Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The sigma receptor, which is labeled with (+)-[3H]3-(3-hydroxyphenyl)-N- 1-(propyl)piperidine [(+)-[3H]3-PPP], is a site that binds several psychotomimetic opiate benzomorphans and certain antipsychotics, such as haloperidol. In order to elucidate the mechanisms involved in sigma receptor ligand binding, equilibrium binding analysis and kinetics of association and dissociation of the relatively selective sigma receptor ligand (+)-[3H]3-PPP were determined in rat brain membranes in the absence and presence of 5'-guanylylimidodiphosphate [Gpp(NH)p]. In the absence of Gpp(NH)p, (+)-3-PPP, cyclazocine, pentazocine, and (+)-SKF 10047 bind to high and low affinity sites (KH = 1.3-7.5 nM; KL = 84-500 nM), as determined by computer assisted analysis of the inhibition of (+)-[3H]3-PPP binding by the sigma ligands. The antipsychotics haloperidol and chlorpromazine inhibit (+)-[3H]3-PPP binding in a manner indicating interaction with a single state of the receptor. Gpp(NH)p (0.1 mM) abolished the high affinity binding component of the sigma agonist-like compounds tested but had no effect on the affinities of the antipsychotics for the receptor. Gpp(NH)p decreased the association rate of (+)-[3H]3-PPP binding 5-fold and also converted the biexponential dissociation kinetics of the ligand, observed in the absence of Gpp(NH)p, to a rapid monophasic dissociation process. Pretreatment of membranes with N-ethylmaleimide and pertussis toxin inhibited (+)-[3H]3-PPP binding and abolished the effect of Gpp(NH)p on the sigma ligand binding. These findings indicate of the sigma receptor is capable of existing in two discrete states, having high and low affinity for sigma agonist-like drugs. The regulation of the high affinity binding state by GTP-binding protein-modifying agents suggests its coupling to GTP-binding protein(s).
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PMID:Multiple affinity binding states of the sigma receptor: effect of GTP-binding protein-modifying agents. 255 9

Our overall goal was to investigate the mechanism by which fentanyl attenuates acetylcholine-induced contraction in porcine coronary artery. We tested the hypothesis that fentanyl attenuates muscarinic coronary contraction via sigma receptor activation. Left coronary artery vascular rings were isolated from porcine hearts and were suspended in organ chambers for isometric tension recording. In untreated coronary vascular rings, acetylcholine administration resulted in dose-dependent contraction. Fentanyl attenuated acetylcholine-induced contraction. The sigma ligands--(+)-pentazocine, (+)-cyclazocine, haloperidol, and 1,3-di-o-tolylguanidine--also inhibited acetylcholine-induced contraction. In contrast, the selective sigma ligand, (+)-3-(3-hydroxyphenyl)-N-(1-propyl) piperidine failed to have an inhibitory effect on acetylcholine-induced contraction. Moreover, metaphit (1-[1(3-isothiocyanatophenyl)cyclohexyl]piperidine), which causes irreversible acylation of sigma receptors, only inhibited acetylcholine-induced contraction when it was present in the organ chamber. We also assessed the effects of inhibiting various points in the signal transduction pathway distal to naloxone-sensitive opioid receptor activation on acetylcholine-induced contraction. Selective (glybenclamide) and nonselective (tetraethylammonium) K(+)-channel inhibition, guanosine triphosphate-binding protein inactivation (pertussis toxin), and Type 1 and Type 2 dopamine receptor inhibition all failed to alter the attenuating effect of fentanyl on acetylcholine-induced contraction. Thus, neither sigma or opioid receptor activation is a prerequisite for fentanyl-induced inhibition of muscarinic coronary contraction.
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PMID:Sigma receptor activation does not mediate fentanyl-induced attenuation of muscarinic coronary contraction. 861 Sep 10

