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)

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

The cytotoxic action of the gamma-isomer of hexachlorocyclohexane (gamma-HCH, lindane) was studied in cultured mouse cerebellar granule neurons maintained in the presence or absence of the GABA(A) receptor agonist THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol). The cells were exposed for 24 hr to lindane (30-300 microM) in the culture medium. Changes in mitochondrial function were investigated by using the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) test. The results showed that lindane-induced cytotoxicity was concentration-dependent. In cerebellar granule cells not treated with THIP, lindane-induced cytotoxicity did not appear to be related to GABA(A) or GABA(B) receptors. However, in THIP-treated cultures, lindane-induced cytotoxicity was found to be mediated by an action of the insecticide on GABA receptors. In the latter case, GABA reduced the lindane-induced cytotoxicity, but the protective effect was not potentiated by flunitrazepam. The GABA(A) receptor agonist muscimol (50 microM) also protected the THIP-treated cultures against lindane-induced cytotoxicity. In addition, the GABA(B) receptor agonist R(+)baclofen protected the cells from lindane-induced cytotoxicity and the effect of baclofen was blocked by GABA(B) receptor antagonists. Pertussis toxin was found to reverse the protective effect of baclofen only at the highest lindane concentration (300 microM). The lindane-induced cytotoxicity could be partly explained as being secondary to excitotoxicity as a mixture of the excitatory amino acid receptor antagonists APV (D-(-)-2-amino-5-phosphonopentanoate) and CNQX (6-cyano-7-nitro-quinoxaline-2,3-dione) shifted the concentration-response curve for lindane-induced cytotoxicity to the right. It is suggested that the cytotoxic effects of lindane in THIP-treated cerebellar granule neurons are primarily related to an action of lindane on GABA(B) receptors and to a lesser extent on inducible low-affinity, benzodiazepine insensitive GABA(A) receptors.
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PMID:Cytotoxic action of lindane in cerebellar granule neurons is mediated by interaction with inducible GABA(B) receptors. 959 Apr 37

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

Previous studies have shown that GABA(B) receptors facilitate cyclic AMP formation in brain slices likely through an indirect mechanism involving intracellular second messengers. In the present study, we have investigated whether a positive coupling of GABA(B) receptors to adenylyl cyclase could be detected in a cell-free preparation of rat olfactory bulb, a brain region where other Gi/Go-coupled neurotransmitter receptors have been found to stimulate the cyclase activity. The GABA(B) receptor agonist (-)-baclofen significantly increased basal adenylyl cyclase activity in membranes of the granule cell and external plexiform layers, but not in the olfactory nerve-glomerular layer. The adenylyl cyclase stimulation was therefore examined in granule cell layer membranes. The (-)-baclofen stimulation (pD2=4.53) was mimicked by 3-aminopropylphosphinic acid (pD2=4.60) and GABA (pD2=3.56), but not by (+)-baclofen, 3-aminopropylphosphonic acid, muscimol and isoguvacine. The stimulatory effect was counteracted by the GABA(B) receptor antagonists CGP 35348 (pA2=4.31), CGP 55845 A (pA2=7.0) and 2-hydroxysaclofen (pKi=4.22). Phaclofen (1 mM) was inactive. The (-)-baclofen stimulation was not affected by quinacrine, indomethacin, nordihydroguaiaretic acid and staurosporine, but was completely prevented by pertussis toxin and significantly reduced by the alpha subunit of transducin, a betagamma scavenger. The betagamma subunits of transducin stimulated the cyclase activity and this effect was not additive with that produced by (-)-baclofen. In the external plexiform and granule cell layers, but not in the olfactory nerve-glomerular layer, (-)-baclofen enhanced the adenylyl cyclase stimulation elicited by the neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP) 38. Conversely, the adenylyl cyclase activity stimulated by either forskolin or Ca2+/calmodulin-(Ca2+/CaM) was inhibited by (-)-baclofen in all the olfactory bulb layers examined. These data demonstrate that in specific layers of rat olfactory bulb activation of GABA(B) receptors enhances basal and neurotransmitter-stimulated adenylyl cyclase activities by a mechanism involving betagamma subunits of Gi/Go. This positive coupling is associated with a widespread inhibitory effect on forskolin- and Ca2+/CaM-stimulated cyclic AMP formation.
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PMID:GABA(B) receptor-mediated stimulation of adenylyl cyclase activity in membranes of rat olfactory bulb. 1018 76

