UMLS:C0043167 - FACTA Search

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

Although it is known that GABA(B) receptors are negatively coupled to adenylyl cyclase, the detailed selectivity of functional interaction between GABA(B) receptors and Gi subfamily members is still ambiguous. (+/-)-Baclofen-stimulated high-affinity GTPase activity, which was competitively antagonized by 2-hydroxy-saclofen, was attenuated by pretreatment of the membranes with N-ethylmaleimide (NEM) in a concentration- and incubation period-dependent manner. The NEM-pretreated (50 microM, 15 min at 4 degrees C) membranes restored the (+/-)-baclofen-sensitive high-affinity GTPase activity when reconstituted with pertussis toxin-sensitive bovine brain G proteins. Among recombinant rat Galpha subunits, G(i alpha(-2)) appeared most effective as compared with other subunits (G(i alpha(-2)) > G(i alpha(-3) > G(i alpha(-1) = G(o alpha). The GABA(B) receptor-mediated high-affinity GTPase activity was also completely eliminated by 100 microM suramin and by 100 microM benzalkonium chloride. These results indicate that GABA(B) receptors in rat cerebral cortex couple to NEM-sensitive G proteins, in particular Gi2, which are sensitive to suramin and benzalkonium chloride.
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PMID:Functional coupling of GABA(B) receptors with G proteins that are sensitive to N-ethylmaleimide treatment, suramin, and benzalkonium chloride in rat cerebral cortical membranes. 1112

The endogenous mechanisms modulating ATP-induced dopamine release in the nucleus accumbens (NAc) were studied by microdialysis in freely moving rats. The ATP analog 2-Methylthio ATP (2-MeSATP) facilitated the release of dopamine in a manner sensitive to pertussis toxin and tetrodotoxin. It is suggested that G-protein-coupled P2Y receptors and voltage-gated sodium channels are involved in this process. N-methyl-D-aspartate (NMDA) applied in a concentration of 100 microM decreased the extracellular dopamine level, whereas 1 and 10 mM NMDA enhanced it. The endogenous agonist glutamate (10 microM) inhibited the basal and facilitated release of dopamine. Infusion with a combination of the ionotropic glutamate receptor antagonists (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), as well as with the metabotropic glutamate receptor antagonist (+/-)-alpha-methyl-4-carboxyphenylglycine (MCPG) increased the basal level of dopamine and potentiated the 2-MeSATP-facilitated dopamine release, suggesting an ATP-mediated glutamate release. The GABA(A) receptor antagonist bicuculline infused into the NAc also enhanced the basal level of dopamine; however, the application of 2-MeSATP in the presence of bicuculline caused an early decrease and a subsequent increase of dopamine release. The facilitatory phase of the 2-MeSATP effect was comparable with that measured in the absence of bicuculline. By contrast, when bicuculline was infused into the ventral tegmental area (VTA) it elevated the accumbal basal dopamine level and in addition facilitated the 2-MeSATP- and the glutamate-induced dopamine release above that measured in the absence of bicuculline. These results suggest that ATP in the NAc has a physiologically relevant function in modulating dopaminergic transmission depending on the mesolimbic neuronal activity. The first component of the ATP effect involves a direct stimulation of the terminals of VTA neurons, while the second inhibitory component involves a sequential activation of glutamate and, finally, via ionotropic and metabotropic glutamate receptors, of GABA neurons projecting to the VTA.
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PMID:Mechanisms of adenosine 5'-triphosphate-induced dopamine release in the rat nucleus accumbens in vivo. 1116 71

Histaminergic neurons of the tuberomammillary nucleus (TM) project monosynaptically to the supraoptic nucleus (SON). This projection remains intact in our hypothalamic slices and permits investigation of both brief synaptic responses and the effects of repetitively activating this pathway. SON oxytocin (OX) neurons respond to single TM stimuli with fast IPSPs, whose kinetics resemble those of GABA(A) or glycine receptors. IPSPs were blocked by the Cl(-) channel blocker picrotoxin, but not by bicuculline or strychnine, and by histamine H(2), but not by H(1) or H(3) receptor antagonists, suggesting the presence of an ionotropic histamine receptor and the possible nonspecificity of currently used H(2) antagonists. G-protein mediation of the IPSPs was ruled out using guanosine 5'-O-(2-thiodiphosphate) (GDP-betaS), pertussis toxin, and Rp-adenosine 3',5'-cyclic monophosphothioate triethylamine (Rp-cAMPs), none of which blocked evoked IPSPs. We also investigated the effects of synaptically released histamine on dye coupling and neuronal excitability. One hundred seventy-three OX neurons were Lucifer yellow-injected in horizontal slices. Repetitive TM stimulation (10 Hz, 5-10 min) reduced coupling, an effect blocked by H(2), but not by H(1) or H(3), receptor antagonists. Because H(2) receptors are linked to activation of adenylyl cyclase, TM-stimulated reduction in coupling was blocked by GDP-betaS, pertussis toxin, and Rp-cAMPs and was mimicked by 8-bromo-cAMP, 3-isobutyl-1-methylxanthine, and Sp-cAMP. Membrane potentials of OX and vasopressin neurons were hyperpolarized, accompanied by decreased conductances, in response to bath application of 8-bromo-cAMP but not the membrane-impermeable cAMP. These results suggest that synaptically released histamine, in addition to evoking fast IPSPs in OX cells, mediates a prolonged decrease in excitability and uncoupling of the neurons.
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PMID:Ionotropic histamine receptors and H2 receptors modulate supraoptic oxytocin neuronal excitability and dye coupling. 1131 81

