Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.14.16.2 (tyrosine hydroxylase)
 14,760 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glutamate (Glu) released by olfactory nerve axons acts on postsynaptic ionotropic and metabotropic glutamate receptors expressed by principal neurones and interneurones of the olfactory bulb (OB). Using ZnSO4 lesioning of the rat olfactory mucosa and semiquantitative RT-PCR, we examined the effect of removal of the glutamatergic input to the OB on the expression of mGluR1a, mGluR1b and GluR1 mRNAs. Two days after lesioning, mGluR1a mRNA levels in OB increased by 45%. At this time, the expression of tyrosine hydroxylase (TH) mRNA, which is strictly dependent on olfactory nerve input, was still unchanged. In contrast, 16 days after lesioning, deafferented OB exhibited a decrease in both mGluR1a (-30%) and TH (-40%) mRNAs. GluR1 and mGluR1b mRNA levels were not affected at either time point. These results suggest that alterations in glutamatergic input to OB selectively modulate the expression of the mGluR1 splicing form possessing a longer C-terminal domain.
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PMID:Glutamatergic deafferentation of olfactory bulb modulates the expression of mGluR1a mRNA. 922 83

Dopamine neurons in the substantia nigra heavily innervate the striatum, making it the nucleus with the highest levels of dopamine in the adult brain. The present study analyzes the time course and the density of striatal innervation by nigral dopamine neurons and characterizes the role of the neurotransmitter glutamate during the development of the nigrostriatal pathway. For this purpose, organotypic cultures containing the cortex, the striatum, and the substantia nigra (triple cultures) were prepared from rat brains at postnatal day (PND) 0-2 and were cultured for up to 60 d in vitro (DIV). Dopamine fibers and neurons were labeled using tyrosine hydroxylase (TH) immunohistochemistry. Striatal TH-ir fiber density was quantitatively analyzed using confocal laser scanning microscopy (CLSM). In long-term triple cultures (44 +/- 3 DIV), the striatal dopamine fiber density was high and was weakly correlated with the number of nigral dopamine neurons. The high striatal dopamine fiber density mainly resulted from an enhanced ingrowth and ramification of dopamine fibers from nigral neurons during 8-17 DIV. The metabotropic glutamate receptor (mGluR) antagonist L(+)-2-amino-3-phosphonopropionic acid (L-AP-3) selectively inhibited this dopaminergic innervation of the striatum, whereas ionotropic GluR antagonists had no effect. The L-AP-3-mediated inhibition was prevented by the mGluR agonist 1S, 3R-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD). The inhibition of the striatal dopaminergic innervation by L-AP-3 was further confirmed by anterograde tracing of the nigrostriatal projection with Phaseolus vulgaris leucoagglutinin. These results indicate that glutamate, by acting on group I mGluRs, plays an important "trophic" role for the development of the nigrostriatal dopamine pathway.
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PMID:Regulation of the nigrostriatal pathway by metabotropic glutamate receptors during development. 959 93

The localization of glutamate receptors in the substantia nigra is of critical importance since glutamate receptor-mediated excitotoxicity is implied in the cause for the neuronal degeneration in Parkinson's disease. The major glutamatergic synaptic inputs to the substantia nigra originate in the subthalamic nucleus, in which hyperactivity is reported in Parkinson's disease. In order to compare directly the localization of different ionotropic and metabotropic glutamate receptors in the substantia nigra of the same animals, rats were perfuse-fixed under deep anesthesia. Sections of the substantia nigra were obtained and receptor immunocytochemistry was performed using commercially available antibodies (against subunits of ionotropic glutamate receptors: GluR1, GluR2/3, GluR4, NMDAR1, NMDAR2A/B; and subtypes of metabotropic glutamate receptors: mGluR1alpha, mGluR2/3). When compared to the localization of tyrosine hydroxylase immunoreactivity, immunoreactivity for GluR1, GluR2/3 and NMDARI was mainly localized in the perikarya and proximal dendrites of the compacta neurons and only in a few reticulata neurons. In contrast, GluR4 immunoreactivity was only detected in the reticulata neurons. Consistent results were obtained by double labeling experiments that revealed tyrosine hydroxylase and GluR1, GluR2/3, GluR4 or NMDAR1 immunoreactivity in the same sections. Immunoreactivity for NMDAR2A/B, mGluR1alpha. and mGluR2/3 was detected in the neuropil of the substantia nigra pars reticulata. No NMDAR2A/B- and mGluR2/3-immunoreactive perikarya were detected. However, a few neurons in the reticulata were found to be mGluR1alpha-immunoreactive. The present results indicate there is a differential localization of different subunits and subtypes of glutamate receptors in the substantia nigra and there may be functional implications in different neuronal elements in the substantia nigra in normal and in Parkinson's disease.
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PMID:Localization of ionotropic and metabotropic glutamate receptors in distinct neuronal elements of the rat substantia nigra. 984 Feb 22

