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)

The mu-opioid [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) inhibited the high voltage-activated calcium channel currents of neonatal rat dorsal root ganglion neurons in a voltage-dependent manner. The low voltage-activated currents were not affected by DAMGO. The inhibitory effect was eliminated by pretreatment of the cell with pertussis toxin, indicating that the receptor was coupled with the pertussis toxin-sensitive G protein. Although the DAMGO inhibition occurred quickly, it was relieved gradually during the 5-min application of DAMGO. The recovery from desensitization after washout of DAMGO was very slow. Pretreatment of the cell with 1 microM DAMGO for 18 hr induced almost complete tolerance to the agonist. GTP-gamma-S also inhibited the high voltage-activated calcium channel currents mimicking DAMGO inhibition and the inhibition diminished during continuous application, suggesting that desensitization could occur without receptor stimulation by the agonist. Baclofen caused a similar inhibition and desensitization to those by DAMGO, and the inhibition by the subsequently applied DAMGO was attenuated. Thus, desensitization by these distinct receptor agonists is heterologous. Modulation of G proteins which are coupled with these agonists may be involved in the desensitization process.
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PMID:Opioid inhibition and desensitization of calcium channel currents in rat dorsal root ganglion neurons. 807 38

Baclofen-induced hyperpolarization of hippocampal CA1 and CA3 pyramidal neurons was examined to assess the impact of ethanol on postsynaptic GABAB receptors. These receptors activate outward K+ currents via a pertussis toxin-sensitive G protein cascade to reduce membrane potential during the slow inhibitory postsynaptic potential. This inhibitory action may play a role in ethanol intoxication and withdrawal excitability. In both types of pyramidal neurons, baclofen applied consecutively in increasing concentrations caused concentration dependent hyperpolarization. There were no significant differences in resting membrane potential, input resistance, maximum baclofen-induced hyperpolarization or EC50 between CA1 and CA3 neurons, although slope values were significantly smaller in the former neurons. These parameters were not significantly changed in the presence of ethanol 10-100 mM. Chronic ethanol treatment (12 days) sufficient to induce physical dependence also did not shift sensitivity or maximum response to baclofen in CA1 neurons. These results suggest that GABAB receptors in this model are essentially insensitive to ethanol and do not confirm our earlier preliminary observation of a possible down-regulation of postsynaptic GABAB receptor function by chronic ethanol treatment.
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PMID:Sensitivity of postsynaptic GABAB receptors on hippocampal CA1 and CA3 pyramidal neurons to ethanol. 891 62

The mechanism underlying the enhancement of the high-voltage-activated (HVA) Ca2+ current (ICa) after application of baclofen, a GABAB agonist, in neurones of the rat dorsal root ganglia was studied by a combined use of the nystatin perforated patch clamp recording and our rapid superfusion system. Baclofen (50 microM) decreased the peak amplitude of HVA ICa and slowed the onset of the current, i.e. produced a typical G-protein-mediated inhibition of ICa. However, when baclofen was rapidly removed from the medium, the amplitude of the current was rather augmented, exceeding the control value obtained before application of the drug. This enhancement was not due to a shift of the voltage dependence of Ca2+ channel activation or a change in ionic permeability to other ions. The enhancement of HVA ICa by baclofen was sensitive to pertussis toxin treatment. The enhancement was evident during superfusion of baclofen. Since the inhibitory effect of baclofen on HVA ICa was not attenuated, even after a continuous application of baclofen for 10 min, the enhancement was not due to relief from tonic G-protein-mediated inhibition of the current or a desensitization of the GABAB receptor-effector system. An extremely prolonged time course of the enhancement of HVA ICa by baclofen strongly suggests an involvement of some intracellular signal transduction system.
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PMID:GABAB-mediated upregulation of the high-voltage-activated Ca2+ channels in rat dorsal root ganglia. 909 59

GABA is the primary transmitter released by neurons of the suprachiasmatic nucleus (SCN), the circadian clock in the brain. Whereas GABAB receptor agonists exert a significant effect on circadian rhythms, the underlying mechanism by which GABAB receptors act in the SCN has remained a mystery. We found no GABAB receptor-mediated effect on slow potassium conductance, membrane potential, or input resistance in SCN neurons in vitro using whole-cell patch-clamp recording. In contrast, the GABAB receptor agonist baclofen (1-100 microM) exerted a large and dose-dependent inhibition (up to 100%) of evoked IPSCs. Baclofen reduced the frequency of spontaneous IPSCs but showed little effect on the frequency or amplitude of miniature IPSCs in the presence of tetrodotoxin. The activation of GABAB receptors did not modulate postsynaptic GABAA receptor responses. The depression of GABA release by GABAB autoreceptors appeared to be mediated primarily through a modulation of presynaptic calcium channels. The baclofen inhibition of both calcium currents and evoked IPSCs was greatly reduced (up to 100%) by the P/Q-type calcium channel blocker agatoxin IVB, suggesting that P/Q-type calcium channels are the major targets involved in the modulation of GABA release. To a lesser degree, N-type calcium channels were also involved. The inhibition of GABA release by baclofen was abolished by a pretreatment with pertussis toxin (PTX), whereas the inhibition of whole-cell calcium currents by baclofen was only partially depressed by PTX, suggesting that G-protein mechanisms involved in GABAB receptor modulation at the soma and axon terminal may not be identical. We conclude that GABAB receptor activation exerts a strong presynaptic inhibition of GABA release in SCN neurons, primarily by modulating P/Q-type calcium channels at axon terminals.
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PMID:Presynaptic GABAB autoreceptor modulation of P/Q-type calcium channels and GABA release in rat suprachiasmatic nucleus neurons. 946 16

