Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study evaluated whether protein kinase C (PKC) activation was involved in the lymphocytosis promoting properties of pertussis toxin (Ptx). The exposure of mouse lymphocytes to phorbol esters (as a means to selectively activate PKC) caused a depression in their subsequent capacity to localize into lymph nodes and Peyer's patches in vivo. This pattern of inhibition was quite similar to that observed with lymphocytes treated with Ptx. The mechanisms responsible for the observed decreases in localization to lymphoid organs caused by these two agents, however, appeared to be distinct. Exposure of lymphocytes to PMA was followed by a time and dosage-dependent decrease in the surface density of MEL-14 defined homing receptors. Ptx-treated lymphocytes retained normal density of this homing receptor. Consequently, PMA-treated lymphocytes lost their capacity to bind to high-endothelial venules in in vitro lymph node binding assays while Ptx-treated cells retained normal high-endothelial venule binding potential. We conclude from this study that: 1) the activation of PKC in lymphocytes by PMA can alter their recirculation properties via mechanisms that diminish their expression of surface receptors which support extravasation into lymph node and mucosal lymphoid tissues, and 2) even though Ptx has been reported to elevate the rate of inositol phosphate turnover in lymphocytes, the loss of extravasation potential of Ptx-treated lymphocytes is not mediated via the modification of surface homing receptors as observed in cells exposed to the known PKC activator, PMA.
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PMID:Molecular mechanisms of lymphocyte extravasation. III. The loss of lymphocyte extravasation potential induced by pertussis toxin is not mediated via the activation of protein kinase C. 273 69

Acetylcholine (ACh) in low doses (0.1-1 microM) reversibly inhibits voltage-dependent activation of the "pacemaker" current, if, in isolated sino-atrial node cells. This action is brought about by a negatively-directed shift of the current activation curve, opposite to that due to catecholamines on the same current. The if inhibition is antagonized by atropine, indicating the involvement of muscarinic receptors. In cells incubated in pertussis toxin-containing solutions, if does not respond to ACh, suggesting that G-proteins mediate the ACh-induced if depression. Further, ACh can inhibit if following catecholamine-induced stimulation, but has a negligible effect on if stimulated by forskolin, a direct activator of adenylate-cyclase. Our results indicate that ACh acts on if by inhibiting basal adenylate-cyclase activity.
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PMID:Acetylcholine inhibits activation of the cardiac hyperpolarizing-activated current, if. 282 12

Transducin is the substrate for a pertussis toxin-catalyzed ADP-ribosylation in isolated retinal rod disk membranes [(1984) J. Biol. Chem. 259, 23-26]. The effects of the toxin on the light responses of intact dark-adapted rods were studied. Applied close to a rod outer segment in a retinal slice, pertussis toxin depolarized the rod by a few millivolts and produced a long-lasting depression of light responses, effects which depended on penetration of toxin into rods. Nicotinamide, an inhibitor of ADP-ribosylation, not only blocked the action of the toxin, but also reversed the effects once established. The action of nicotinamide itself on rods indicates the presence of endogenous ADP-ribosyltransferases which may constitute a control system modulating phototransduction. Inhibition of phospholipase C by neomycin had only transient effects indicating that the cGMP, rather than a phosphoinositide, pathway is primary in vertebrate phototransduction. Rapid reversal of pertussis toxin action suggests possible clinical applications of nicotinamide or congeners to the treatment of disease caused by ADP-ribosylating bacterial toxins.
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PMID:Block of light responses of salamander rods by pertussis toxin and reversal by nicotinamide. 283 Oct 82

Activation of M2-muscarinic receptors alters the configuration of the action potential due to depression of the calcium-dependent components, the shoulder in the falling phase and the afterhyperpolarization, in isolated superior cervical ganglionic neurons of rabbits. This effect was inhibited by preincubation of the cells with pertussis toxin, or by the intracellular administration of guanosine 5'-O-(2-thiodiphosphate) (GDP-beta-S). The muscarinic effect persisted in the cells loaded with guanosine 5'-O-(3-thiotriphosphate) (GTP-gamma-S). Intracellular application of cAMP and 3-isobutyl-l-methylxanthine did not change the muscarinic effect. The results suggest that a GTP-binding protein is involved in the cAMP-independent, M2-muscarinic receptor-mediated regulation of action potential firing in sympathetic neurons.
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PMID:GTP-binding proteins mediate the M2-muscarinic effect on the action potential in isolated sympathetic neurons of rabbits. 285 47

