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)

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

Nucleotides can activate ionotropic P2X receptors that induce calcium-responses in rat midbrain synaptosomes. In this report, we show that ATP elicits Ca(2+) responses producing a monophasic dose-response curve with an EC(50) value of 24.24+/-1.42 micro M. In the presence of gamma-aminobutyric acid (GABA), the ATP dose-response curve becomes biphasic with EC(50) values of 3.69+/-0.44 nM and 59.65+/-8.32 micro M. Moreover, the maximal calcium response induced by ATP is 52.1% higher than the control. This effect is mimicked or blocked by the specific GABA(B) receptor agonist and antagonist, baclofen and saclofen, respectively. Presynaptic GABA(B) receptors, identified by immunocytochemistry are present in 62% of the total synaptosomal population. Adenylate cyclase and protein kinase A cascades are involved in the potentiatory effects mediated by baclofen and their activation or inhibition modifies calcium signalling and synaptosomal cAMP levels. The potentiatory action of baclofen was confirmed by microfluorimetry performed on single synaptic terminals. In its presence, 86% of the terminals responding to 100 micro M ATP, are also able to respond to nanomolar concentrations (100 nM) of this nucleotide. This potentiatory effect is reduced to 32% in the presence of pertussis toxin. Our data suggest that the activity of P2X receptors is modulated by GABA(B) receptors in midbrain synaptosomes.
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PMID:GABAB receptor-mediated presynaptic potentiation of ATP ionotropic receptors in rat midbrain synaptosomes. 1260 91

In islets of Langerhans, L-glutamate is stored in glucagon-containing secretory granules of alpha-cells and cosecreted with glucagon under low-glucose conditions. The L-glutamate triggers secretion of gamma-aminobutyric acid (GABA) from beta-cells, which in turn inhibits glucagon secretion from alpha-cells through the GABAA receptor. In the present study, we tested the working hypothesis that L-glutamate functions as an autocrine/paracrine modulator and inhibits glucagon secretion through a glutamate receptor(s) on alpha-cells. The addition of L-glutamate at 1 mmol/l; (R,S)-phosphonophenylglycine (PPG) and (S)-3,4-dicarboxyphenylglycine (DCPG), specific agonists for class III metabotropic glutamate receptor (mGluR), at 100 micromol/l; and (1S,3R,4S)-1-aminocyclopentane-1,3,4-tricarboxylic acid (ACPT-I) at 50 micromol/l inhibited the low-glucose-evoked glucagon secretion by 87, 81, 73, and 87%, respectively. This inhibition was dose dependent and was blocked by (R,S)-cyclopropyl-4-phosphonophenylglycine (CPPG), a specific antagonist of class III mGluR. Agonists of other glutamate receptors, including kainate and quisqualate, had little effectiveness. RT-PCR and immunological analyses indicated that mGluR4, a class III mGluR, was expressed and localized with alpha- and F cells, whereas no evidence for expression of other mGluRs, including mGluR8, was obtained. L-Glutamate, PPG, and ACPT-I decreased the cAMP content in isolated islets, which was blocked by CPPG. Dibutylyl-cAMP, a nonhydrolyzable cAMP analog, caused the recovery of secretion of glucagon. Pertussis toxin, which uncouples adenylate cyclase and inhibitory G-protein, caused the recovery of both the cAMP content and secretion of glucagon. These results indicate that alpha- and F cells express functional mGluR4, and its stimulation inhibits secretion of glucagon through an inhibitory cAMP cascade. Thus, L-glutamate may directly interact with alpha-cells and inhibit glucagon secretion.
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PMID:Metabotropic glutamate receptor type 4 is involved in autoinhibitory cascade for glucagon secretion by alpha-cells of islet of Langerhans. 1504 15

We examined synaptic plasticity at intrasuprachiasmatic nucleus (SCN) gamma-aminobutyric acid (GABA)ergic synapses by measuring the paired-pulse ratio between pairs of evoked inhibitory postsynaptic currents (IPSCs). Interstimulus intervals were chosen to represent the range of spontaneous action potential firing frequencies found in SCN neurons. A majority of synapses studied during the day exhibited paired-pulse depression (PPD), whereas a majority of synapses studied during the night showed no PPD. Two types of PPD were found. Type 1 PPD expresses the greatest inhibition at shorter interstimulus intervals, is predominant in the early morning and is likely to be a result of vesicle depletion. Type 2 showed the greatest inhibition at interstimulus intervals between 175 and 225 ms, is found throughout the day yet rarely at night and is likely to be a result of a Ca(2+)-dependent mechanism that is independent of pertussis toxin-sensitive G-proteins. Thus, multiple mechanisms of synaptic plasticity modulate intra-SCN communication throughout the diurnal cycle.
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PMID:GABAergic synapses of the suprachiasmatic nucleus exhibit a diurnal rhythm of short-term synaptic plasticity. 1514 12

