Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.9.3.1 (cytochrome oxidase)
 8,822 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

After nigrostriatal dopaminergic denervation, the output nuclei of the basal ganglia, the medial globus pallidus and substantia nigra pars reticulata (Snr), become overactive, in part, because of increased activity of excitatory afferents from the subthalamic nucleus (STN). Because STN uses glutamate as a transmitter, we examined whether there are regulatory changes in glutamate receptor binding in the basal ganglia. Rats received unilateral 6-hydroxydopamine lesions of the medial forebrain bundle and substantia nigra pars compacta that were confirmed by apomorphine-induced rotation and 3H-GBR-12935 binding. As an indirect index of relative synaptic activity, succinate dehydrogenase and cytochrome oxidase activities were assayed histochemically in sections adjacent to those used for receptor binding. There were increases in enzymatic activity in entopeduncular nucleus (EP; the rodent homolog of medial globus pallidus), SNr, and globus pallidus (GP, the rodent homolog of lateral globus pallidus) in the lesioned hemisphere, suggesting increased synaptic activity, perhaps due to increased firing of the STN. Ipsilateral to the lesion, and postsynaptic to the STN, there were profound decreases in the binding of 3H-AMPA (alpha-amino-3-hydroxy-5-methylisoxazole propionic acid) in EP and SNr (45% and 30%, respectively); there were no alterations in the striatum, globus pallidus, or STN, and binding throughout the unlesioned hemisphere was equivalent to that in unlesioned control animals. In contrast, 3H-MK-801 binding to the NMDA receptor ion channel was not reduced in SNr, and was too low to be measured reliably in EP and STN. 3H-MK-801 binding was reduced by 6% in striatum and 39% in globus pallidus.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Polysynaptic regulation of glutamate receptors and mitochondrial enzyme activities in the basal ganglia of rats with unilateral dopamine depletion. 796 8

Excitotoxicity and defects in neuronal energy metabolism have both been implicated in the pathogenesis of neurodegenerative disease. These two mechanisms may be linked through the NMDA receptor, activation of which is dependent on neuronal membrane potential. Because the ability to maintain membrane potential is dependent on neuronal energy metabolism, bioenergetic defects may affect NMDA receptor-mediated excitotoxicity. We now report that reversible inhibition of succinate dehydrogenase (SDH), an enzyme central to both the tricarboxylic acid cycle and the electron transport chain, produces an "excitotoxic" lesion in rat striatum that can be blocked by the NMDA antagonist MK-801. Male Sprague-Dawley rats received intrastriatal stereotaxic injections of the SDH inhibitor malonic acid (1 or 2 mumol) in combination with intraperitoneal injections of vehicle or MK-801 (5 mg/kg) 30 min before and 210 min after malonic acid. Animals were killed 72 h after surgery, and brains were processed for histology, cytochrome oxidase activity, and [3H]MK-801 and [3H]AMPA autoradiography. The higher dose of malonic acid (2 mumol) produced large lesions that were markedly attenuated by treatment with MK-801 (28.1 +/- 3.6 vs. 4.7 +/- 2.6 mm3; p < 0.001). [3H]MK-801 and [3H]AMPA binding were reduced in the lesions by 60 and 63%, respectively. One micromole of malonic acid produced smaller lesions that were almost completely blocked by MK-801 treatment (9.6 +/- 1.3 vs. 0.06 +/- 0.04 mm3; p < 0.0001). The toxic effects of malonic acid were due specifically to inhibition of SDH inasmuch as coinjection of a threefold excess of succinate with the malonic acid blocked the striatal lesions (p < 0.002).(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Inhibition of succinate dehydrogenase by malonic acid produces an "excitotoxic" lesion in rat striatum. 836 Jun 80

Subunit proteins that comprise functional AMPA receptors were localized by immunocytochemical methods in the adult macaque primary visual cortex (V1). GluR1, GluR2/3/4c, and GluR4 immunoreactivity consisted of rich plexuses of punctate profiles scattered throughout the neuropil, in radial arrays, and outlining the membrane of somata and proximal dendrites. Cytoplasmic immunoreactivity was limited. GluR2/3/4c immunostaining was more prominent along the somata surface and exhibited greater levels of cytoplasmic immunoreactivity than GluR1 and GluR4 immunostaining. The density of AMPA subunit immunoreactive elements also varied across layers and compartments of macaque V1. Immunoreactivity for GluR1, GluR2/3/4c, and GluR4 was densest in three bands that corresponded to layers IVA, IVC, and VI. Immunostaining for each subunit was also unevenly distributed within many of the layers. In layers II-III, patches of intense immunostaining coincided with cytochrome oxidase (CO)-rich blobs. In layer IVA, intense subunit staining formed a conspicuous honeycomb pattern. In layer IVC, subunit staining formed a radial lattice. GluR2/3/4c subunit immunostaining was also preferentially distributed within the CO-rich blobs of layers V-VI. These findings demonstrate that AMPA subunit immunoreactivity is densely concentrated in layers and compartments receiving direct geniculocortical innervation. This distribution, which differs from that of excitatory synapses, suggests that the density of AMPA receptors is unevenly distributed at synaptic and possibly extrasynaptic sites within macaque visual circuits.
 ...
PMID:Immunocytochemical characterization of AMPA-selective glutamate receptor subunits: laminar and compartmental distribution in macaque striate cortex. 909 68