Pharmacological properties of pre- and postsynaptic GABAB receptors were compared in CA1 hippocampal pyramidal neurons in vitro. The postsynaptic effects mediated by GABAB receptors, i.e., the baclofen-induced hyperpolarization, the bicuculline-resistant GABA response, and the slow inhibitory postsynaptic potential elicited by CA1 afferent stimulation, are all blocked by pertussis toxin (which inactivates some G proteins). These events are also suppressed by stimulating protein kinase C by phorbol esters and blocked by the selective GABAB antagonist phaclofen. In contrast, the baclofen-induced presynaptic depression of the excitatory postsynaptic potential elicited by CA1 afferent stimulation is resistant to the action of pertussis toxin and is not antagonized by phaclofen. However, this presynaptic inhibition can be antagonized by phorbol esters. These results indicate that the pre- and postsynaptic effects mediated by GABAB receptors in hippocampus have distinctly different pharmacological properties and possibly a different coupling mechanism.
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PMID:Pre- and postsynaptic GABAB receptors in the hippocampus have different pharmacological properties. 285 99

Studies were undertaken to evaluate factors capable of influencing the intensity of contact hypersensitivity (CH) and delayed-type hypersensitivity (DTH) responses in mice. It is well known that the exposure of animals to ultraviolet radiation (UVR) causes a depression of CH and DTH responses whereas the injection of mice with nanogram quantities of pertussis toxin (PT) before sensitization results in greatly augmented CH responses following hapten challenge. Histopathology and biochemical quantitation of myeloperoxidase (MPO) activity in biopsies obtained from the challenged ears from normal, UVR-exposed, or PT-treated animals determined that a direct correlation existed between the intensity of the ear-swelling response and the degree of neutrophil infiltrate into the challenge site. Few neutrophils were observed to infiltrate into the ears of UVR-exposed animals when compared to normal animals, whereas a pronounced neutrophil infiltration was observed in the challenged ears of PT-pretreated animals. These observations led us to question whether tissue-infiltrating neutrophils, or their products, might be involved in controlling the intensity of CH and DTH responses. The direct injection of murine neutrophils, neutrophil homogenates, and a neutrophil granular fraction into the ear pinnae of normal mice resulted in a dosage-dependent ear-swelling reaction after 24 hours that was histologically similar to antigen-induced CH or DTH responses (primarily mononuclear cell infiltrate). Additional studies determined that an injection of elastase, collagenase, or peptides of elastin or collagen generated by elastase or collagenase treatment of insoluble elastin or collagen also caused a pronounced ear-swelling accompanied by a mononuclear cell infiltration. On the basis of these studies, coupled to experiments that demonstrated an inhibitory influence of alpha-1-antitrypsin (alpha 1-AT) on CH and DTH responses, we propose that neutrophil proteases may play an important role in regulating the intensity of CH and DTH responses in mice through their capacity to degrade extracellular matrix proteins whose peptide fragments are chemotactic for mononuclear cells and fibroblasts.
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PMID:The role of neutrophils in tissue localized cell-mediated immunologic responses: I. The intensity of contact-type and delayed-type hypersensitivity responses may be influenced by the extent of extracellular matrix degradation by neutrophil proteases. 285 42

In reviewing our own and other work, it is clear that pertussis toxin treatment of neutrophils causes a time- and concentration-dependent inhibition of granule enzyme secretion induced by formylmethionylleucylphenylalanine (fMet-Leu-Phe), C5a, leukotriene (LT) B4 and platelet-activating factor (PAF). Chemotaxis, O2- generation, aggregation, and arachidonic acid production induced by fMet-Leu-Phe are also inhibited by pertussis toxin. Granule enzyme release caused by A23187 or phorbol 12-myristate 13-acetate is not inhibited. The inhibition of neutrophil function correlates closely with the NAD-ribosylation of a 41,000-dalton protein in the neutrophil plasma membrane, presumably the GTP-binding regulatory protein Ni. Pertussis toxin treatment prevents or obtunds the increased influx of Ca2+ induced by fMet-Leu-phe and LTB4, but not that caused by stimulation of neutrophils with PAF. Pertussis toxin prevents the receptor-induced breakdown of polyphosphoinositides in intact neutrophils and isolated membrane and prevents or decreases the production of inositol 1,4,5-trisphosphate (IP3) and 1,2-diacylglycerol. The hypothesis advanced by us and others is that pertussis toxin interacts with a GTP-binding regulatory protein identical or similar to Ni, which couples receptor-chemotactic factor interaction to phospholipase C activation. Inhibition of the activation prevents the production of IP3 and the resulting release of Ca2+ from intracellular stores and of 1,2-diacylglycerol and thus, the activation of protein kinase C. The lack of these two mediators is the immediate cause of the depression of neutrophil activation resulting from pertussis toxin. Some of the limitations and uncertainties of our present knowledge with respect to this hypothesis are discussed.
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PMID:Pertussis toxin as a probe of neutrophil activation. 301 23