Ionotropic glutamate receptors in the substantia nigra pars compacta regulate the activity of dopamine neurons. We have used dual-label immunofluoresence and confocal laser microscopy to study the localization of subunits of two types of ionotropic receptors within the substantia nigra pars compacta of the rat. Immunostaining for N-methyl-D-aspartate receptor 1 and glutamate receptor 2/3 was prominent in the soma and proximal dendrites of all tyrosine hydroxylase-immunopositive cells, while only low amounts of N-methyl-D-aspartate receptor 2A and N-methyl-D-aspartate receptor 2B were present. Selective antibodies were used to determine the isoforms of N-methyl-D-aspartate receptor 1 present. Immunostaining for the N1, C1 and C2 variably spliced segments of N-methyl-D-aspartate receptor 1 were scarce in the substantia nigra pars compacta, while immunoreactivity for the alternative C2' terminus of N-methyl-D-aspartate receptor 1 was quite abundant. Staining for glutamate receptor 1 was heterogeneous; about half of the tyrosine hydroxylase immunopositive cells stained intensely, while the other half were immunonegative. The glutamate receptor 1-stained cells were concentrated in the ventral tier of the substantia nigra pars compacta. Glutamate receptor 4 was not found in tyrosine hydroxylase-immunopositive cells within the substantia nigra pars compacta. Together, these data demonstrate that dopaminergic neurons in the substantia nigra pars compacta express primarily glutamate receptor 1, glutamate receptor 2/3 and N-methyl-D-aspartate receptor 1 isoforms containing the alternative C2' terminus.
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PMID:Immunohistochemical localization of N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor subunits in the substantia nigra pars compacta of the rat. 1005 Dec 30

Resting and evoked extracellular dopamine levels in the striatum of the anesthetized rat were measured by fast-scan cyclic voltammetry in conjunction with carbon fiber microelectrodes. Identification of the substance detected in vivo was achieved by inspection of background-subtracted voltammograms. Intrastriatal microinfusion of kynurenate, a broad-spectrum antagonist of ionotropic glutamate receptors, caused a decrease in the resting extracellular level of dopamine. The kynurenate-induced decrease was unaffected by systemic pretreatment with pargyline, an inhibitor of monoamine oxidase, but was significantly attenuated by systemic pretreatment with alpha-methyl-p-tyrosine, an inhibitor of tyrosine hydroxylase. Although glutamate by itself did not affect resting extracellular dopamine levels, glutamate did attenuate the kynurenate-induced decrease. Kynurenate decreased dopamine release in response to electrical stimulation of the medial forebrain bundle, an effect that was also attenuated by glutamate. These results suggest that both spontaneous and evoked dopamine release in the rat striatum are under the local tonic excitatory influence of glutamate. Interactions between central dopamine and glutamate systems that have been implicated in the etiologies of Parkinson's disease, schizophrenia, stress, and substance abuse. The precise nature of those interactions, however, remains a matter of some controversy.
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PMID:Glutamate regulates the spontaneous and evoked release of dopamine in the rat striatum. 1122 75

