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)

Receptors for biogenic amines such as dopamine, serotonin and epinephrine belong to the family of receptors that interact with G proteins and share a putative seven transmembrane domain structure. Using a strategy based on nucleotide sequence homology between the corresponding genes, we have isolated Drosophila cDNA clones encoding a new member of the G protein-coupled receptor family. This protein exhibits highest homology to the human alpha 2 adrenergic receptors, the human 5HT1A receptor and a recently cloned Drosophila serotonin receptor. The corresponding mRNA is found predominantly in adult Drosophila heads. Membranes from mammalian cells expressing this receptor displayed high affinity binding sites for [3H]yohimbine, an alpha 2 adrenergic receptor antagonist (Kd = 4.45 x 10(-9) M). Tyramine was the most efficient of the putative Drosophila neurotransmitters at displacing [3H]yohimbine binding (EC50 = 1.25 x 10(-6) M). Furthermore tyramine induced an inhibition of adenylate cyclase activity in NIH 3T3 cells expressing this receptor. The Drosophila tyramine receptor that we have isolated might therefore be an invertebrate equivalent of the mammalian alpha 2 adrenergic receptors.
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PMID:Cloning and characterization of a Drosophila tyramine receptor. 217 Jan 18

Using a strategy based on nucleotide sequence homology between genes encoding receptors that interact with guanine nucleotide-binding proteins, we have isolated Drosophila genomic and cDNA clones encoding a functional serotonin receptor (5HT-dro receptor). This protein is expressed predominantly in Drosophila heads and exhibits highest homology with the human 5HT1A receptor. The predicted structure of the 5HT-dro receptor reveals two unusual features: (i) eight putative transmembrane domains instead of the expected seven and (ii) a Gly-Ser repeat that is a potential glycosaminoglycan attachment site. When stably introduced into mouse NIH 3T3 cells, the 5HT-dro receptor activates adenylate cyclase in response to serotonin and is inhibited by serotonin receptor antagonists such as dihydroergocryptine. The 5HT-dro receptor or closely related receptors might be responsible for the serotonin-sensitive cyclase that has been suggested to play a role in learning and modulation of circadian rhythm in a number of invertebrate systems.
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PMID:Cloning and characterization of a Drosophila serotonin receptor that activates adenylate cyclase. 217 67

In this article we review serotonergic signal transduction mechanisms in the central and peripheral nervous systems and in a variety of target organs. The various classes of pharmacologically defined serotonergic receptors are coupled to three major effector systems: (1) adenylate cyclase; (2) phospholipase C mediated phosphoinositide (PI) hydrolysis and (3) ion channels (K+ and Ca++). Long term occupancy of serotonergic receptors also appears to induce alterations in mRNA and protein synthesis. For all three types of signal transduction there is evidence accumulating which suggests the involvement of guanine nucleotide regulatory proteins. Recent findings suggest that the distinct types of pharmacologically defined serotonergic receptors (5HT1A, 5HT1B, 5HT1c, 5HT2) may be coupled to one or more signal transduction systems. Thus, 5HT1 receptors may both activate and inhibit adenylate cyclase and increase K+-ion conductance in the hippocampus. 5HT2 receptors which activate PI hydrolysis in the brain, both open voltage-gated calcium channels and activate PI metabolism in certain smooth muscle preparations. Thus, each class of serotonergic receptor may be linked to one or more distinct biochemical transduction mechanisms. The possibility is raised that selective agonists and antagonists might be developed which have specific effects on a particular receptor-linked effector system.
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PMID:Multiple mechanisms of serotonergic signal transduction. 244 Dec 25

MDL 73005EF has been recently described as a potent, highly selective 5-HT1A ligand. Although proposed to act predominantly as an antagonist (M. Hibert, A.K. Mir, G. Maghioros, P. Moser, D.N. Middlemiss, M.D. Trickleband and J.R. Fozard, 1988, The Pharmacological properties of MDL 73005EF: a potent and selective ligant at 5-HT1A receptors, Br. J. Pharmacol. 93, 2P), we have demonstrated that MDL 73005EF also acts as a highly efficacious partial agonist at the 5HT1A receptor, based on its ability to inhibit forskolin-stimulated adenylate cyclase in rat hippocampal membranes. Compared with two structurally related 5-HT1A partial agonists, the rank order of potency of MDL 73005EF in the FSC assay was comparable to affinity calculated by radioligand binding.
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PMID:MDL 73005EF: partial agonist at the 5-HT1A receptor negatively linked to adenylate cyclase. 256 Apr 32

