate, adenylate cyclase activities in both preparations remained unaffected by 8-phenyltheophylline. In rat cerebral-cortical membranes, with inhibitory (Ri-site) receptors for adenosine, 8-phenyltheophylline significantly enhanced adenylate cyclase activity only in the presence of GTP and if ATP was the substrate. In rat cardiac ventricular membranes, which are devoid of any adenylate cyclase-coupled adenosine receptor, the methylxanthine had no GTP-dependent effect, irrespective of the substrate used. All assay systems contained sufficiently high amounts of adenosine deaminase (2.5 units/ml), since no endogenous adenosine, formed from ATP, was found chromatographically. In order to demonstrate a direct influence of phosphorylated adenosine derivatives on adenylate cyclase activity, we investigated AMP in a dATP assay system. AMP was verified chromatographically to remain reasonably stable under the adenylate cyclase assay conditions. In the microvessels, AMP increased enzyme activity in the range 0.03-1.0 mM, an effect competitively antagonized by 8-phenyltheophylline. In the cortical membranes, 0.1 mM-AMP inhibited adenylate cyclase, which was partially reversed by the methylxanthine. The presence of GTP was again necessary for all observations. In the ventricular membranes, AMP had no effect. Since the efficacy of adenosine-receptor agonists and, probably, that of other hormones on adenylate cyclase activity can be more efficiently measured with dATP as the enzyme substrate, this nucleotide seems preferable for adenylate cyclase measurements in systems susceptible to modulation by adenosine.
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PMID:Phosphorylated adenosine derivatives as low-affinity adenosine-receptor agonists. Methodological implications for the adenylate cyclase assay. 633 7

Incubation of a preparation of cardiac plasma membranes with 20 microM (--)-isoproterenol and 1 microM guanyl-5'-yl imidodiphosphate (Gpp(NH)p) results in prolonged and maximal activation of adenylate cyclase and prolonged binding of [3H]Gpp(NH)p to the membranes. The total number of [3H]Gpp(NH)p sites must exceed those required for enzyme activation (N-sites) since the rate of binding is much slower than the rate of activation. Attempts to measure the amount of [3H]Gpp(NH)p released from N-sites during incubation of membranes with isoproterenol and GTP were frustrated by limited (about 20%) reversal of binding and of enzyme activation. However, the amount of [3H]-Gpp(NH)p bound to membranes could be reduced by preincubating them in a concentration of App(NH)p (0.1-0.5 mM) which does not interact with the N-site and most of the [3H]Gpp(NH)p subsequently bound could be removed by further incubation of the membranes with EDTA, propranolol, and Gpp(NH)p. Under these conditions, full enzyme activation was retained and was associated with residual bound [3H]Gpp(NH)p of about 0.3 pmol/mg of protein. This amount equals the concentration of beta-adrenoreceptors; and the rate and Kd (0.22 microM) for the binding residual [3H]-Gpp(NH)p approximate the rate and Ka for enzyme activation. The rate of enzyme activation and [3H]-Gpp(NH)p binding to the residual component was increased in the presence of isoproterenol. Competition binding studies for the residual component revealed that Gpp(NH)p congruent to GTP greater than GDP greater than GMP. The results suggest that residual [3H]Gpp(NH)p binding is to the adenylate cyclase-coupled guanine nucleotide binding protein.
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PMID:A minor component of the binding of [3H]guanyl-5'-yl imidodiphosphate to cardiac membranes associated with the activation of adenylate cyclase. 679 May 29