Interaction between GABAA and GABA(B) receptors was studied in rat cerebellar granule cells in culture, by the whole-cell patch-clamp approach. Our data show that the GABA(B) agonist (-)baclofen is not able, per se, to significantly change the muscimol-activated chloride current. However, (-)baclofen dose-dependently prevents the reduction of GABA(A) receptor function by forskolin, an activator of adenylate cyclase. The effect of baclofen is mediated by a pertussis toxin-sensitive G protein. In fact, in cells treated with pertussis toxin, baclofen and forskolin, the toxin is able to block baclofen action, allowing forskolin to act fully. The protective effect by GABA(B) receptor activation under these circumstances is most probably related to the prevention of cyclic AMP increases after forskolin treatment. In fact, in these neurons cyclic AMP and protein kinase A activation result in a down-regulation of GABA(A) receptor function. On the whole, the data indicate the presence of complex modulation of GABA(A) receptors by GABA(B) receptor types in cerebellum granule cells.
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PMID:GABA(B) receptor activation protects GABA(A) receptor from cyclic AMP-dependent down-regulation in rat cerebellar granule cells. 1047 72

The membrane density of L-type voltage-sensitive Ca(2+) channels (L-VSCCs) of rat hippocampal neurons increases over age [days in vitro (DIV)] in long-term primary cultures, apparently contributing both to spontaneous cell death and to enhanced excitotoxic vulnerability. Similar increases in L-VSCCs occur during brain aging in vivo in rat and rabbit hippocampal neurons. However, unraveling both the molecular basis and the functional implications of these age changes in VSCC density will require determining whether the other types of high-threshold VSCCs (e.g., N, P/Q, and R) also exhibit altered density and/or changes in regulation, for example, by the important G-protein-coupled, membrane-delimited inhibitory pathway. These possibilities were tested here in long-term hippocampal cultures. Pharmacologically defined whole-cell currents were corrected for cell size differences over age by normalization with whole-cell capacitance. The Ca(2+) channel current density (picoamperes per picofarad), mediated by each Ca(2+) channel type studied here (L, N, and a combined P/Q + R component), increased through 7 DIV. Thereafter, however, only L-type current density continued to increase, at least through 21 DIV. Concurrently, pertussis toxin-sensitive G-protein-coupled inhibition of non-L-type Ca(2+) channel current induced by the GABA(B) receptor agonist baclofen or by guanosine 5'-3-O-(thio)triphosphate declined dramatically with age in culture. Thus, the present studies identify selective and novel parallel mechanisms for the time-dependent alteration of Ca(2+) influx, which could importantly influence function and vulnerability during development and/or aging.
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PMID:Decreased G-protein-mediated regulation and shift in calcium channel types with age in hippocampal cultures. 1049 68

In lamprey, sensory transmission from mechanosensory receptors (dorsal cells) to central neurons is presynaptically inhibited by GABA(B) receptor activation. The mechanisms underlying this effect were investigated using isolated dorsal cells, where voltage-dependent calcium currents were recorded in the whole-cell configuration. Activation of GABA(B) receptors by baclofen decreased the peak amplitude of high voltage-activated (HVA) calcium currents and slowed the activation phase. The role of G-proteins in mediating the effects of baclofen was examined. Intracellular dialysis of GTPgammaS occluded the effects of baclofen. Intracellular dialysis of GDPbetaS and preincubation in pertussis toxin both attenuated the effect of baclofen. Specific calcium channel blockers were used to study the types of HVA calcium channels involved in the GABA(B)-mediated modulation. The baclofen-induced inhibition was not affected by the L-type calcium channel antagonist nimodipine, but was partially blocked by the N-type blocker omega-conotoxin GVIA, and completely occluded by omega-conotoxin MVIIC, a blocker of both N- and P/Q-type channels. The pharmacology of dorsal cell GABA(B) receptors was studied using two agonists, baclofen and CGP 27492, and four antagonists, CGP 35348, CGP 55845, phaclofen and saclofen. The inhibition induced by either of the two agonists was blocked by CGP 55845, phaclofen and saclofen. The antagonist CGP 35348 completely blocked the inhibition of HVA calcium current induced by the agonist CGP 27492, but had no effect on baclofen-induced GABA(B) receptor activation. This study thus demonstrates that GABA(B) receptor activation in lamprey mechanosensory neurons inhibits N- and P/Q-type calcium channels in a voltage- and G-protein-dependent manner.
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PMID:GABA(B) receptor activation inhibits N- and P/Q-type calcium channels in cultured lamprey sensory neurons. 1057 86