Adenosine and caffeine modulate locomotor activity and striatal gene expression, partially through the activation and blockade of striatal A(2A) receptors, respectively. The elucidation of the roles of these receptors benefits from the construction of A(2A) receptor-deficient mice (A(2A)-R(-/-)). These mice presented alterations in locomotor behaviour and striatal expression of genes studied so far, which are unexpected regarding the specific expression of A(2A) receptor by striatopallidal neurones. To clarify the functions of A(2A) receptors in the striatum and to identify the mechanisms leading to these unexpected modifications, we studied the basal expression of immediate early and constitutive genes as well as dopamine and glutamate neurotransmission in the striatum. Basal zif268 and arc mRNAs expression was reduced in mutant mice by 60-80%, not only in the striatum but also widespread in the cerebral cortex and hippocampus. Striatal expression of substance P and enkephalin mRNAs was reduced by about 50% and 30%, respectively, whereas the expression of GAD67 and GAD65 mRNAs was slightly increased and unaltered, respectively. In vivo microdialysis in the striatum revealed a 45% decrease in the extracellular dopamine concentration and three-fold increase in extracellular glutamate concentration. This was associated with an up-regulation of D(1) and D(2) dopamine receptors expression but not with changes in ionotropic glutamate receptors. The levels of tyrosine hydroxylase and of striatal and cortical glial glutamate transporters as well as adenosine A(1) receptors expression were indistinguishable between A(2A)-R(-/-) and wild-type mice. Altogether these results pointed out that the lack of A(2A) receptors leads to a functional hypodopaminergic state and demonstrated that A(2A) receptors are necessary to maintain a basal level in immediate early and constitutive genes expression in the striatum and cerebral cortex, possibly via their control of dopamine pathways.
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PMID:Functional striatal hypodopaminergic activity in mice lacking adenosine A(2A) receptors. 1143 85

To elucidate the morphological changes in immunopositive cells of ionotropic glutamate receptors within intrastriatal 'developing' grafts of fetal ventral mesencephalon (VM) in 6-hydroxydopamine-lesioned rats, immunohistochemistry was performed to detect cells expressing N-methyl-D-aspartate (NMDA) receptor subunit 1 (NR1), the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor subunits (GluR1, GluR2/3, and GluR4), or tyrosine hydroxylase (TH) in the intrastriatal VM grafts at 1, 4, and 12 weeks following transplantation. One week after transplantation, TH-positive cells were detected without any immunoreactivity of the NMDA and AMPA receptor subunits in the grafts. Four weeks after transplantation, TH-positive cells, distributed homogeneously in the grafts, appeared to be multipolar and larger compared to those at 1 week post-grafting. At this stage, we could observe immunopositive cells of NMDA and AMPA receptors distributed homogeneously in the grafts. Twelve weeks after transplantation, the numbers of NR1- and GluR1-positive cells were smaller than that at 4 weeks post-grafting, whereas TH-positive cells appeared to be more matured in shape and size. On the other hand, the numbers of GluR2/3- and GluR4-positive cells were not changed as compared with those at 4 weeks post-grafting. These results suggest that the ionotropic glutamate receptors have differential roles during the developmental period of the intrastriatal VM grafts.
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PMID:Morphological changes in immunopositive cells of ionotropic glutamate receptor subunits during the development of transplanted fetal ventral mesencephalic neurons. 1202 Aug 78

Immunohistochemical studies were conducted to assess the subunits of ionotropic and metabotropic glutamate receptor present in the rostral ventrolateral medulla (RVLM) of the rat. Double labeling the medullary sections with polyclonal GluR1, GluR2/3, GluR4, NMDAR1, NMDAR2A/B, mGluR1alpha, and mGluR2/3 antiserum and monoclonal tyrosine hydroxylase (TH) antiserum revealed nearly all TH immunoreactive (irTH) cells and many TH-negative neurons were immunoreactive to GluR2/3 (irGluR2/3), NMDAR1 (irNMDAR1), and NMDAR2A/B (irNMDAR2A/B). A few RVLM neurons were immunoreactive to GluR1 (irGluR1) and GluR4 (irGluR4), but they were generally TH-negative. Immunoreactivity to mGluR1alpha (irmGluR1alpha) appeared to be localized exclusively to fiber-like elements in the RVLM area. Our results show that neurons in the RVLM, including irTH, are endowed mainly with GluR2/3 and NMDAR1 or NMDAR2A/B ionotropic receptor subunits, and that irmGluR1alpha splice variant appears to be located on nerve fibers ramifying within the RVLM. Moreover, TH-negative neurons in the RVLM appear to bear similar subunits of ionotropic glutamate receptors.
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PMID:Glutamate receptor subunit immunoreactivity in neurons of the rat rostral ventrolateral medulla. 1214 41