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

GABA and the GABA(B) receptor agonist (-)-baclofen inhibited 4-aminopyridine (4AP)- and KCl-evoked, Ca2+-dependent glutamate release from rat cerebrocortical synaptosomes. The GABA(B) receptor antagonist CGP 35348, prevented this inhibition of glutamate release, but phaclofen had no effect. (-)-Baclofen-mediated inhibition of glutamate release was insensitive to 2 microg/ml pertussis toxin. As determined by examining the mechanism of GABA(B) receptor modulation of glutamate release, (-)-baclofen caused a significant reduction in 4AP-evoked Ca2+ influx into synaptosomes. The agonist did not alter the resting synaptosomal membrane potential or 4AP-mediated depolarization; thus, the inhibition of Ca2+ influx could not be attributed to GABA(B) receptor activation causing a decrease in synaptosomal excitability. Ionomycin-mediated glutamate release was not affected by (-)-baclofen, indicating that GABA(B) receptors in this preparation are not coupled directly to the exocytotic machinery. Instead, the data invoke a direct coupling of GABA(B) receptors to voltage-dependent Ca2+ channels linked to glutamate release. This coupling was subject to regulation by protein kinase C (PKC), because (-)-baclofen-mediated inhibition of 4AP-evoked glutamate release was reversed when PKC was stimulated with phorbol ester. This may therefore represent a mechanism by which inhibitory and facilitatory presynaptic receptor inputs interplay to fine-tune transmitter release.
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PMID:Presynaptic GABA(B) receptor modulation of glutamate exocytosis from rat cerebrocortical nerve terminals: receptor decoupling by protein kinase C. 952 68

1. Voltage-dependent Ca2+ currents of dissociated rat supraoptic nucleus (SON) neurones were measured using the whole-cell configuration of the patch-clamp technique to examine direct postsynaptic effects of GABAB receptor activation on SON magnocellular neurones. 2. The selective GABAB agonist baclofen reversibly inhibited voltage-dependent Ca2+ currents elicited by voltage steps from a holding potential of -80 mV to depolarized potentials in a dose-dependent manner. The ED50 of baclofen for inhibiting Ca2+ currents was 1.4 x 10-6 M. Baclofen did not inhibit low threshold Ca2+ currents elicited by voltage steps from -120 to -40 mV. 3. Inhibition of high threshold Ca2+ currents by baclofen was rapidly and completely reversed by the selective GABAB antagonists, CGP 35348 and CGP 55845A, when the antagonists were added at the molar ratio vs. baclofen of 10 : 1 and 0.01 : 1, respectively. It was also reversed by a prepulse to +150 mV lasting for 100 ms. 4. The inhibition of Ca2+ currents was abolished when the cells were pretreated with pertussis toxin for longer than 20 h or with N-ethylmaleimide for 2 min. It was also abolished when GDPbetaS was included in the patch pipette. When GTPgammaS was included in the patch pipette, baclofen produced irreversible inhibition of Ca2+ currents and this inhibition was again reversed by the prepulse procedure. 5. The inhibition of N-, P/Q-, L- and R-type Ca2+ channels by baclofen (10-5 M) was 24.1, 10.5, 3.1 and 3. 6 %, respectively, of the total Ca2+ currents. Only the inhibition of N- and P/Q-types was significant. 6. These results suggest that GABAB receptors exist in the postsynaptic sites of the SON magnocellular neurones and mediate selective inhibitory actions on voltage-dependent Ca2+ channels of N- and P/Q-types via pertussis toxin-sensitive G proteins, and that such inhibitory mechanisms may play a role in the regulation of SON neurones by the GABA neurones.
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PMID:Inhibition of N- and P/Q-type calcium channels by postsynaptic GABAB receptor activation in rat supraoptic neurones. 957 87

