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: UMLS:C0043167 (pertussis)
19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1508-1517, 1998. Whole cell recordings (nystatin-perforated patch) were carried out on magnocellular neurons of the rat supraoptic nucleus (SON) to study the modulation of inhibitory postsynaptic currents (IPSCs) by gamma-aminobutyric acid-B (GABAB) receptors. Field stimulation adjacent to the SON in the presence of kynurenic acid, evoked monosynaptic GABAergic IPSCs. Baclofen reversibly reduced the amplitude of the IPSCs in a dose-dependent manner (EC50: 0.68 microM) without apparent effect on the holding current (Vh = -80 mV) or input resistance and altered neither the kinetic properties, nor the reversal potential of IPSCs. Concomittant to IPSC depression, baclofen enhanced the paired-pulse ratio for two consecutive IPSCs [interstimulus interval (ISI): 50 ms], an effect consistent with a presynaptic locus of action. Both actions of baclofen were abolished by CGP35348 (500 microM), a GABAB receptor antagonist. In testing for involvement of synaptically activated presynaptic GABAB receptors, we only recorded paired-pulse facilitation at most ISIs tested (50-500 ms), suggesting that the classical GABAB autoreceptors may not normally be activated in our conditions. However, enhancement of local GABA concentration by perfusion of a GABA uptake inhibitor (NO-711) revealed an action of endogenous GABA at these presynaptic GABAB receptors. The nonselective K+ channel blocker Ba2+ abolished baclofen's effect and pertussis toxin (PTX) pretreatment (200-500 ng/ml for 18-24 h) was ineffective in blocking the baclofen-induced inhibition, making an involvement of PTX-sensitive G protein unlikely. The present results show that presynaptic GABAB receptors that are coupled to PTX-insensitive G-proteins may be activated by endogenous GABA under conditions of reduced GABA uptake, thus regulating the inhibitory synaptic input to SON.
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PMID:Activation of presynaptic GABAB receptors inhibits evoked IPSCs in rat magnocellular neurons in vitro. 949 28

The effect of pretreatment with pertussis toxin at the doses of 0.25 and 0.50 microg per mouse ICV on the amnesic effect produced by baclofen (0.1 4 mg kg(-1) i.p.), diphenhydramine (15-30 mg kg(-1) i.p.) and scopolamine (0.5-5 mg kg(-1) i.p.) was investigated in the mouse passive avoidance test. Ten days after a single injection of pertussis toxin, baclofen (2 4 mg kg(-1) i.p.) amnesia was prevented. By contrast, pertussis toxin had no effect on diphenhydramine- and scopolamine-induced amnesia. Pretreatment with pertussis toxin at both doses used did not impair motor coordination of the mice, as revealed by the rota-rod test. The present results indicate that the activation of pertussis toxin-sensitive G-proteins represents an important transduction step in memory impairment induced by GABA(B) (gamma-aminobutyric acid B) agonists, but not by antihistaminic and antimuscarinic drugs.
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PMID:Effect of pertussis toxin on baclofen- and diphenhydramine-induced amnesia. 960 May 77

1. The modulatory effect of 5-hydroxytryptamine (5-HT) on the gamma-aminobutyric acid(A) (GABA(A)) response was investigated in the neurones freshly dissociated from the rat sacral dorsal commissural nucleus (SDCN) using the nystatin perforated patch recording configuration under the voltage-clamp conditions. 2. 5-HT potentiated GABA-induced Cl- current (IGABA) without affecting the reversal potential of IGABA and the apparent affinity of GABA to its receptor. 3. Alpha-Methyl-5-HT mimicked the potentiation effect of 5-HT on IGABA while ketanserine blocked it. 1-Oleoyl-2-acetyl-glycerol (OAG) potentiated IGABA, and the effect of 5-HT on IGABA was occluded by OAG pretreatment. In the presence of chelerythrine, 5-HT failed to potentiate IGABA, suggesting that protein kinase C (PKC) is involved in the pathway through which the activation of the 5-HT2 receptor potentiates the IGABA. 4. The facilitatory effect of 5-HT on IGABA remained in the presence of BAPTA-AM. LiCl also had no effect on 5-HT-induced potentiation of IGABA. 5. H-89, genistein, okadaic acid and pervanadate all had no effects on 5-HT potentiation of IGABA. Pertussis toxin treatment for 6-8 h did not block the facilitatory effect of 5-HT on IGABA. 6. The present results show that GABA(A) receptor in the rat SDCN could be modulated in situ by 5-HT, one of the major transmitters involved in the supraspinal control of nociception, and that the phosphorylation of GABA(A) receptor by PKC may be sufficient to support such modulation. The results also strongly support the hypothesis that the cotransmission by 5-HT and GABA has an important role in the spinal cord.
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PMID:5-HT potentiation of the GABA(A) response in the rat sacral dorsal commissural neurones. 969 Aug 71