Cerebellar Purkinje cells integrate motor information conveyed by excitatory synaptic inputs from parallel and climbing fibres. Purkinje cells abundantly express B-type G-protein-coupled gamma-aminobutyric acid receptors (GABABR) that are assumed to mediate major responses, including postsynaptic modulation of the synaptic inputs. However, the identity and function of effectors operated by GABABR are not fully elucidated. Here we characterized an inwardly rectifying current activated by baclofen (Ibacl), a GABABR agonist, in cultured mouse Purkinje cells using a ruptured-patch whole-cell technique. Ibacl is operated by GABABR via Gi/o-proteins, as it is not inducible in pertussis-toxin-pretreated cells. Ibacl is carried by K+ because its reversal potential shifts with the equilibrium potential of K+. Ibacl is blocked by 10(-3) M Ba2+ or Cs+, and 10(-8) M tertiapin-Q. Upon the onset and offset of a hyperpolarizing step, Ibacl is activated and deactivated, respectively, with double-exponential time courses (time constants, <1 ms and 30-80 ms). Based on similarities in the above properties, G-protein-coupled inwardly rectifying K+ (GIRK) channels are thought to be responsible for Ibacl. Perforated-patch recordings from cultured Purkinje cells demonstrate that Ibacl hyperpolarizes the resting potential and the peak level achieved by glutamate-evoked potentials initiated in the dendrites. Moreover, cell-attached recordings from Purkinje cells in cerebellar slices demonstrate that Ibacl impedes spontaneous firing. Therefore, Ibacl may reduce the postsynaptic and intrinsic excitability of Purkinje cells under physiological conditions. These findings give a new insight into the role of GABABR signalling in cerebellar information processing.
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PMID:GABAergic activation of an inwardly rectifying K+ current in mouse cerebellar Purkinje cells. 1563 97

The lateral septal nucleus receives a diffuse dopaminergic input originating from the ventral tegmental area of the brain stem. We examined whether dopamine (DA) modulates synaptic transmission in the slice preparation of the rat dorsolateral septal nucleus (DLSN). Bath application (10-15 min) of DA (30 muM) markedly depressed the amplitude of fast and slow inhibitory postsynaptic potentials (IPSPs) in DLSN neurons, while it produced only a minor depression of the amplitude of excitatory postsynaptic potentials (EPSPs) obtained in the presence of bicuculline. DA (30 muM) depressed the monosynaptic fast IPSP to approximately 50% of control, but did not depress the inward current (I(GABA)) induced by exogenous gamma-aminobutyric acid (GABA). DA decreased the frequency of miniature fast IPSPs (m-fIPSPs) without significantly changing their amplitude. PD 168077, a selective D4 receptor agonist, depressed the fast and slow IPSPs but not the EPSP and decreased the frequency of m-fIPSPs. Both DA and PD 168077 increased the paired-pulse ratio of the monosynaptic fast IPSP. The inhibitory effect of DA on the fast IPSP was significantly attenuated by L-741,742, an antagonist at D4 receptors, but not by SCH 23390 and sulpiride, a D1-like and a D2-like receptor antagonist, respectively. N-ethylmaleimide, a blocker of pertussis toxin (PTX)-sensitive G protein (G(i/o)), attenuated the DA-induced depression of the fast IPSP. N-[2-((p-bromocinnamyl) amino)ethyl]-5-isoquinoline sulfonamide, a protein kinase A (PKA) inhibitor, attenuated the DA-induced depression of the fast IPSP. These results suggest that DA inhibits spontaneous and evoked release of GABA via the D4 receptor-G(i)-protein-PKA system in DLSN neurons.
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PMID:Dopamine presynaptically depresses fast inhibitory synaptic transmission via D4 receptor-protein kinase A pathway in the rat dorsolateral septal nucleus. 1664 81

Many postsynaptic neurons release a retrograde transmitter that modulates presynaptic neurotransmitter release. In the suprachiasmatic nucleus (SCN), retrograde signaling is suggested by the presence of dendritic dense-core vesicles. Whole-cell voltage-clamp recordings were made from rat SCN neurons to determine whether a retrograde messenger could modulate the activity of afferent gamma-aminobutyric acid (GABA)ergic inputs. The frequency and amplitude of spontaneous GABAergic currents was significantly reduced in a subpopulation of SCN neurons (eight out of 13) following a postsynaptic depolarization. Similarly, a postsynaptic depolarization significantly reduced the amplitude of evoked GABAergic currents during both day and night recordings. A postsynaptic depolarizing pulse eliminated paired-pulse inhibition of GABAergic currents consistent with a presynaptic mechanism. Muscimol-activated currents were not altered by postsynaptic depolarization, demonstrating that the activity of GABA(A) receptors was not altered. Depolarization-induced inhibition of the GABAergic currents was not observed when a Ca2+ chelator was included in the microelectrode. Postsynaptic depolarization significantly increased the Ca2+ concentration in both the soma and dendrites. The dendritic Ca2+ levels increased faster, to a higher concentration and decayed faster than in the soma. The depolarization-induced inhibition of the evoked GABAergic current was blocked by the G-protein uncoupling agent N-ethylmaleimide, suggesting that the retrograde messenger acts on a pertussis toxin-sensitive G-protein-coupled receptor. Because the majority of SCN neurons receive GABAergic input from neighboring cells, these results describe a retrograde signaling mechanism by which SCN neurons can modulate GABAergic synaptic input.
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PMID:Retrograde suppression of GABAergic currents in a subset of SCN neurons. 1682 11