The purpose of the present study was to characterize more precisely an inhibitory, adenylate cyclase-coupled bradykinin receptor in guinea pig ileum membranes. Therefore, the effects of various well-known bradykinin B2 receptor antagonists were examined at the level of bradykinin-induced inhibition of ileal adenylate cyclase activity and compared with both their binding affinities and their potencies to antagonize ileal contraction evoked by bradykinin. A group of three highly potent antagonists was found to be able to antagonize both bradykinin-induced adenylate cyclase inhibition and smooth muscle contraction. Several other antagonists abolished the bradykinin-induced ileal contraction but did not influence its action on adenylate cyclase. The compound [D-Nal1, Thi5,8, D-Phe7]bradykinin which is known to inhibit the bradykinin-induced contraction in the rat uterus but not in the guinea pig ileum was found to be a weak but selective antagonist for the adenylate cyclase-coupled bradykinin receptor in guinea pig ileum. Altogether, in guinea pig ileum membranes the inhibitory, adenylate cyclase-coupled bradykinin B2 receptor with pM affinity towards bradykinin exhibits a unique antagonist profile and is distinguished from the excitatory bradykinin B2 receptor with nM affinity towards bradykinin.
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PMID:The adenylate cyclase-inhibiting bradykinin receptor in guinea pig ileum membranes exhibits an unique antagonist profile. 762 18

This study was designed to evaluate the effects of a chronic treatment with the classical neuroleptic drug haloperidol on the preproenkephalin (ppEnk) mRNA synthesis and its consequences for opioid and dopamine (DA) receptor-regulated adenylate cyclase in the developing and adult rat striatum. Prenatal exposure to haloperidol (2 mg/kg, 14 days) caused a 40% reduction of striatal ppEnk mRNA levels, but had no consequences for DA-stimulated or Met-enkephalin-inhibited adenylate cyclase activity in striatal slices from embryonic day 21 (E21) foetal brain. Postnatal treatment of rat pups from day 10 (P10) until P23 and adult rats resulted in significant increases of mRNA levels of 8 and 41%, respectively, a clear reduction of D1 DA receptor-stimulated cAMP production and a profound desensitization of delta-opioid receptors inhibitory coupled to adenylate cyclase. Since striatal D2 receptor-mediated inhibition of adenylate cyclase activity, in contrast to its activation through D1 receptors, is not present in the prenatal period, this study indicates that the tonic inhibitory effect of DA on striatal ppEnk mRNA synthesis is dependent on the presence of adenylate cyclase-coupled D2 receptors which gradually develops postnatally and further supports the idea that striatal D1 and D2 DA receptors have bidirectional effects on enkephalin synthesis in this brain area. The adaptive changes in D1 DA and delta receptor-regulated adenylate cyclase activity are discussed in relation to the well-known increase in the locomotor and reinforcing effects of mu-opioid receptor agonists upon chronic neuroleptic treatment.
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PMID:Adaptive changes in rat striatal preproenkephalin expression and dopamine-opioid interactions upon chronic haloperidol treatment during different developmental stages. 791 3

The lateral mobility of membrane integral receptors has been implicated as playing a significant role in signal transduction. The adenylate cyclase-coupled vasopressin V2 receptor has been shown to be highly laterally mobile in membranes of LLC-PK1 renal epithelial cells at physiological temperature using a fluorescent vasopressin agonist, with lateral mobility of the V2 receptor proposed to play a role in both adenylate cyclase activation and ligand induced receptor internalization and down-regulation. This study reports the synthesis and characterization of two new fluorescent antagonists [(beta-mercapto-beta,beta-cyclopentamethylene propionic acid)1,D-Tyr2,Ile4,Lys9(N6-fluoresceinylaminothiocarbonyl )]AVP (FL-AVP-anta) and [(beta-mercapto-beta,beta-cyclopentamethylene propionic acid)1,D-Tyr2,Ile4,Lys9(N6-tetramethylrhodamylaminothioca rbonyl)]AVP (TR-AVP-anta) for the V2 receptor. The latter was used to determine the parameters of lateral mobility of the V2 receptor in the non-activated antagonist-occupied form. Using fluorescence photobleaching techniques, results were largely comparable to those for agonist-occupied receptor, indicating high mobility at 37 degrees C. Antagonistic properties of the V2 receptor ligands are apparently not related to decreased receptor lateral mobility. Photobleaching measurements, however, did show that in contrast to V2 agonist, V2 antagonist did not induce receptor immobilization due to aggregation with time at 37 degrees C, indicating that this could be of mechanistic importance in the internalization process.
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PMID:Lateral mobility of the antagonist-occupied V2 vasopressin receptor in membranes of renal epithelial cells. 808 94


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