The role of guanosine triphosphate-binding proteins (G-proteins) in the generation of the outward current during transient oxygen-glucose deprivation (OGD) was investigated in CA3 pyramidal cells in rat hippocampal organotypic slice cultures using the single-electrode voltage-clamp technique with KMeSO4-filled microelectrodes. To simulate ischaemia, brief chemical OGD (2 mM 2-deoxyglucose and 3 mM NaN3 for 4-9 min) was used, which induced an outward K+ current associated with an increase in input conductance. OGD failed to induce the outward current under conditions where G-protein function was disrupted by loading cells with guanosine 5'-O-(2-thiodiphosphate) [GDPbetaS] or after prolonged injection of guanosine 5'-O(3-thiotdphosphate) [GTPgammaS]. However, in slices treated with pertussis toxin (PTX), OGD still elicited the outward current, indicating that PTX-insensitive G-proteins are involved. Consistent with this insensitivity to PTX, neither adenosine receptors nor GABA(B) (gamma-aminobutyric acid) receptors, which operate via PTX-sensitive G-proteins, mediate the OGD-induced outward current. When adenosine receptors or GABA(B) receptors were blocked with 1,3-dipropyl-8-psulphophenylxanthine (DPSPX, 5 microM) or CGP 52 432 (10 microM), respectively, the OGD-induced response was not modified. The response also persisted following pretreatment of slice cultures with tetanus toxin to prevent vesicular release of neurotransmitters and neuromodulators from presynaptic terminals. Both PTX-sensitive and PTX-insensitive G-protein-mediated responses were suppressed during OGD. The inward current induced by the metabotropic glutamate receptor agonist 1 S, 3R-1-aminocyclopentane-1,3-dicarboxylate (1S,3R-ACPD) and the outward current elicited by adenosine or baclofen were strongly or completely attenuated. In contrast, the ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) response was not affected. These findings suggest that during OGD there is a functional uncoupling of receptors from G-proteins, and a direct receptor-independent activation of PTX-insensitive G-proteins leading to an increase in membrane K+ conductance.
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PMID:Effects of transient oxygen-glucose deprivation on G-proteins and G-protein-coupled receptors in rat CA3 pyramidal cells in vitro. 975 91

The antinociceptive action of the alkaloid cis-8, 10-di-n-propyllobelidiol hydrochloride dehydrate (DPHD), isolated from Siphocampylus verticillatus, given i.p., p.o., i.t., or i.c.v., was assessed in chemical and thermal models of nociception in mice, such as acetic acid-induced abdominal constriction, formalin- and capsaicin-induced licking, and hot-plate and tail-flick tests. DPHD given by i.p., p.o., i.t., or i.c.v. elicited significant and dose-related antinociception. At the ID50 level, DPHD was about 2- to 39-fold more potent than aspirin and dipyrone, but it was about 14- to 119-fold less potent than morphine. Its analgesic action was reversed by treatment of animals with p-chlorophenylalanine, naloxone, cyprodime, naltrindole, nor-binaltrorphimine, L-arginine, or pertussis toxin. Its action was also modulated by adrenal-gland hormones but was not affected by gamma-aminobutyric acid type A or type B antagonist, bicuculine, or phaclofen, nor was it affected by glibenclamide. DPHD, given daily for up to 7 days, did not develop tolerance to itself nor did it induce cross-tolerance to morphine. However, animals rendered tolerant to morphine presented cross-tolerance to DPHD. The antinociception of DPHD was not secondary to its anti-inflammatory effect, nor was it associated with nonspecific effects such as muscle relaxation or sedation. DPHD, in contrast to morphine, did not decrease charcoal meal transit in mice, nor did it inhibit electrical field stimulation of the guinea pig ileum or mouse vas deferens in vitro. Thus, DPHD produces dose-dependent and pronounced systemic, spinal, and supraspinal antinociception in mice, including against the neurogenic nociception induced by formalin and capsaicin. Its antinociceptive effect involves multiple mechanisms of action, namely interaction with mu, delta, or kappa opioid systems, L-arginine-nitric oxide and serotonin pathways, activation of Gi protein sensitive to pertussis toxin, and modulation by endogenous glucocorticoids.
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PMID:Antinociceptive properties of the new alkaloid, cis-8, 10-di-N-propyllobelidiol hydrochloride dihydrate isolated from Siphocampylus verticillatus: evidence for the mechanism of action. 1008 33

