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Query: UNIPROT:P06889 (Mol)
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Nitrendipine and other dihydropyridine voltage-sensitive calcium channel (VSCC) antagonists have been demonstrated to possess anticonvulsant and neuroprotectant activity in a variety of model systems. Likewise, antagonists of the N-methyl-D-aspartate (NMDA) glutamate receptor subtype act as potent anticonvulsant and neuroprotective agents. Both VSCC and NMDA antagonists exert their effects by inhibiting the neuronal influx of calcium associated with activation of VSCCs or the NMDA receptor, respectively. Although results that provide evidence for crossreactivity between compounds acting at dihydropyridine-sensitive VSCCs and the NMDA receptor-channel complex have been reported, direct modulation of NMDA receptor function by dihydropyridines has not been demonstrated. In the present investigation, we report that nanomolar concentrations of nitrendipine reduced NMDA/glycine-evoked calcium flux and single-channel current in mouse cerebellar granule cell cultures. As measured with the calcium-specific probe indo-1, nitrendipine (0.1-10 microM) attenuated inward calcium flux evoked by bath application of NMDA (100 microM) and glycine (100 microM), in a concentration-dependent (IC50, 0.56 +/- 0.21 microM; 95% confidence interval, 0.19-1.3 microM) and reversible manner. Over a similar concentration range (0.01-100 microM), nitrendipine also inhibited the binding of [3H]MK-801 to mouse cortical and hippocampal membranes (IC50, 0.56 +/- 0.12 microM; 95% confidence interval, 0.37-0.84 microM). Finally, nitrendipine concentration- and voltage-dependently reduced the frequency of NMDA (10 microM)- and glycine (1 microM)-evoked single-channel openings and bursts recorded from excised outside-out patches of mouse cerebellar granule cells. These results indicate that nitrendipine suppresses NMDA/glycine-mediated calcium influx by a rapid and direct interaction with the NMDA receptor-channel complex. Furthermore, these results suggest that the interaction of nitrendipine with the NMDA receptor-channel complex is not tissue specific and probably does not require participation of calcium-dependent second messenger systems. Together, the data presented here support the novel hypothesis that nitrendipine may exhibit anticonvulsant and neuroprotectant activity via the combined ability to modulate both NMDA-associated ion channels and L-type VSCCs.
Mol Pharmacol 1993 Aug
PMID:The dihydropyridine nitrendipine modulates N-methyl-D-aspartate receptor channel function in mammalian neurons. 839 97

In this study we have shown, by in situ hybridization and RNase protection assay, a significant trkC mRNA increase confined to the dentate gyrus of hippocampus, both after seizures induced by intracerebroventricular injection of kainic acid and bicuculline. Moreover, after bicuculline treatment we observed an earlier increase of trkC mRNA level, which peaked after 3 h and returned back to normal levels by 12 h. In contrast, the kainic acid treatment produced a delayed increase of trkC mRNA, which initiated after 6 h, peaked at 12 h, and returned to normal levels at 24 h. This increase, which involves also trkC mRNA receptor with tyrosine kinase activity, was mediated by non-NMDA receptors and counteracted by GABA potentiating agent diazepam. Using embryonic neuronal cultures from cerebral hemispheres, including hippocampus, we found that glutamate receptor agonists, including glutamate, kainate, NMDA, and t-ACPD, increase trkC mRNA levels with the following rank order of efficacy: NMDA > t-ACPD > kainic acid > glutamate. In conclusion, our data show that trkC mRNA expression in granule cells of the hippocampus dentate gyrus is increased during seizure activity and that it is mediated by non-NMDA receptors.
J Mol Neurosci 1995
PMID:Seizures increase trkC mRNA expression in the dentate gyrus of rat hippocampus. Role of glutamate receptor activation. 856 16

Similar to the gamma-aminobutyric acidA receptor and the N-methyl-D-aspartate subtype of glutamate receptor, neuronal nicotinic acetylcholine receptors are subject to positive modulatory control by allosterically acting ligands. Exogenous ligands such as galanthamine and the neurotransmitter 5-hydroxytryptamine, when applied in submicromolar concentrations with nicotinic agonists, significantly increase the frequency of opening of nicotinic receptor channels and potentiate agonist-activated currents. Because these effects have been shown to be blocked by the monoclonal antibody FK1, they are mediated by binding sites that are located on alpha subunits of nicotinic receptors and distinct from those for acetylcholine and acetylcholine-competitive ligands. At higher concentrations, the potentiating effect of these ligands decreases and is eventually overcome by an inhibition of the agonist-induced response. The sensitizing actions of galanthamine, 5-hydroxytryptamine, and related compounds, at submicromolar concentrations, may reflect the existence of cross-talk between adjacent neuroreceptors and synapses in the central nervous system and thus suggests the formation of transiently active chemical networks in the vertebrate brain.
Mol Pharmacol 1996 Jan
PMID:Agonist responses of neuronal nicotinic acetylcholine receptors are potentiated by a novel class of allosterically acting ligands. 856 94

