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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The influence of glutamate and its analogues on the expression of BDNF mRNA was studied in cultured cerebellar granule cells. Four-hour exposure of the neurons to the glutamate receptor agonists, quisqualate, kainate, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and N-methyl-D-aspartate (NMDA), increased levels of BDNF mRNA. Glutamate in combination with antagonists of the ionotropic glutamate receptors, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), D-2-amino-5-phosphonovalerate (AP-5) and/or (+)-5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine hydrogen maleate (MK-801), also increased levels of BDNF mRNA. However, the addition of glutamate itself to the cultures produced severe neuronal death and failed to increase the mRNA level. The onset of the increase in BDNF mRNA by kainate and NMDA lagged behind that by quisqualate. These results indicate that the non-ionotropic glutamate receptor might be involved in the induction of BDNF mRNA. Quisqualate is known to be a potent agonist of both the AMPA/kainate receptor and the metabotropic glutamate receptor. The specific antagonists of the AMPA/kainate receptor, CNQX and 6,7-dinitroquinoxaline-2,3-dione (DNQX) failed to block the increase of BDNF mRNA by quisqualate. Moreover, the desensitization of the metabotropic glutamate receptor by phorbol ester abolished the increase of BDNF mRNA by quisqualate. These results suggest that stimulation of the metabotropic glutamate receptor may be the most predominant component to increase BDNF mRNA in cerebellar granule cell culture.
Brain Res Mol Brain Res 1993 May
PMID:Glutamate receptor agonists enhance the expression of BDNF mRNA in cultured cerebellar granule cells. 768 81

Many actions of the classical gonadal and adrenal steroid hormones are at the level of transcriptional regulation. Recent studies have shown, however, that endogenous brain metabolites of steroids exert important nongenomic modulatory effects on neuronal mechanisms. Potentiation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor by the neurosteroid pregnenolone sulfate (PS) was studied using cultured hippocampal neurons and patch-clamp techniques. The magnitude of NMDA-activated whole-cell currents was approximately doubled in the presence of 100 microM PS. The dose-response curve of PS action showed significant potentiation above 250 nM and a half-maximal effect at approximately 29 microM. Maximum potentiation was reached within 25 sec, and the potentiation was completely reversed with 60 sec of washout. The enhancement of the NMDA current is probably not due to activation of a new ionic conductance, because the reversal potential of the I-V curve did not shift in the presence of PS. Potentiation is specific for the NMDA subtype of glutamate receptor; non-NMDA currents showed only a slight inhibition (approximately 6%) in the presence of 50 microM PS. Potentiation of the NMDA current by PS occurred in the presence of saturating concentrations of NMDA and glycine, indicating that at saturating concentrations of the coagonists PS does not change the affinity between the coagonists and the NMDA receptor. The dose-response relations for NMDA and glycine were shifted slightly to the left, and the percent potentiation was significantly higher for lower concentrations of coagonists, suggesting that at low concentrations of the coagonists PS may slightly increase their affinity for the NMDA receptor. The fractional open time (nPo) of single NMDA-activated channels was potentiated by PS in patch-clamp recordings using both the outside-out and cell-attached configurations. The potentiation of nPo resulted from increases in the frequency of opening and in the mean channel open time. No effect was seen on single-channel conductances.
Mol Pharmacol 1993 May
PMID:Pregnenolone sulfate potentiation of N-methyl-D-aspartate receptor channels in hippocampal neurons. 768 17

In primary cultures of striatal neurons, stimulation of N-methyl-D-aspartic acid (NMDA) receptors or associative activation (but not separate activation) of (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and metabotropic glutamate receptors (mGluR) strongly increased arachidonic acid (AA) release via activation of phospholipase A2 (PLA2). Depolarizing agents, such as veratridine, were as potent as NMDA in stimulating AA release. However, increasing the intracellular Ca2+ concentration via voltage-sensitive Ca2+ channels did not result in a significant stimulation of PLA2. Substitution of sodium by lithium, a monovalent cation that does not participate in the Na+/Ca2+ exchanger activity but permeates ionotropic glutamate receptor channels, blocked AA release induced by veratridine or AMPA plus mGluR agonists. It also reduced the NMDA-induced AA release, to a lesser extent. The contribution of the Na+/Ca2+ exchanger to the activation of PLA2 after veratridine, NMDA receptor, or AMPA receptor plus mGluR stimulation was confirmed by using a selective inhibitor of the Na+/Ca2+ exchanger.
Mol Pharmacol 1993 Jun
PMID:Stimulation by glutamate receptors of arachidonic acid release depends on the Na+/Ca2+ exchanger in neuronal cells. 768 47