Kainate receptors are a subtype of ionotropic glutamate receptors, permeable to cations and thus expected to have an excitatory depolarizing action on neurons. However, kainate receptor activation inhibits gamma-aminobutyric acid release in the hippocampus through activation of protein kinase C in a pertussis toxin-dependent manner, suggesting a coupling of kainate receptors to G proteins. Thus, we directly investigated the G protein coupling of kainate receptors in the rat hippocampus by using a selective kainate receptor agonist, [(3)H](2S,4R)-4-methylglutamate ([(3)H]MGA). [(3)H]MGA bound to a single site to hippocampal membranes with a K(D) value of 32 nM and a B(max) value of 1024 fmol/mg protein. This binding likely represents kainate receptors because it was displaced by domoate (K(i) = 4 nM), kainate (K(i) = 11 nM), and 6-cyano-7-nitroquinoxaline-2,3-dione (K(i) = 1.4 microM), but not by alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (K(i) > 10 microM), (RS)-alpha-methyl-4-phosphonophenylglycine (K(i) > 10 microM), or (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (K(i) > 10 microM). Guanylylimidodiphosphate (30 microM), which uncouples all G protein-coupled receptors, shifted to the right the saturation curve of [(3)H]MGA (K(D) = 133 nM). This effect was mimicked by pretreatment of hippocampal membranes with modifiers of G(i)/G(o) proteins [30 microM N-ethylmaleimide (K(D) = 98 nM) or 25 microgram/ml pertussis toxin (K(D) = 95 nM)] but not by a modifier of G(s) proteins [50 microgram/ml cholera toxin (K(D) = 32 nM)]. Treatment of solubilized hippocampal membranes with pertussis toxin (25 microgram/ml) decreased [(3)H]MGA affinity (K(D) = 105-113 nM), which was recovered by reconstitution of these pretreated solubilized hippocampal membranes with G(i)/G(o) proteins (K(D) = 41-76 nM). These results indicate that hippocampal kainate receptors are coupled to G(i)/G(o) proteins.
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PMID:Kainate receptors coupled to G(i)/G(o) proteins in the rat hippocampus. 1041 64

gamma-Hydroxybutyrate (GHB), an anesthetic adjuvant analog of gamma-aminobutyrate (GABA), depresses cell excitability in hippocampal neurons by inducing hyperpolarization through the activation of a prominent inwardly rectifying K(+) (Kir3) conductance. These GABA type B (GABA(B))-like effects are clearly shown at high concentrations of GHB corresponding to blood levels usually reached during anesthesia and are mimicked by the GABA(B) agonist baclofen. Recent studies of native GABA(B) receptors (GABA(B)Rs) have favored the concept that GHB is also a selective agonist. Furthermore, cloning has demonstrated that GABA(B)Rs assemble heteromeric complexes from the GABA(B)R1 and GABA(B)R2 subtypes and that these assemblies are activated by GHB. The surprisingly high tissue content, together with anti-ischemic and protective effects of GHB in the heart, raises the question of a possible influence of GABA(B) agonists on excitable cardiac cells. In the present study, we provide electrophysiological evidence that GHB activates an inwardly rectifying K(+) current in rat ventricular myocytes. This effect is mimicked by baclofen, reversibly inhibited by GABA(B) antagonists, and prevented by pertussis toxin pretreatment. Both GABA(B)R1 and GABA(B)R2 are detected in cardiomyocytes by Western blotting and are shown to coimmunoprecipitate. Laser scanning confocal microscopy discloses an even distribution of the two receptors in the sarcolemma and along the transverse tubular system. Hence, we conclude that GABA(B)Rs are distributed not only in neuronal tissues but also in the heart, where they can be activated and induce electrophysiological alterations through G-protein-coupled inward rectifier potassium channels.
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PMID:gamma-aminobutyric acid type B receptors are expressed and functional in mammalian cardiomyocytes. 1090 22