The excitatory amino acids (EAA), L-glutamate and L-aspartate were initially advanced as excitatory neurotransmitters some 30 years ago but in the past few years investigations on EAA have proceeded rapidly from the identification of the putative neurotransmitters and characterization of their receptors to the clarification of their role in development, learning, memory, and neuropathology. The NMDA(N-methyl-D-aspartate) class of glutamate receptor has been the subject of much recent interdisciplinary study, as NMDA receptors render over stimulated neurons susceptible to injury and death. This review is focused on the involvement of polyamines in EAA receptor-mediated neuronal signal transduction mechanisms.
Mol Cell Biochem
PMID:Excitatory amino acid receptor-mediated neuronal signal transduction: modulation by polyamines and calcium. 856 34

The RNA amplification technique was used to examine the pattern of coexpression of mRNAs encoding 16 subtypes/subunits of the glutamate receptor (GluR) in acutely dissociated neurons from adult rat striata. THe signal intensity for each mRNA varied within single neurons, but the general pattern of low versus high expression signals was similar among neurons, except for the GluR4 subunit of the (+/-)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. The mRNAs for GluR1-3 subunits of the AMPA receptor were present in all cells, with the signal intensity of GluR1 mRNAs usually the lowest. The kainate receptor subunit mRNAs (GluR5-7) were present in most neurons, and the signal intensity for GluR6 mRNA was the highest. The signals for N-methyl-D-aspartate (NMDA)R1 and NMDAR2B mRNAs were high in most neurons; however, NMDAR2A and NMDAR2C mRNAs gave low or undetectable signals. For mRNAs encoding metabotropic GluRs (mGluRs), signals for mGluR1, mGluR2, and mGluR3 mRNAs were low or undetectable, whereas mGluR4 and mGluR5 mRNA signals were high in most neurons. In most cases (12 of 16 mRNAs), the results agreed with data from in situ hybridization experiments in which individual mRNAs were examined. All neurons expressed subtypes/subunits mRNAs for all four types of GluRs; however, there were differences in the relative intensity of the mRNA signals detected in individual cells, suggesting that these receptors could exist in various combinations within individual neurons and thus confer synapse-specific function for information processing in the striatum.
Mol Pharmacol 1996 May
PMID:Multiplicity of glutamate receptor subunits in single striatal neurons: an RNA amplification study. 862 35

Two cDNA clones encoding putative ionotropic glutamate receptor subunits were isolated from a brain cDNA library of a freshwater fish, Oreochromis sp. The deduced amino acid sequences of these two cDNAs, fGluR2 alpha and fGluR2 beta, display the highest sequence identity (85%) to that of the rat GluR2 (AMPA receptor subunit) and they contain an arginine codon at the Q/R editing site of the TM2 segment. Genomic sequence analysis of the exons encoding the TM2 reveals the presence of an arginine codon at the Q/R site, suggesting that the RNA editing mechanism acting in the mammalian GluR2 does not operate at the homologous site in these two fish genes. In contrast to the absence of RNA editing at the Q/R site, transcripts of fGluR2 alpha and fGluR2 beta are subjected to RNA editing at a second site, the R/G site. A splicing variant of fGluR2 alpha, fGluR2 alpha-c, with a shorter C-terminal sequence was found; however, no C-terminal splicing variant of fGluR2 beta was detected in the mature fish. Similar to the mammalian AMPA receptor, variants created by the alternate choice of flip and flop modules were found among transcripts of fGluR2 alpha-c and fGluR2 beta. The amino acid sequences of flip and flop modules of fGluR2 beta are identical to that of the rat GluR2, whereas the amino acid sequences of the flip and flop modules of fGluR2 alpha-c differ from the invariant consensus sequences of the rat AMPA receptor subunits.
Brain Res Mol Brain Res 1996 Jan
PMID:Characterization of two fish glutamate receptor cDNA molecules: absence of RNA editing at the Q/R site. 871 47

Using in situ hybridization, we examined temporal changes of the EAAC1 glutamate transporter mRNA within the suprachiasmatic nuclei (SCN) of rats in constant darkness. Film autoradiographs showed that the SCN and supraoptic nuclei (SON) contained a marked density of hybridization signal. Analysis of silver grains per cell in emulsion-dipped sections indicated that cellular expression of EAAC1 mRNA in the SCN was elevated during the latter part of the subjective night and at the beginning of the subjective day, with a peak at circadian time 23.1 as determined by cosinor analysis. The times at which EAAC1 mRNA is highest correspond to the time points at which extracellular glutamate, a neurotransmitter that putatively mediates photic entrainment, has been reported to be low within the SCN. The presence of EAAC1 mRNA in the SCN and SON may partially explain the resistance of these nuclei to glutamate receptor-mediated excitotoxins; furthermore, the raised level preceding subjective dawn in the SCN may ensure sub-toxic levels of extracellular glutamate at the onset of photic stimulation during the LD cycle. In contrast, cellular expression of EAAC1 mRNA in the cingulate cortex and reticular thalamus remained constant at all time points studied. These results suggest that there is circadian control of the EAAC1 mRNA by the clock intrinsic to the SCN.
Brain Res Mol Brain Res 1996 Jan
PMID:Circadian variation of EAAC1 glutamate transporter messenger RNA in the rat suprachiasmatic nuclei. 871 55