The neuropeptide melanin concentrating hormone (MCH) is synthesised only by neurons of the lateral hypothalamic (LH) area in the CNS. MCH cells project widely throughout the brain. Despite the growing interest in this peptide, in part related to its role in feeding, little has been done to characterise its physiological effects in neurons. Using whole-cell recording with current and voltage clamp, we examined the cellular actions in neurons from the LH. MCH induced a consistent decrease in the frequency of action potentials and reduced synaptic activity. Most fast synaptic activity in the hypothalamus is mediated by GABA or glutamate. MCH inhibited the synaptic activity of both glutamatergic and GABAergic LH neurons, each tested independently. MCH reduced the amplitude of glutamate-evoked currents and reduced the amplitude of miniature excitatory currents, indicating an inhibitory modulation of postsynaptic glutamate receptors. In the presence of tetrodotoxin to block action potentials, MCH caused a depression in the frequency of miniature glutamate-mediated postsynaptic currents, suggesting a presynaptic site of receptor expression. In voltage clamp experiments, MCH depressed the amplitude of calcium currents, suggesting that a mechanism of inhibition may involve a reduced calcium-dependent release of amino acid transmitter. Previous reports have suggested that MCH activated potassium channels in non-neuronal cells transfected with the MCH receptor gene. We found no effect of MCH on voltage-dependent potassium channels in LH neurons. Baclofen, a GABAB receptor agonist, activated G-protein gated inwardly rectifying potassium (GIRK)-type channels; in the same neurons, MCH had no effect on GIRK channels. MCH showed no modulation of sodium currents. Blockade of the Gi/Go protein with pertussis toxin eliminated the actions of MCH. The inhibitory actions of MCH on both excitatory and inhibitory synaptic events, coupled with opposing excitatory actions of hypocretin, another LH peptide that projects to many of the same loci, suggest a substantial level of complexity in neuropeptide modulation of LH actions.
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PMID:Melanin concentrating hormone depresses synaptic activity of glutamate and GABA neurons from rat lateral hypothalamus. 1135 Oct 31

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

The activation of pituitary GABA(B) receptors by the specific agonist baclofen inhibits pituitary hormone secretion in vitro. Here we studied the mechanism of action of GABA(B) receptors in rat adenohypophysis. Anterior pituitary cells were obtained by trypsinization and were either plated for hormonal studies and cAMP determination or incubated in FURA 2AM for calcium measurements. Baclofen (BACL: 1 x 10(-5) M) significantly inhibited basal and thyrotropic releasing hormone (TRH)-stimulated (1 x 10(-7) M) PRL secretion in anterior pituitary cells from proestrous rats. In the presence of pertussis toxin (PTX: 150 ng/ml, 20 h), which leads to the uncoupling of the G(i/o)-protein from the receptor, both effects of BACL were abolished while the effect of dopamine (DA: 1 x 10(-8) M), used as an inhibitory control, was reduced from 70 to 25%. PTX also reversed BACL-induced inhibition of gonadotropin-releasing hormone (GnRH)-elicited luteinizing hormone (LH) secretion in anterior pituitary cells from 15-day-old female rats. In addition, though working in a pituitary mixed cell population, in which only some cell types possess GABA(B) receptors, BACL (1 x 10(-5) M) attenuated the forskolin-induced (0.5 microM) increase in cAMP. This effect was prevented by co-incubation with the antagonist 2 hydroxysaclofen and by preincubation with PTX. BACL (5 x 10(-5) M) and DA (5 x 10(-7) M) inhibited basal intracellular calcium concentrations ([Ca(2+)](i)) in pituitary cells and the effect of the latter was significantly stronger. The effect of BACL on [Ca(2+)](i) was abolished after preincubation with PTX. In the presence of the potassium channel blocking agents barium (200 microM and 1 mM) and tetraethylammonium (10 mM), BACL was still able to inhibit [Ca(2+)](i). Blockade of voltage-sensitive calcium channels (VSCC) with either verapamil (5 x 10(-6) M) or nifedipine (1 x 10(-6) M) completely abolished the effect of BACL on [Ca(2+)](i). In the presence of 12.5 mM potassium concentration baclofen significantly inhibited [Ca(2+)](i). In conclusion, our results describe the negative coupling of adenohypophyseal GABA(B) receptors to VSCC through PTX-sensitive G-proteins. These characteristics suggest a resemblance of these receptors to the typical presynaptic GABA(B) sites described in the central nervous system.
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PMID:GABA(B) receptors in anterior pituitary cells. Mechanism of action coupled to endocrine effects. 1139 6