The role of glutamate as a neurotransmitter in the zebrafish olfactory bulb (OB) was established by examining neuronal activation following 1). glutamate receptor agonist stimulation of isolated olfactory bulbs and 2). odorant stimulation of intact fish. Four groups of neurons (mitral cells, projection neurons; granule cells, juxtaglomerular cells, and tyrosine hydroxylase-containing cells; interneurons) were identified on the basis of cell size, cell location, ionotropic glutamate receptor (iGluR) agonist/odorant sensitivity, and glutamate, gamma-aminobutyric acid (GABA), and tyrosine hydroxylase immunoreactivity. Immunoreactive glutamate levels were highest in olfactory sensory neurons (OSNs) and mitral cells, the putative glutamatergic neurons. The sensitivity of bulbar neurons to iGluR agonists and odorants was established using a cationic channel permeant probe, agmatine (AGB). Agmatine that permeated agonist- or odor-activated iGluRs was fixed in place with glutaraldehyde and detected immunohistochemically. N-methyl-D-aspartic acid (NMDA) and alpha-amino-3-hydroxyl-5-methylisoxazole-4-propionic acid (AMPA)/kainic acid (KA) iGluR agonists and odorants (glutamine, taurocholic acid) stimulated activity-dependent labeling of bulbar neurons, which was blocked with a mixture of the iGluR antagonists, D-2-amino-5-phosphono-valeric acid (APV) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). The AMPA/KA antagonist CNQX completely blocked glutamine-stimulated AGB labeling of granule cells and tyrosine hydroxylase-containing cells, suggesting that, in these cell types, AMPA/KA receptor activation is essential for NMDA receptor activation. However, blocking AMPA/KA receptor activity failed to eliminate AGB labeling of mitral cells or juxtaglomerular cells. Collectively, these findings indicate that glutamate is the primary excitatory neurotransmitter in the zebrafish OB and that iGluR subtypes function heterogeneously in the bulbar neurons.
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PMID:Odor-stimulated glutamatergic neurotransmission in the zebrafish olfactory bulb. 1244 20

The distribution of N-methyl-D-aspartate- (NMDA) and kainic acid- (KA) sensitive ionotropic glutamate receptors (iGluR) in the zebrafish olfactory bulb was assessed using an activity-dependent labeling method. Olfactory bulbs were incubated with an ion channel permeant probe, agmatine (AGB), and iGluR agonists in vitro, and the labeled neurons containing AGB were visualized immunocytochemically. Preparations exposed to 250 microM KA in the presence of a NMDA receptor antagonist (D-2-amino-5-phosphono-valeric acid) and an alpha-amino-3-hydroxyl-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist (sym 2206), revealed KA receptor-mediated labeling of approximately 60-70% of mitral cells, juxtaglomerular cells, tyrosine hydroxylase-positive cells and granule cells. A higher proportion of ventral olfactory bulb neurons were KA-sensitive. Application of 333 microM NMDA in the presence of an AMPA/KA receptor antagonist (6-cyano-7-nitroquinoxaline-2,3-dione) resulted in NMDA receptor-mediated labeling of almost all neurons. The concentrations eliciting 50% of the maximal response (effective concentration: EC(50)s) for NMDA-stimulated labeling of different cell types were not significantly different and ranged from 148 microM to 162 microM. These results suggest that while NMDA receptors with similar binding affinities are widely distributed in the neurons of the zebrafish olfactory bulb, KA receptors are heterogeneously expressed among these cells and may serve unique roles in different regions of the olfactory bulb.
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PMID:Pharmacological characterization of ionotropic glutamate receptors in the zebrafish olfactory bulb. 1464 70


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