The serotonin (5HT1A) receptor subtype is one member of the 5HT1 receptor family and is constitutively expressed on Jurkat cells and is elevated on human T lymphocytes after mitogenic activation. Published reports show that human T lymphocytes and monocytes also release 5HT after stimulation with PHA or IFN-gamma. In lymphocytes and the central nervous system, the 5HT1A receptor is coupled to regulation of adenylate cyclase. The 5HT1A receptor agonists inhibit activation of adenylate cyclase. The purpose of the experiments reported here was to investigate further the role 5HT and the 5HT1A receptor may play in the regulation of human and murine T cell activity. For this purpose, human PBMC or murine spleen cells were used for experimental purposes rather than Jurkat cells. The results show that inhibition of 5HT synthesis inhibits IL-2-stimulated human T cell proliferation and that addition of 5-hydroxytryptophan, a precursor of 5HT, reverses inhibition of T cell proliferation. The 5HT1 receptor antagonist, metitepine, and the 5HT1A selective antagonist, pindobind-5HT1A, also block T cell proliferation. Inhibition by metitepine is reversed by 5HT and by the selective 5HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino) (8-OH-DPAT). Selective 5HT1A receptor antagonists cause elevation of cAMP in human T cells. In a murine model, selective 5HT1A receptor antagonists inhibit contact sensitivity responses but not Ab responses to oxazalone in vivo. Inhibition is reversed by 8-OH-DPAT. In addition, production of Th1 cytokines, such as IL-2 and IFN-gamma, by Ag-stimulated, immune murine spleen cells is inhibited by 5HT1A receptor antagonists in vitro but not by 5HT1C/2 receptor antagonists.
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PMID:Inhibitors of serotonin synthesis and antagonists of serotonin 1A receptors inhibit T lymphocyte function in vitro and cell-mediated immunity in vivo. 802 90

5HT1A receptors occur in the retina of various species and the administration of 5HT1A agonists results in the inhibition of outgrowth from postcrush goldfish retinal explants. The levels of cyclic AMP (cAMP) play a role in the modulation of the outgrowth of the nevous system. Moreover, the stimulation of central 5HT1A receptors with the agonist 8-hydroxy-2-(di-n-propylamino)tetralin has been reported to produce an increase or decrease in the activity of adenylate cyclase. In the present investigation we studied the effect of adenylate cyclase stimulation by forskolin, as well as the modulatory effects of 5HT1A receptor agonists and antagonists on the production of cAMP in the goldfish retina, and on the outgrowth of this tissue in vitro. 8-Hydroxy-2-(di-n-propylamino)tetralin produced a significant and dose-dependent increase in cAMP concentration. This effect was not additive to the stimulation produced by forskolin. By contrast, as previously described, the 5HT1A agonist decreased cAMP concentration in the hippocampus of the rat. Both effects were significantly impaired by the 5HT1A antagonist WAY-100,135. A significant effect of the antagonist alone was observed only in the goldfish retina. The increase in cAMP levels was greater in the intact than in the postcrush retina. In addition, forskolin decreased the outgrowth of postcrush retinal explants in a dose-dependent manner, suggesting the importance of critical levels of cAMP in this process. Taken together, 5HT1A receptors seem to be positively coupled to adenylate cyclase in the goldfish retina, where cAMP plays a role as a modulator of outgrowth and regeneration. The inhibitory effect of 5HT1A receptor agonists on retinal outgrowth might be mediated through the production of cAMP. The activation of other subtypes of 5HT receptors positively coupled to adenylate cyclase by the 5HT1A agonist, such as 5HT7, cannot be discarded.
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PMID:5HT1A receptor agonist differentially increases cyclic AMP concentration in intact and lesioned goldfish retina. In vitro inhibition of outgrowth by forskolin. 893 55