Neuropeptide Y (NPY) is an amidated 36-amino acid peptide with a wide distribution in the central and peripheral nervous system. It can evoke numerous physiological responses by activating specific receptors. Studies using NPY analogs in various model systems and cell types demonstrate different orders of ligand potency and receptor binding affinity. These studies suggest the existence of multiple subtypes of NPY receptors. NPY has been described to bind to at least three different receptors, Y1, Y2 and Y3. NPY has also been shown to interact with sigma receptor in vivo and in vitro. There are indications that more subtypes might exist. Ligand binding studies reveal that Y1, Y2 and Y3 receptors are all G-protein coupled. It is not yet confirmed whether the sigma receptor that interacts with NPY is G-protein coupled. Some studies show that NPY receptors may interact with other classical receptors, including alpha- and beta-adrenoceptors and cholinergic receptors. In the case of alpha- and beta-adrenoceptors, the receptor-receptor interaction is possibly via a pertussis toxin-sensitive G-protein. NPY receptors are coupled to various signal transduction mechanisms including inhibition of adenylate cyclase, and stimulation or inhibition of increases in intracellular Ca2+. Specific links between individual NPY receptor subtype and a particular signal transduction pathway are not established.
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PMID:Neuropeptide Y receptor subtypes. 900 38

Most physiological effects of sigma1 receptor ligands are sensitive to pertussis toxin, suggesting a coupling with cell membrane-bound G proteins. However, the cloning of the sigma1 receptor has allowed the identification of an intracellular protein anchored on the endoplasmic reticulum. Here, we show, using the isolated adult guinea pig brainstem preparation, that activation of the sigma1 receptor results in its translocation from the cytosol to the vicinity of the cell membrane and induces a robust and rapid decrease in hypoglossal activity, which is mediated by phospholipase C. The subsequent activation of protein kinase C beta1 and beta2 isoforms and the phosphorylation of a protein of the same molecular weight as the cloned sigma1 receptor lead to a desensitization of the sigma1 motor response. Our results indicate that the intracellular sigma1 receptor regulates several components implicated in plasma membrane-bound signal transduction. This might be an example of a mechanism by which an intracellular receptor modulates metabotropic responses.
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PMID:Intracellular sigma1 receptor modulates phospholipase C and protein kinase C activities in the brainstem. 1039 71

In radioligand binding assays, AH-9700 (1-[2-(3,4-dihydro-6,7-dimethyl-2-naphthalenyl)ethyl]pyrrolidine fumarate) had high affinity for sigma receptors and moderate affinity for muscarinic receptors. The affinity of AH-9700 for sigma(1) receptors was significantly reduced in the presence of 5'-guanylyl-imidodiphosphate (GppNHp). In isolated bladder strips of rats, AH-9700 inhibited carbachol-induced contractions. In anesthetized rats, i.v. administration of AH-9700 and typical sigma receptor ligands, (+)-pentazocine and 1,3-di-o-tolylguanidine (DTG), but not oxybutynin, dose-dependently inhibited rhythmic isovolumetric reflex bladder contractions. AH-9700 and oxybutynin suppressed the amplitude of rhythmic bladder contractions. On the other hand, at doses lower than used i.v., the i.c.v. administration of AH-9700 or the sigma receptor ligands inhibited rhythmic bladder contractions without suppressing the amplitude. This inhibitory effect of AH-9700 was markedly reduced by pretreatment with i.c.v. pertussis toxin. These results suggest that AH-9700 exerts a marked anti-micturition reflex effect through central sigma receptors possibly related to pertussis toxin-sensitive Gi/o-proteins and a moderate spasmolytic effect based on its peripheral anti-muscarinic activity.
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PMID:Pharmacological actions of AH-9700 on micturition reflex in anesthetized rats. 1116 28