Glutamate-mediated neurotransmission occurs through the activation of multimeric postsynaptic receptors. One mechanism by which functional diversity of glutamate responsiveness may occur is by a single cell expressing multiple receptors containing different subunits. In a direct test of this hypothesis, we examined the glutamate receptor subunit mRNA composition of several individual CA1 neurons in hippocampal slices. Experiments used amplified antisense RNA coupled with expression profiling and polymerase chain reaction amplification to identify and determine the relative amounts of subunit mRNAs co-localized in single cells. The results demonstrate that each CA1 neuron contains varying amounts of most glutamate receptor mRNAs. In addition to relative mRNA levels, the single-cell approach also highlighted other possible sources of receptor diversity. This included the existence of novel, alternatively spliced forms of the N-methyl-D-aspartate receptor type 1 and glutamate-kainate receptor type 2 subunits. Surprisingly, levels of N-methyl-D-aspartate receptor type 1 mRNA were relatively low, compared with those of other glutamate receptor mRNAs. One postulated source of potential heterogeneity, RNA editing, was not a general cellular mechanism. There was no evidence that glutamate receptor type 5 mRNA was edited in any of the cells that were examined. These data show that individual CA1 neurons, in the intact synaptic network of hippocampal slices, generate glutamate receptor mRNA diversity in several ways, which together contribute to the diversity of functional receptors observed electrophysiologically.
Mol Pharmacol 1993 Aug
PMID:Diversity of glutamate receptor subunit mRNA expression within live hippocampal CA1 neurons. 768 43

Concanavalin A, cyclothiazide, and aniracetam, ligands that modulate desensitization at glutamate receptors, were tested for their actions on responses at kainate-preferring receptors in dorsal root ganglion (DRG) neurons and at alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-preferring receptors in hippocampal neurons. In DRG neurons concanavalin A blocked desensitization produced by either kainate or 5-chlorowillardiine and strongly potentiated the peak amplitude of responses to both agonists. However, in hippocampal neurons concanavalin A produced only weak potentiation of responses to kainate and 5-chlorowillardiine, and after treatment with lectin responses to 5-chlorowillardiine remained strongly desensitizing. In contrast, cyclothiazide completely blocked desensitization produced by 5-chlorowillardiine in hippocampal neurons and strongly potentiated responses to kainate; the action of aniracetam was similar but much weaker. In DRG neurons cyclothiazide and aniracetam had no effect on desensitization and instead produced weak inhibition of responses to kainate. The different sensitivities of native AMPA- and kainate-preferring glutamate receptors to cyclothiazide and concanavalin A should prove useful for the differentiation of glutamate receptor subtypes in other areas of the central nervous system.
Mol Pharmacol 1993 Sep
PMID:Differential modulation by cyclothiazide and concanavalin A of desensitization at native alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid- and kainate-preferring glutamate receptors. 769 Apr 48