5-Hydroxytryptamine-1A (5-HT1A) receptor agonists, including flesinoxan, reduce anxiety and activate the hypothalamus-pituitary-adrenal (HPA) axis under basal conditions. In order to investigate the underlying neural mechanisms we investigated immunoreactivity for the immediate early gene protein product Fos (Fos-ir) in rat brains 1 h after flesinoxan treatment (0.0, 0.3 or 3.0 mg/kg p.o.). Typically, 5-HT1A receptor-containing brain areas, such as the dorsal raphe nuclei, hippocampus, septum, diagonal band and the cortical and basomedial amygdala, do not show Fos-ir. Apparently, binding of flesinoxan at the 5-HT1A receptor does not directly lead to activation of c-fos in the cell, probably due to its negative coupling to adenylate cyclase. However, in typically non-5HT1A receptor-containing brain areas Fos-ir is increased due to flesinoxan treatment, as in the paraventricular nucleus of the hypothalamus (PVN), the dorsolateral part of the bed nucleus of the stria terminalis (BNSTdl) and the central amygdala (CeA). Flesinoxan-treated rats also exhibited higher plasma corticosterone levels than vehicle-treated animals, which suggests the involvement of corticotropin-releasing hormone (CRH) or vasopressin in the hypothalamus. After double immunolabelling (Fos/CRH or Fos/vasopressin), every CRH neuron detected in the PVN also contained Fos. Moreover, a significant correlation existed between the number of Fos-ir neurons in the PVN and the plasma corticosterone level. Hardly any Fos/vasopressin double labelling was visible in the PVN. Accordingly, flesinoxan exerts its activating effects on the HPA axis via CRH neurons in the PVN. These effects are trans-synaptically mediated by other brain areas, such as the CeA and BNSTdl, which also show increased Fos-ir.
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PMID:5-HT1A receptor agonist flesinoxan enhances Fos immunoreactivity in rat central amygdala, bed nucleus of the stria terminalis and hypothalamus. 895 98

cAMP regulates immune responses, and modifications in cAMP signaling are involved in the pathophysiology and treatment of depression. In the present report, basal and forskolin-stimulated levels of cAMP were determined in mononuclear cells and lymphocytes from control individuals and major depression patients. Twenty-eight patients between 24 and 59 years old were diagnosed for a major depression episode according to the criteria of the Structural Clinical Interview for Disorders of Axis I of the American Psychiatric Association. These patients presented a score of 25 for severity as measured by Hamilton Rating Scale of Depression (HAM-D), and 23 for Beck Inventory of Depression (BID). Control and patient mononuclear cells were isolated by Ficoll/Hypaque gradients and their lymphocytes were separated from the total mononuclear population by differential adhesion to plastic surface. The basal concentration of cAMP was 50% lower in mononuclear cells and lymphocytes from the depressed patients compared with the control subjects. The response to forskolin was significantly smaller in lymphocytes of major depression patients than in the controls, but no difference was evident in the mononuclear cell preparations. There was a significant increase in cAMP produced by 5HT in mononuclear cells from the control group, but not in their lymphocytes. This effect on mononuclear cells was reduced by the antagonist of 5HT1A receptors, WAY-100,135. However, the simultaneous addition of a specific agonist of 5HT1A receptors, 8-hydroxy-(dipropylamino)tetralin (DPAT) and WAY-100,135 resulted in higher levels of cAMP than with the agonist alone. This effect probably indicates the blockade of 5HT1A receptors and action of 5HT1A agonist on the other subtypes of serotonin receptors expressed on human lymphocytes. This response was not observed in the patient's lymphocytes. In lymphocytes from major depression patients, serotonin and 8-hydroxy-(dipropylamino)tetralin significantly increased cAmp levels, which was slightly reduced by WAY-100,135. The present report indicates: (1) differential responses of immune cells from control individuals and depressed patients, with lower apparent adenylate cyclase activity in patient's cells; (2) variation in the population of cells, with responses to serotonergic agonists being lower in mononuclear cells and higher in lymphocytes from major depression patients; (3) increases of cAMP levels by serotonin and 5HT1A agonist in the patient's cells; and (4) evidence of impairment in serotonergic transduction systems in immune cells during depression.
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PMID:Differential cAMP levels and serotonin effects in blood peripheral mononuclear cells and lymphocytes from major depression patients. 1527 25