Pregnenolone sulfate (PREGS), one of the most abundantly produced neurosteroids in the mammalian brain, improves cognitive performance in rodents. The mechanism of this effect has been attributed to its allosteric modulatory actions on glutamate- and gamma-aminobutyric acid-gated ion channels. Here we report a novel effect of PREGS that could also mediate some of its actions in the nervous system. We found that PREGS induces a robust potentiation of the frequency but not the amplitude of miniature excitatory postsynaptic currents (mEPSCs) mediated by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors in cultured hippocampal neurons. PREGS also decreased paired pulse facilitation of autaptic EPSCs evoked by depolarization, indicating that it modulates glutamate release probability presynaptically. PREGS potentiation of mEPSCs was mimicked by dehydroepiandrosterone sulfate and (+)-pentazocine but not by (-)-pentazocine, the synthetic (-)-enantiomer of PREGS or the inactive steroid isopregnanolone. The sigma receptor antagonists, haloperidol and BD-1063, blocked the effect of PREGS on mEPSCs, as did pertussis toxin and the membrane-permeable Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (acetoxymethyl) ester. These results suggest that PREGS increases spontaneous glutamate release via activation of a presynaptic G(i/o)-coupled sigma receptor and an elevation in intracellular Ca2+ levels. We postulate that presynaptic actions of neurosteroids have a role in the maturation and/or maintenance of synaptic networks and the processing of information in the central nervous system.
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PMID:Neurosteroids enhance spontaneous glutamate release in hippocampal neurons. Possible role of metabotropic sigma1-like receptors. 1204 5

Sigma receptors are unique endoplasmic reticulum proteins that mediate signaling for a variety of drugs. We determined the effect of sigma(1) receptor agonists on immune responses in a syngeneic lung cancer model. Sigma(1) receptor agonists, including cocaine, up-regulated splenocyte IL-10 mRNA and protein production in vitro in a sigma receptor-dependent, pertussis toxin-sensitive manner. In vivo, sigma(1) receptor agonists promoted tumor growth and induced IL-10 at the tumor site. Increased tumor growth was prevented by administration of specific Abs to IL-10 or by administration of specific sigma(1) receptor antagonists. We report that sigma(1) receptor ligands, including cocaine, augment tumor growth through an IL-10 dependent mechanism.
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PMID:IL-10 mediates sigma 1 receptor-dependent suppression of antitumor immunity. 1264 21

The endogenous neurosteroid pregnenolone sulfate (PS) is known to enhance memory and cognitive function at nanomolar concentrations. However, the effect of these low concentrations on synaptic transmission has not been previously studied. The effects of PS on GABAA receptor-mediated inhibitory postsynaptic currents were studied in cultured hippocampal pyramidal neurons. Concentrations of PS similar to those endogenous in the hippocampus (10-30 nM) reduced the frequency of both action potential-dependent (spontaneous inhibitory postsynaptic current) and -independent (miniature inhibitory postsynaptic current; mIPSC) inhibitory postsynaptic currents. This effect of PS was mimicked by the selective sigma1 receptor agonist [2S-(2alpha,6alpha,11R]-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(2-propenyl)-2,6-methano-3-benzazocin-8-ol hydrochloride [(+)-SKF 10047] and blocked the specific sigma1 receptor antagonists 1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine dihydrochloride (BD-1063) and haloperidol and by pertussis toxin. The GABAB antagonist baclofen and the metabotropic glutamate receptor antagonist (R,S)-a-cyclopropyl-4-phosphonophenylglycine had no effect on the PS-mediated inhibition of mIPSC frequency. The postsynaptic effects of PS occurred at micromolar concentrations but not at nanomolar concentrations. A comparison of the pre- and postsynaptic effects of PS demonstrated that it was 100-fold more potent in inhibiting presynaptic GABAergic synaptic mechanisms than GABAA receptors. These studies demonstrate that concentrations of PS, similar to those endogenous in the hippocampus, inhibit GABAergic synaptic transmission by a presynaptic effect. PS causes specific activation of G protein-coupled sigma1 receptors, resulting in modulation of both action potential-dependent and -independent IPSCs. These findings improve our understanding of the physiological function of PS.
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PMID:A presynaptic action of the neurosteroid pregnenolone sulfate on GABAergic synaptic transmission. 1450 Jul 42