The effects of muscarinic agonists on GABAergic synaptic transmission were examined using whole-cell patch-clamp recording in chick brain slices containing the lateral spiriform nucleus. Bath application of muscarine (10 microM) both increased the frequency of spontaneous GABAergic postsynaptic currents and reduced the amplitude of evoked GABAergic polysynaptic postsynaptic currents elicited by focal afferent fiber electrical stimulation. Both of these muscarinic actions were reversible and dose-dependent. Two M(1) antagonists, telenzepine and pirenzipine, and to a lesser extent the M(2) antagonist methoctramine, protected against muscarine's inhibition of the evoked polysynaptic currents. Other M(2) antagonists (tripitramine and gallamine) as well as the M(3) antagonist 4-DAMP mustard (4-diphenylacetoxy-N-(2-chloroethyl)-piperidine hydrochloride) and an M(4) antagonist (tropicamide) provided little or no protection against muscarine in this assay. In contrast, 4-diphenylacetoxy-N-(2-chloroethyl)-piperidine hydrochloride, tropicamide and telenzepine, but not pirenzepine, methoctramine, tripitramine and gallamine, blocked muscarine's enhancement of spontaneous GABAergic currents. McN-A-343 [(4-hydroxy-2-butynyl)-1-trimethylammonium-m-chlorocarbanilate chloride] and CDD-0097 (5-propargyloxycarbonyl-1,4,5,6-tetrahydropyrimidine hydrochloride), two M(1) agonists, mimicked muscarine's inhibition of the evoked polysynaptic GABAergic currents but did not mimic muscarine's enhancement of spontaneous GABAergic currents. Both actions of muscarine persisted when slices were pretreated with pertussis toxin or N-ethylmaleimide, which inactivate G-proteins coupled to M(2) and M(4) receptors while leaving G-proteins coupled to M(1), M(3) and M(5) receptors intact. Muscarine had no significant effect on the amplitude of the direct postsynaptic current elicited by exogenous GABA in the presence of tetrodotoxin. The results demonstrate that distinct muscarinic receptors oppositely modulate GABAergic transmission in the lateral spiriform nucleus. The receptor mediating the inhibition of evoked GABAergic polysynaptic currents is pharmacologically similar to an M(1) receptor, while the enhancement of spontaneous GABAergic currents appears to be mediated by an M(3) receptor.
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PMID:Distinct muscarinic receptors enhance spontaneous GABA release and inhibit electrically evoked GABAergic synaptic transmission in the chick lateral spiriform nucleus. 1145 90

The mechanism of calcium-independent spontaneous GABA release in a long-living (3-10 weeks) rat hippocampal neuron culture was studied. It was found that Cd2+ (100 microM), a Ca2+ channel blocker, reversibly decreased the frequency and amplitude of GABAergic spontaneous miniature inhibitory postsynaptic currents (smIPSCs). Besides, Cd2+ decreased the currents evoked by muscimol application onto the neurons, which is evidence of an additional postsynaptic effect. The GABAB receptor agonist baclofen (0.1-50 microns) produced a concentration-dependent decrease in the smIPSC frequency, while not affecting the current amplitude. The baclofen effect was blocked by the pertussis toxin. The baclofen efficacy both in the presence of Cd2+ (presumably compete blocking of Ca2+ channels) and in the absence of this agent were similar and could be completely accounted for by the loss of an equivalent smIPSC fraction. Thus, the presynaptic baclofen-induced inhibition of the spontaneous GABA release can be entirely independent of the calcium channel modulation (the latter playing a decisive role in a mediator release induced by the action potential). Therefore, the smIPSC measurements (widely used in the past decade for the study of presynaptic drug activity) may inadequately reflect the drug effect in the intact brain.
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PMID:[Calcium-independent inhibition of the spontaneous release of GABA by baclofen in the rat hippocampus]. 1154 95