The functional effects of G protein-linked glutamate receptor activation have been studied in mouse mesencephalic neurons in vitro. We have been able to identify two receptor classes, one linked to phosphoinositide hydrolysis and another that inhibits adenylate cyclase. The agonist (1S,3R)-aminocyclopentane-1,3-dicarboxylate (ACPD) affected the two responses with similar potency (EC50 = 2 and 7 microM, respectively). In contrast, (2S,3S,4S)-alpha-(carboxycyclopropyl)glycine selectively decreased adenylate cyclase activity (EC50 = 150 nM), without interfering with the phosphoinositide pathway. Activation of ion channel-linked glutamate receptors in mesencephalic neurons leads to cGMP formation. In this study, we demonstrate that cell pretreatment with ACPD or (2S,3S,4S)-alpha-(carboxycyclopropyl)glycine prevented, in a dose-dependent fashion, N-methyl-D-aspartate (NMDA)-induced cGMP formation but not the kainate-stimulated response. The pharmacological profile suggests that receptors that are negatively coupled to adenylate cyclase are responsible for this effect. Coexposure of neurons to ACPD and Ba2+, a K+ channel blocker, counteracted the ACPD-induced blockade of NMDA receptors, suggesting that activation of K+ conductances could be involved in the post-transduction events triggered by metabotropic receptors in the mesencephalon. Neuronal treatment with NMDA for 10 min caused a reduction in mitochondrial activity. Direct inhibition of nitric oxide synthase with the inhibitor NG-nitro-L-arginine or removal of extracellular nitric oxide with reduced hemoglobin did not prevent this metabolic impairment, thus excluding a role for nitric oxide in this test for excitotoxicity. On the contrary, the mitochondrial function was maintained when neurons exposed to NMDA were preincubated with metabotropic receptor agonists. To summarize, our results suggest that metabotropic receptors that are negatively coupled to adenylate cyclase exert modulatory control specifically on NMDA receptor activity. This event could also contribute to the reduction of neurotoxic effects due to NMDA receptor hyperactivity.
Mol Pharmacol 1995 May
PMID:Metabotropic glutamate receptors negatively coupled to adenylate cyclase inhibit N-methyl-D-aspartate receptor activity and prevent neurotoxicity in mesencephalic neurons in vitro. 774 73

Prolonged exposure of cultured cortical cells or cultured cerebellar granule cells to the residue 25-35 fragment of beta-amyloid peptide (beta AP), beta AP(25-35), induced neuronal apoptosis, as revealed by morphological analysis, fluorescent chromatin staining, and immunodetection of oligonucleosomes released from the nucleus into the cytoplasm. beta AP(25-35)-induced apoptosis was insensitive to ionotropic glutamate receptor antagonists but was substantially attenuated by the metabotropic glutamate receptor (mGluR) agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid. The neuroprotective action of (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid was antagonized by (RS)-alpha-methyl-4-carboxyphenylglycine and was mimicked by (2S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine (a selective agonist of mGluR2 and -3 subtypes) and by L-2-amino-4-phosphobutanoate and L-serine-O-phosphate (selective agonists of mGluR4, -6, and -7 subtypes). However, whereas all of these drugs behaved as neuroprotectants in cultured cortical cells, only L-2-amino-4-phosphobutanoate and L-serine-O-phosphate [and not (2S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine] reduced beta AP(25-35)-induced apoptosis in cultured cerebellar granule cells. The neuroprotective activity of mGluR agonists may be related to their ability to inhibit membrane Ca2+ conductance, because drugs that block voltage-sensitive Ca2+ channels, such as nimodipine or Co2+, could also attenuate beta AP(25-35)-induced apoptosis.
Mol Pharmacol 1995 May
PMID:Activation of metabotropic glutamate receptors protects cultured neurons against apoptosis induced by beta-amyloid peptide. 774 77

The editing status of mRNA at the Q/R site of the glutamate receptor subtypes -A, -B, -5 and -6 modulates channel conductivity and ion selectivity of glutamate operated ion channels [4,15,26,30]. In order to investigate whether a modification of this editing process may be involved in kindling epileptogenesis, the percentage of edited variant was determined in the hippocampus of kindled rats and compared to the percentage in control animals. In the latter, GluR-A mRNA was detected only in the unedited form (with detection threshold for edited form < 0.7%), whereas GluR-B was completely edited (> 99%). For percentages were not significantly changed in Schaffer collateral/commissural pathway kindled animals that were sacrificed 24 h after the last generalized seizure. It is concluded that the increased sensitivity for the induction of seizures characteristic for Schaffer collateral kindled animals is not related to a less selective or less efficient mRNA editing process of the different glutamate receptor subunits in the hippocampus.
Brain Res Mol Brain Res 1995 Mar
PMID:Editing status at the Q/R site of glutamate receptor-A, -B, -5 and -6 subunit mRNA in the hippocampal kindling model of epilepsy. 776 99