We investigated the effects of 4-(N-{1-[2-(4-cyanophenyl)ethyl]-4-hydroxypiperidin-4-ylmethyl}-N-methylamino)benzoic acid monohydrochloride (M58996), a novel analgesic, on persistent and neuropathic pain in rats. In the formalin test, oral M58996 (0.3 - 10 mg/kg) reduced nociceptive behaviors only in the late phase. In the neuropathic pain model, oral M58996 (1 - 10 mg/kg) attenuated mechanical allodynia and heat hyperalgesia in the nerve-injured paw without affecting normal responses of the uninjured paw. High doses (10 - 100 mg/kg) of oral M58996 did not influence normal motor function. Thus, M58996 had a wide dose range showing antinociceptive, antiallodynic, and antihyperalgesic effects without motor dysfunction. In addition, we studied the possible mechanisms involved in the M58996-induced antinociception. The antinociceptive effect of M58996 was reversed by intrathecal pertussis toxin, an inhibitor of the inhibitory- and other-GTP-binding protein (G(i/o) protein), but not by subcutaneous naloxone, an opioid-receptor antagonist. This effect was also reversed by intracerebroventricular or intrathecal tropisetron, a 5-hydroxytryptamine(3) (5-HT(3))-receptor antagonist, and intraperitoneal bicuculline, a gamma-aminobutyric acid(A) (GABA(A))-receptor antagonist. These results suggest that M58996 produces its antinociceptive effect by a pertussis toxin-sensitive G protein mechanism. In addition, the GABA released by the activation of supraspinal and/or spinal 5-HT(3) receptors is likely to contribute to the M58996-induced antinociception.
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PMID:Pharmacological profiles of the novel analgesic M58996 in rat models of persistent and neuropathic pain. 1703 Oct 69

The sulphydryl alkylating agent N-ethylmaleimide (NEM) has been often used as an uncoupler of pertussis toxin-sensitive G-proteins. However, the effects of NEM on gamma-aminobutyric acid (GABA)ergic synaptic transmission remain controversial. Using the whole-cell patch-clamp technique, GABA(A) receptor-mediated postsynaptic currents (IPSCs) have been recorded from Cajal-Retzius (CR) cells in layer I of the neonatal mouse visual cortex. NEM increased the frequencies of both spontaneous and miniature IPSCs (mIPSCs) without an effect on the median mIPSC amplitudes or mIPSC kinetics. The NEM actions on mIPSCs did not depend on the extracellular Ca(2+), Ca(2+) release from intracellular stores, adenylyl cyclase and protein kinase A activities. NEM increased the mean amplitudes of evoked IPSCs and strongly decreased the paired-pulse ratio. The size of the readily releasable pool of presynaptic vesicles (RRP) was estimated using a high-frequency stimulation protocol. The RRP size was not affected by NEM. In addition, NEM significantly decreased the latency between the stimulus and the onset of GABA release. These results suggest that NEM selectively increases GABA release probability. At postnatal day 2, mIPSCs were observed only in about 30% of CR cells. NEM application revealed, however, that more than 90% of CR cells receive GABAergic inputs. Therefore, NEM seems to be a useful tool to verify the existence of 'silent' GABAergic synapses.
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PMID:N-ethylmaleimide increases release probability at GABAergic synapses in layer I of the mouse visual cortex. 1715

Prostaglandin E(2) (PGE(2)) has been shown to produce fever by acting on EP3 receptors within the preoptic area of the brain. However, there is little information about the molecular events downstream of EP3 activation in preoptic neurons. As a first step toward this issue, we examined PGE(2)-induced gene expression changes at single-cell resolution in preoptic neurons expressing EP3. Brain sections of the preoptic area from PGE(2)- or saline-injected rats were stained with an anti-EP3 antibody, and the cell bodies of EP3-positive neurons were dissected and subjected to RNA amplification procedures. Microarray analysis of the amplified products demonstrated the possibility that gene expression of gamma-aminobutyric acid type A (GABA(A)) receptor subunits is decreased upon PGE(2) injection. Indeed, we found that most EP3-positive neurons in the mouse preoptic area are positive for the alpha2 or gamma2 GABA(A) receptor subunit. Moreover, PGE(2) decreased the preoptic gene expression of these GABA(A) subunits via an EP3-dependent and pertussis toxin-sensitive pathway. PGE(2) also attenuated the preoptic protein expression of the alpha2 subunit in wild-type but not in EP3-deficient mice. These results indicate that PGE(2)-EP3 signaling elicits G(i/o) activation in preoptic thermocenter neurons, and we propose the possibility that a rapid decrease in preoptic GABA(A) expression may be involved in PGE(2)-induced fever.
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PMID:Prostaglandin E2 attenuates preoptic expression of GABAA receptors via EP3 receptors. 1829 84


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