A number of studies have shown that activation of gamma-aminobutyric acid(B) (GABA(B)) receptors potentiates neurotransmitter-induced accumulation of cyclic AMP in brain slices, but the mechanisms involved in the facilitatory effect have not been fully elucidated. In the present study, we showed that in membranes of rat frontal cortex the GABA(B) receptor agonist (-)baclofen increased basal adenylyl cyclase activity and potentiated the maximal enzyme stimulation elicited by corticotropin-releasing hormone (CRH). The less active enantiomer (+)baclofen had no effect on cyclic AMP formation, whereas the natural agonist GABA mimicked the stimulatory action of (-)baclofen. In radioligand-binding experiments, the affinity and maximal binding capacity of (125)I-Tyr-CRH was not affected by (-)baclofen. The GABA(B) receptor antagonist CGP 55845A competitively counteracted the (-)baclofen potentiation of CRH-stimulated adenylyl cyclase activity with a pA(2) value of 6.70. Moreover, both (-)baclofen and GABA, but not (+)baclofen, caused a concentration-dependent stimulation of [(35)S]GTP gamma S binding to membrane G-proteins. The intracerebral injection of pertussis toxin significantly reduced the facilitatory effects of (-)baclofen on both basal and CRH-stimulated adenylyl cyclase activities. Moreover, membrane incubation with the GDP-bound form of the alpha subunit of transducin, a scavenger of G protein beta gamma subunits, blocked the stimulatory effects of (-)baclofen. The data indicate that in rat frontal cortex activation of GABA(B) receptors potentiates the CRH stimulation of adenylyl cyclase activity through a mechanism involving the beta gamma subunits of the pertussis toxin-sensitive G protein G(i)/G(o).
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PMID:Beta gamma-mediated enhancement of corticotropin-releasing hormone-stimulated adenylyl cyclase activity by activation of gamma-aminobutyric acid(B) receptors in membranes of rat frontal cortex. 1138 76

Immunization with the whole-cell pertussis vaccine (Pw), while effective at preventing whooping cough in infants, has been associated with local, systemic, and neuronal reactions, including fevers and convulsions in children. In contrast, the new acellular pertussis vaccines (Pa) have a considerably improved safety profile. The lack of an appropriate animal model has restricted investigations into the mechanisms by which neurological reactions are induced by vaccination. Here we describe a novel murine model wherein seizure-like behavioral changes are induced following parenteral administration of Pw. The proinflammatory cytokine interleukin-beta (IL-1beta), production of which has been associated with many neurodegenerative conditions, was significantly increased in the hippocampus and hypothalamus of vaccinated animals. Accompanying this change was a decrease in release of the inhibitory neurotransmitters gamma-aminobutyric acid and adenosine in the hippocampus. Seizure-like behavioral changes were significantly reduced following inhibition of IL-1beta production by the administration of an inhibitor of IL-1beta-converting enzyme and were almost completely abrogated in IL-1 receptor type I knockout mice. These results suggest a causal relationship between IL-1beta induction and convulsive behavior following Pw vaccination. Significantly, Pa neither increased IL-1beta nor induced behavioral changes in mice, but did induce the anti-inflammatory cytokine IL-10. In contrast, administration of active pertussis toxin and lipopolysaccharide, residual in Pw but absent from Pa, also induced convulsive activity. Our findings provide the first direct evidence of an immunological basis for pertussis vaccine reactogenicity and suggest that active bacterial toxins are responsible for the neurologic disturbances observed in children immunized with Pw.
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PMID:Whole-cell but not acellular pertussis vaccines induce convulsive activity in mice: evidence of a role for toxin-induced interleukin-1beta in a new murine model for analysis of neuronal side effects of vaccination. 1140 57

Modulation of Chelidonii herba on gamma-aminobutyric acid (GABA) activated chloride current in the acutely dissociated periaqueductal gray (PAG) neuron was studied by nystatin-perforated patch-clamp technique. High concentrations of Chelidonii herba elicited ion current, that was blocked by bicuculline. Low concentrations reduced the GABA activated current in PAG. Two types of inhibitory action of Chelidonii herba on GABA activated current have been implicated in PAG. One is the inhibitory action of Chelidonii herba on GABA was abolished by naltrexone and the other is that of Chelidonii herba was potentiated by naltrexone. In addition, all of two types of action of Chelidonii herba are linked to pertussis toxin-sensitive GTP-binding proteins. These results suggest that the inhibitory modulation of Chelidonii herba on GABA activated current via G-proteins in PAG neuron is an important analgesic mechanism.
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PMID:Modulation of Chelidonii herba on GABA activated chloride current in rat PAG neurons. 1152 69


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