Excessive activation of glutamate receptors is thought to play a critical role in neuronal excitotoxicity. To compare the cytotoxic potential of different glutamate receptor subtypes and correlate receptor biophysical properties with cytotoxicity, we have expressed recombinant receptors in human embryonic kidney 293 (HEK-293) cells. Survival of transfected cells was analyzed under conditions of defined agonist concentration and exposure time. For HEK-293 cells transfected with N-methyl-D-aspartate (NMDA) receptors, the EC50 for NMDA-induced cytotoxicity was 300 microM. Experiments using ion substitution, or cells expressing mutant NMDA receptors with low calcium permeability, suggested that both calcium and sodium influx through NMDA receptors contributed to cytotoxicity. In contrast, cytotoxicity was not observed in cells transfected with calcium permeable alpha-amino 3-hydroxy-5-methyl-4-isoxazole propionate- or kainate-type glutamate receptors even at saturating agonist concentrations, unless inhibitors of agonist-dependent desensitization were included. These results directly demonstrate that calcium permeability and desensitization kinetics play important roles in determining the excitotoxic potential of different glutamate receptor subtypes.
Mol Cell Neurosci 1996 Feb
PMID:Glutamate receptor ion channel properties predict vulnerability to cytotoxicity in a transfected nonneuronal cell line. 873 79

Low-molecular-weight kainate receptors from nonmammalian vertebrate brain belong structurally to the ionotropic glutamate receptor superfamily. In this study, two previously cloned goldfish kainate receptor subunits (GFKAR alpha and GFKAR beta) were transiently expressed in human embryonic kidney 293 cells, and their ligand-binding properties and some associated structural features were characterized, resulting in the following findings. 1) Both subunits form homomeric receptors with high affinity for [3H]kainate (KD = 16 and 31 nM, respectively) and L-glutamate (KD = 2 and 40 microM, respectively). 2) A deletion mutant lacking the originally proposed second-transmembrane domain was efficiently expressed and retains the overall ligand-binding properties of wild-type GFKAR alpha, strongly indicating that this region is not a transmembrane domain. 3) Mutations of Q12, A53, and Y54 of GFKAR beta indicate that these three residues are important for ligand binding (particularly L-glutamate), which is consistent with the sequence homology to bacterial periplasmic binding proteins. 4) Mutation of the three extracellular cysteine residues of GFKAR beta indicated that the two conserved cysteine residues (C305 and C385), located between two transmembrane segments, form a solvent-accessible disulfide bond. Analysis of [3H]kainate binding to wild-type and cysteine mutations of GFKAR beta indicate that in the absence of the disulfide bond, the affinity for kainate is increased 3-fold. These data lend further evidence in support of a model of glutamate receptor topology with three transmembrane segments and reveal several general structural features of the extracellular ligand-binding domain of the kainate receptors. These results are consistent with the notion that the ligand-binding domain has close structural similarities to bacterial periplasmic binding proteins.
Mol Pharmacol 1996 Oct
PMID:Ligand-binding characteristics and related structural features of the expressed goldfish kainate receptors: identification of a conserved disulfide bond and three residues important for ligand binding. 886 21

Kindling refers to a phenomenon in which repeated application of initially subconvulsive electrical stimulations produces limbic and clonic motor seizures of progressively increasing severity. Once established, the increased excitability is lifelong. Several lines of investigation suggest that the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor participates in the expression of the increased neuronal excitability of the kindled brain. Many studies demonstrate that kindling results in altered NMDA receptor functional and pharmacological properties, indicating that kindling may cause changes intrinsic to the NMDA receptor itself. It is possible that altered expression of NMDA receptor subunit genes and splice isoforms of genes leads to subunit combinations resulting in the novel NMDA receptor properties identified in the hippocampus of kindled animals. To begin to address this possibility, we previously examined the hippocampal expression of known NMDA receptor genes and found no differences in expression between control and kindled animals either 24 h or 28 days after the last kindled seizure. Here, we extend that earlier study by examining the expression of NMDAR1 splice isoforms in the hippocampus of control and kindled animals. We report that kindling induces the transient reduction of specific splice isoforms of NMDAR1 containing the first of the carboxy-terminal splice cassettes (exon 21). We discuss the potential significance of this regulation in terms of its relevance to previous findings in the kindling model and possible effects on NMDA receptor function.
Brain Res Mol Brain Res 1996 Sep 05
PMID:Regulation of alternative splicing of NMDAR1 in the kindling model. 888 39


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