Whole-cell patch recordings were made from immature (six- to 12-day-old) rat rostral ventrolateral medulla neurons in brainstem slices. GABA or the specific GABA(B) receptor agonist (-)baclofen (10-50 microM) by superfusion or by pressure ejection induced an outward current or a hyperpolarization, which persisted in a tetrodotoxin (0.3 microM)-containing Krebs' solution in nearly every cell tested. The GABA(B) receptor antagonists 2-hydroxy saclofen (50-200 microM) and CGP 35348 (50-200 microM) dose-dependently suppressed baclofen-currents. Baclofen-currents were suppressed by barium (1 mM) but not by tetraethylammonium (20 mM), low Ca2+ (0.24 mM) solution or in a solution containing the Ca2+ chelator BAPTA-AM (10 microM). The outward current had an estimated reversal potential of -98, -77 and -52 mV in 3.1, 7 and 15 mM [K+]o. Pre-incubation of slices with pertussis toxin (500 microg/ml for 5-7 h) or intracellular dialysis with GDP-beta-S (500 microM) markedly reduced baclofen-currents. Baclofen in low concentrations (1-3 microM) that caused slight or no change of holding currents and of inward or outward currents induced by exogenously applied glutamate or glycine/GABA, decreased excitatory and inhibitory postsynaptic currents by an average of 86.5 +/- 4.3% and 78.4 +/- 2.7%. The GABA(B) antagonist CGP 35348 (100 microM) increased the excitatory postsynaptic currents by an average of 64%, without causing a significant change in holding currents in 10/18 cells tested. Our results indicate the presence of post- and presynaptic GABA(B) receptors in the rostral ventrolateral medulla neurons. Activation of postsynaptic GABA(B) receptors induces an outward K+ current which is barium-sensitive, Ca2+-independent and may be coupled to a pertussis-sensitive G-protein. Activation of presynaptic GABA(B) receptors attenuates excitatory or inhibitory synaptic transmission. More importantly, the observation that CGP 35348 enhanced excitatory synaptic currents implies a removal of tonic activation of presynaptic GABA(B) receptors by endogenously released GABA (disinhibition), supporting the hypothesis that these receptors may have a physiological role in regulating the input and output ratio in a subset of rostral ventrolateral medulla neurons in vivo.
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PMID:Post- and presynaptic GABA(B) receptor activation in neonatal rat rostral ventrolateral medulla neurons in vitro. 969 55

Presynaptic inhibition exerted by the common inhibitor on the closer and opener muscles and by the specific inhibitor on the opener muscle was investigated in the crab Eriphia spinifrons. In the closer muscle, activation of GABA(B) receptors by baclofen reduced the mean quantal content of excitatory junctional currents by about 25%. Blocking GABA(B) receptors with CGP 55845 diminished presynaptic inhibition at a similar percentage. GABA(B) receptor-mediated presynaptic inhibition is linked to G proteins. Application of pertussis toxin eliminated about 25% of the inhibition exerted by the common inhibitory neuron. GABA(B) receptors participate in presynaptic inhibition at release boutons of the slow and the fast closer excitor at a similar percentage. In the opener muscle, presynaptic inhibition of transmitter release from the same endings of the opener excitor was about 15% stronger with the specific inhibitor than with the common inhibitor. About 10% of the presynaptic inhibition produced by either one of the two inhibitors could be abolished by blocking GABA(B) receptors. The amplitudes of the excitatory junctional currents in the opener were reduced in the presence of baclofen by about 25%, suggesting that synaptic terminals of the opener excitor are endowed with a similar percentage of GABA(B) receptors as terminals of the slow and the fast closer excitors. Baclofen had no effect on postsynaptic inhibition, indicating that GABA(B) receptors are not involved in postsynaptic neuromuscular inhibition.
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PMID:Presynaptic inhibition and the participation of GABA(B) receptors at neuromuscular junctions of the crab Eriphia spinifrons. 1075 44

This study used whole cell patch clamp recordings in rat hypothalamic slice preparations to evaluate the effects of GABA(B) receptor activation on GABA(A)-mediated inhibitory postsynaptic currents (IPSCs) in paraventricular nucleus magnocellular neurons evoked by electrical stimulation in the suprachiasmatic nucleus (SCN). Baclofen induced a dose-dependent (1-10 microM) and reversible reduction in SCN-evoked IPSC amplitude (11/11 cells), blockable with 2-hydroxysaclofen (300 microM; 3/3 cells). IPSCs displayed paired-pulse depression (PPD), attenuated by both baclofen and 2-hydroxysaclofen, but neither altered resting membrane conductances or IPSC time constants of decay. Baclofen induced a significant dose-dependent (1-100 microM) reduction in frequency, but not amplitude, of spontaneous IPSCs and miniature IPSCs, reversible with 2-hydroxysaclofen pretreatment. Baclofen effects and PPD persisted in slices pretreated with pertussis toxin (PTX) and N-ethylmaleimide, implying that these GABA(B) receptors are coupled to PTX-insensitive G proteins. Responses were unaltered by barium (2 mM) or nimodipine, ruling out involvement of K(+) channels and L-type Ca(2+) channels. Thus pre- and postsynaptic GABA(B) and GABA(A) receptors participate in SCN entrainment of paraventricular neurosecretory neurons.
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PMID:GABA(B) presynaptically modulates suprachiasmatic input to hypothalamic paraventricular magnocellular neurons. 1080 Dec 89


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