The hippocampal slice preparation was used to classify cholinergic effects in terms of muscarinic receptor subtypes (M1 or M2) and biochemical effector systems linked to these effects in CA1 pyramidal cells. Based on the action of the M1 antagonist pirenzepine and the M2 antagonist gallamine, the muscarinic-induced membrane depolarization and blockade of the afterhyperpolarization appear to result from activation of an M1 receptor, while the cholinergic depression of the EPSP and the blockade of a potassium current termed the M-current appears to involve the activation of an M2 receptor. All of the muscarinic actions could be observed in pertussis toxin-treated hippocampi, suggesting that a pertussis toxin-sensitive G-protein is not involved in these actions. Cholinergic agents that are weak agonists of phosphoinositide (PI) turnover are fully effective in all of the muscarinic actions except the blockade of the M-current on which they had little agonist activity and actually blocked the action of full agonists. These results strongly suggest that the blockade of the M-current may involve stimulation of PI turnover. In addition, we show that the blockade of the M-current is mimicked by intracellular application of inositol trisphosphate. Our results do not show any obvious relationship between the muscarinic receptor subtypes and the biochemical effector systems.
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PMID:Classification of muscarinic responses in hippocampus in terms of receptor subtypes and second-messenger systems: electrophysiological studies in vitro. 314 94

Effects of pertussis toxin (PT) and betamethasone on delayed-type hypersensitivity (DTH) in mice were studied. When mice received PT (1 microgram/mouse) at the time of immunization or elicitation, a depression of DTH responses was observed. In addition, when mice received PT five days before and at the time of immunization, the DTH responses were suppressed. The administration of betamethasone along with PT at the time of immunization and elicitation caused an inhibition of DTH responses. These results suggest that PT depressed the DTH responses and that betamethasone suppressed such responses. Based on these findings, possible mechanisms by which PT and betamethasone affect DTH are discussed.
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PMID:Delayed-type hypersensitivity responses in mice treated with pertussis toxin and betamethasone. 322 95

Organotypic cultures of fetal mouse spinal cord-ganglion explants (2-4 weeks in vitro) contain forskolin-stimulated adenylate cyclase (AC) activity that is inhibited by levorphanol and other opioid agonists in a dose-dependent manner. Inhibition by levorphanol no longer occurs if sodium is omitted from the incubation and the levorphanol inhibition is blocked by the opioid antagonist, naloxone. These findings together with the ineffectiveness of dextrorphan indicate that the opioid inhibition of forskolin-stimulated AC is receptor mediated. Both the delta- and kappa-receptor subtypes appear to be involved since the selective delta-opioid agonist, [D-Pen2, D-Pen5]enkephalin, and the selective kappa-opioid agonist, t-3,4-dichloro-N-methyl-N[2-(1-pyrrolidinyl)cyclohexyl]-benzene acetamide (U-50,488H) are both effective at nanomolar concentrations. In contrast, the selective mu-opioid agonist, Tyr-D-Ala-Gly-N-MePhe-Gly-ol, has no significant effect even at micromolar concentrations. Both cord and ganglion components of the explants contain opioid-sensitive AC. Forskolin-stimulated AC of the explants is also inhibited by serotonin and carbachol. The serotonin effect appears to be mediated by 5-HT1A receptors, based on relative agonist and antagonist selectivity. Chronic exposure of cultures to morphine results in enhanced basal and forskolin-stimulated AC as well as attenuation of opioid-inhibition of AC assayed in the presence of forskolin; treatment of explants with pertussis toxin causes similar changes in the AC system. The inhibitory effect of serotonin is also attenuated by the pertussis toxin treatment. Basal AC activity of the explants (assayed without forskolin present) is stimulated to a small but significant extent by opioids and by serotonin. The opioid stimulatory effect is markedly enhanced following either morphine or pertussis toxin treatment of the explants. The attenuation of opioid- and serotonin-inhibition of AC produced by chronic exposure to pertussis toxin and the attenuation of opioid inhibition produced by exposure to morphine are consonant with the attenuation of opioid and monoaminergic depression of sensory evoked dorsal horn network responses after similar chronic treatments. It is proposed that the inhibitory effects of opioids and serotonin on these neurons are mediated by receptors that are negatively coupled via a pertussis toxin sensitive Gi protein to AC. Furthermore, alterations of AC with chronic morphine treatment may be involved in the development of physiologic tolerance to opioids.
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PMID:Modulation of adenylate cyclase activity of mouse spinal cord-ganglion explants by opioids, serotonin and pertussis toxin. 337 Apr 65


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