Postsynaptic GABA(B) receptor-mediated events have previously been shown to be reduced by prior treatment with pertussis toxin in rat brain. In the present study genetic absence epilepsy rats from Strasbourg (GAERS) were given single bilateral injections of pertussis toxin (PTx 0.4 microg), denatured-PTx or vehicle saline into the relay nuclei of the thalamus under anaesthesia. After recovery the spike and wave discharge duration (SWD) was monitored for up to 6 days following which the brains were removed and GABA(B) or GABA(A) receptor autoradiography performed on 10 microm transverse sections. By 6 days the SWD of the rats treated with PTx was suppressed by 96% compared with vehicle-injected rats with a significant (62%) reduction even after 1 day. Denatured toxin had no effect at any time. After 6 days GABA(B), but not GABA(A), receptor binding was significantly reduced by 70-80% in the ventrolateral and ventral posteriolateral thalamic nuclei. No changes in other brain regions were detected and denatured toxin failed to alter GABA(A) or GABA(B) receptor binding in any brain region. These data implicate G-protein mechanisms in the generation of SWD in GAERS and support the role of GABA(B) receptors in their induction within the thalamus.
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PMID:Pertussis toxin decreases absence seizures and GABA(B) receptor binding in thalamus of a genetically prone rat (GAERS). 1058 85

Neuronal GABA(B) receptors regulate calcium and potassium currents via G-protein-coupled mechanisms and play a critical role in long-term inhibition of synaptic transmission in the CNS. Recent studies have demonstrated that assembly of GABA(B) receptor GABA(B)R1 and GABA(B)R2 subunits into functional heterodimers is required for coupling to potassium channels in heterologous systems. However whether heterodimerization is required for the coupling of GABA(B) receptors to effector systems in neurons remains to be established. To address this issue, we have studied the coupling of recombinant GABA(B) receptors to endogenous Ca(2+) channels in superior cervical ganglion (SCG) neurons using nuclear microinjection to introduce both sense and antisense expression constructs. Patch-clamp recording from neurons injected with both GABA(B)R1a/1b and GABA(B)R2 cDNAs or with GABA(B)R2 alone produced marked baclofen-mediated inhibition of Ca(2+) channel currents via a pertussis toxin-sensitive mechanism. The actions of baclofen were blocked by CGP62349, a specific GABA(B) antagonist, and were voltage dependent. Interestingly, SCGs were found to express abundantly GABA(B)R1 but not GABA(B)R2 at the protein level. To determine whether heterodimerization of GABA(B)R1 and GABA(B)R2 subunits was required for Ca(2+) inhibition, the GABA(B)R2 expression construct was microinjected with a GABA(B)R1 antisense construct. This resulted in a dramatic decrease in the levels of the endogenous GABA(B)R1 protein and a marked reduction in the inhibitory effects of baclofen on Ca(2+) currents. Therefore our results suggest that in neurons heteromeric assemblies of GABA(B)R1 and GABA(B)R2 are essential to mediate GABAergic inhibition of Ca(2+) channel currents.
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PMID:Heteromeric assembly of GABA(B)R1 and GABA(B)R2 receptor subunits inhibits Ca(2+) current in sympathetic neurons. 1075 39

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


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