We have used the whole cell patch clamp method and fura-2 fluorescence imaging to study the actions of gabapentin (1-(aminoethyl) cyclohexane acetic acid) on voltage-activated Ca(2+) entry into neonatal cultured dorsal root ganglion (DRG) neurones and differentiated F-11 (embryonic rat DRG x neuroblastoma hybrid) cells. Gabapentin (2.5 microM) in contrast to GABA (10 microM) did not influence resting membrane potential or input resistance. In current clamp mode gabapentin failed to influence the properties of evoked single action potentials but did reduce the duration of action potentials prolonged by Ba(2+). Gabapentin attenuated high voltage-activated Ca(2+) channel currents in a dose- and voltage- dependent manner in DRG neurones and reduced Ca(2+) influx evoked by K(+) depolarisation in differentiated F-11 cells loaded with fura-2. The sensitivity of DRG neurones to gabapentin was not changed by the GABA(B) receptor antagonist saclofen but pertussis toxin pre-treatment reduced the inhibitory effects of gabapentin. Experiments following pre-treatment of DRG neurones with a PKA-activator and a PKA-inhibitor implicated change in phosphorylation state as a mechanism, which influenced gabapentin action. Sp- and Rp-analogues of cAMP significantly increased or decreased gabapentin-mediated inhibition of voltage-activated Ca(2+) channel currents. Culture conditions used to maintain DRG neurones and passage number of differentiated F-11 cells also influenced the sensitivity of Ca(2+) channels to gabapentin. We analysed the Ca(2+) channel subunits expressed in populations of DRG neurones and F-11 cells that responded to gabapentin had low sensitivity to gabapentin or were insensitive to gabapentin, by Quantitative TaqMan PCR. The data obtained from this analysis suggested that the relative abundance of the Ca(2+) channel beta(2) and alpha(2)delta subunit expressed was a key determinant of gabapentin sensitivity of both cultured DRG neurones and differentiated F-11 cells. In conclusion, gabapentin inhibited part of the high voltage-activated Ca(2+) current in neonatal rat cultured DRG neurones via a mechanism that was independent of GABA receptor activation, but was sensitive to pertussis toxin. Gabapentin responses identified in this study implicated Ca(2+) channel beta(2) subunit type as critically important to drug sensitivity and interactions with alpha(1) and alpha(2)delta subunits may be implicated in antihyperalgesic therapeutic action for this compound.
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PMID:Gabapentin-mediated inhibition of voltage-activated Ca2+ channel currents in cultured sensory neurones is dependent on culture conditions and channel subunit expression. 1189 14

Presynaptic receptors that are coupled to heterotrimeric G-proteins are found throughout the brain and are responsible for modulating synaptic transmission. At least 10 G-protein-coupled receptors (GPCRs) reduce transmission in hippocampal neurons. Additionally, hippocampal neurons express up to 17 different Galpha, Gbeta, and Ggamma subunits, making for a striking array of possible heterotrimer compositions and GPCR-heterotrimer interactions. The identity of the Galpha subunit is likely a critical determinant in coupling specificity between GPCRs and their molecular effectors mediating presynaptic inhibition. We studied the role of four Galpha(i/o) subunits (Galpha(o1), Galpha(i1,) Galpha(i2), and Galpha(i3)) in mediating presynaptic inhibition in hippocampal neurons by expressing pertussis toxin-insensitive (PTx-ins) Galpha(i/o) mutants. PTx treatment of these cells disrupts coupling of endogenous subunits, leaving only the mutant Galpha subunits to couple with native GPCRs and betagamma subunits. Successful rescue of presynaptic inhibition indicates that the expressed mutant Galpha subunit can couple to the GPCR of interest. All four PTx-ins Galpha subunits rescued presynaptic inhibition by adenosine A1 receptors. A PTx-ins Galpha subunit also rescued adenosine A1-mediated inhibition of spontaneous vesicle fusion frequency. Of the remaining GPCRs tested, cannabinoid CB1, somatostatin, and GABA(B) receptors displayed an alpha subunit-dependent selectivity in binding to G-protein heterotrimers, whereas group III metabotropic glutamate receptor-mediated inhibition was not rescued by expression of any of the four PTx-ins Galpha subunits. Differential coupling of G-protein alpha subunits may be a means of achieving specificity between different GPCRs and their molecular targets for mediating presynaptic inhibition.
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PMID:G-protein alpha subunit isoforms couple differentially to receptors that mediate presynaptic inhibition at rat hippocampal synapses. 1192 10

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