We have recently reported that the majority of cultured rat cerebellar granule neurons undergo apoptosis when maintained in the presence of physiological concentrations of K+ (nondepolarizing conditions). We now report that exposure of cultured cerebellar granule neurons, maintained under nondepolarizing conditions, to the muscarinic cholinergic receptor (mAchR) agonists carbachol and muscarine results in a concentration- and time-dependent inhibition of apoptosis. The nicotinic cholinergic receptor agonist (-)-nicotine fails to mimic, and the nicotinic cholinergic receptor antagonist dihydro-beta-erythroidine fails to antagonize, the survival-promoting effects of carbachol. In contrast, relatively low concentrations of atropine completely prevent the effects of carbachol in blocking apoptotic death of cultured granule neurons. Although the m1- and m2-preferring mAchR antagonists pirenzepine and gallamine, respectively, fail to reverse the effects of carbachol, the m3-preferring antagonist 4-diphenylacetoxyl-N- methylpiperidine methiodide completely blocks the survival-promoting effects of carbachol. These data demonstrate that activation of the mAchR (possibly of the m3 subtype) blocks apoptosis of cultured cerebellar granule neurons. The antiapoptotic effects of mAchR agonists are not indirectly mediated via glutamate release from granule neurons, because antagonists of either N-methyl-D-aspartate or non-N-methyl-D-aspartate glutamate receptors fail to affect the antiapoptotic effects of carbachol or muscarine. Moreover, exposure of cultured cerebellar granule neurons to antiapoptotic concentrations of carbachol, in contrast to high concentrations of K+ or glutamate receptor agonists, results in only a small and transient elevation of the intracellular Ca2+ concentration, as measured by fura-2 microfluorimetry. Slow neurotransmitters such as acetylcholine, acting via their cognate G protein-coupled receptors, may prevent neuronal apoptosis in the developing (and perhaps adult) central nervous system.
Mol Pharmacol 1995 Feb
PMID:Activation of muscarinic cholinergic receptors blocks apoptosis of cultured cerebellar granule neurons. 787 32

Prenatal ethanol exposure-induced alteration in poly-phosphoinositide (PPI) hydrolysis stimulated by excitatory amino acids (EAA) was studied in rat cerebellar granule cells previously labeled with [3H]myoinositol. The prenatal exposure to ethanol was achieved via maternal consumption of a Sustacal (chocolate flavored) liquid diet containing either 5% ethanol (w/v, 35% of calories) or isocaloric sucrose (pair-fed) substituted for ethanol from gestation d 11 until the day of parturition. The ionotropic glutamate receptor agonists, N-methyl-D-aspartate, kainate or (+/-)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) (100 microM each) induced a two- to four-fold increase in PPI hydrolysis over the basal level, regardless of the liquid dietary treatment. Stimulation with quisqualate (QA), an agonist activating both metabotropic and ionotropic glutamate receptors, resulted in a much stronger and dose-dependent response in PPI hydrolysis and exposure in utero to ethanol significantly reduced this response. Tetrodotoxin, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), or (+/-)-3-(2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid (CPP) had no effect on QA-stimulated PPI hydrolysis nor on the suppression of this hydrolysis by ethanol. Exposure in utero to ethanol did not affect PPI hydrolysis stimulated by a selective metabotropic glutamate receptor agonist, trans-(+/-)-l-amino-1,3-cyclopentanedicarboxylic acid (t-ACPD). Although the PPI hydrolysis stimulated by t-ACPD could be blocked by (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG), an antagonist of the metabotropic glutamate receptor, MCPG was incapable of affecting QA-induced PPI hydrolysis and the suppressive effects of prenatal ethanol exposure on this hydrolysis. Taken together, the data suggest that the long-lasting suppressive effects of prenatal ethanol exposure on QA-stimulated PPI hydrolysis in cerebellar granule cell cultures is through a metabotropic QA receptor pathway that may be different from the one activated by t-ACPD.
Mol Chem Neuropathol 1994 Sep
PMID:Prenatal ethanol exposure reduces phosphoinositide hydrolysis stimulated by quisqualate in rat cerebellar granule cell cultures. 789 31


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