Evidence is increasing that mitochondrial dysfunction is involved in amyotrophic lateral sclerosis, a neurodegenerative disease characterized by selective motoneuron death. To study the role of mitochondrial dysfunction in the pathways leading to motoneuron death, we developed an in vitro model of chronic motoneuron toxicity, based on malonate-induced inhibition of complex II in the mitochondrial electron transport chain. Treatment with malonate resulted in a dose-dependent decrease in cellular ATP levels. We observed that motoneurons were significantly more vulnerable to mitochondrial inhibition than control neurons in the dorsal horn. We could reproduce this dose-dependent phenomenon with the complex IV inhibitor sodium azide. The free radical scavenger alpha-phenyl-N-tert-butylnitrone, the AMPA/kainate receptor blocker 6-cyano-7-nitroquinoxaline-2,3-dione, and riluzole, a drug that is currently used for the treatment of amyotrophic lateral sclerosis, were protective against malonate-induced motoneuron death. Furthermore, the caspase inhibitors N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone and z-Asp-Glu-Val-Asp-fluoromethyl ketone were both protective against malonate toxicity. Our model shows that chronic mitochondrial inhibition leads to selective motoneuron death, which is most likely apoptotic.
 ...
PMID:Chronic mitochondrial inhibition induces selective motoneuron death in vitro: a new model for amyotrophic lateral sclerosis. 1069 48

Glutamate and its various receptors are known to play an important role in excitatory synaptic transmission throughout the CNS, including the primary visual cortex. Among subunits of the AMPA receptors (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid), subunit 2 (GluR2) is of special significance because it controls their Ca2+ permeability. In the past, this subunit has been studied mostly in conjunction with other AMPA subunits. The present study sought to determine if GluR2 alone has a distinct laminar distribution in the normal macaque visual cortex, and if its pattern correlated with that of cytochrome oxidase (CO) under normal and monocularly deprived conditions. In the normal adult cortex, GluR2 immunoreactivity (ir) had a patchy distribution in layers II/III, in register with CO-rich puffs. GluR2-ir highlighted the upper border of layer II, the lower border of layer IV (previously termed IVC(beta dark)) and, most prominently, layer VI. Labeled neurons were primarily of the pyramidal type present in the upper border and lower half of layer VI, layers II/III, and scattered in layers V and upper IVB. Labeled nonpyramidal cells were large in layer IVB and small in IVC(beta dark). Notably, the bulk of CO-rich layers IVC and IVA had very low levels of GluR2-ir. At fetal day 13, however, GluR2 labeling showed a honeycomb-like pattern in layer IVA not found in the adult. A fragment of GluR2 cDNA was generated from a human cDNA library, and in situ hybridization revealed an expression pattern similar to that of GluR2 proteins. After 1-4 weeks of monocular impulse blockade with tetrodotoxin (TTX), alternating rows of strong and weak GluR2-ir in layers VI and II/III appeared in register with CO-labeled dark and light ocular dominance columns in layer IVC and puffs in II/III, respectively. Our results indicate that various cortical layers are differentially influenced by glutamate. The bulk of the major geniculate-recipient layers IVC and IVA have low levels of GluR2, presumably favoring synaptic transmission via Ca(2+)-permeable glutamate receptors. GluR2 plays a more important role in supragranular and infragranular layers, where the initial geniculate signals are further modified and are transmitted to other cortical and subcortical centers. The maintenance of GluR2 in these output layers is governed by visual input and neuronal activity, as monocular impulse blockade induced a down-regulation of this subunit in deprived ocular dominance columns.
 ...
PMID:AMPA glutamate receptor subunit 2 in normal and visually deprived macaque visual cortex. 1250 23

Ionotropic glutamate receptors, the principal excitatory neurotransmitter receptors in the CNS, are classified into NMDA and non-NMDA subtypes. Previously, we found a direct relationship between neuronal activity and NMDA receptor subunit 1 in rat primary neuronal cultures and monkey visual cortex. The present study focused on the relationship between neuronal activity and subunit 2 of AMPA glutamate receptor, GluR2. GluR2 controls Ca(2+) permeability of AMPA receptors, and the transcription of its gene is activated by nuclear respiratory factor 1, which also activates the transcription of a few subunit genes of cytochrome oxidase (CO). Primary neuronal cultures of postnatal rat visual cortex were subjected to impulse blockade with tetrodotoxin (TTX) for 6 days, or 20 mM KCl depolarizing treatment for 1, 2, 5, 10, 20, 30, and 40 hrs. After 20 hrs of KCl treatment, GluR2 immunoreactivity and CO activity were significantly increased above controls (P < 0.01), and both remained high at 30 and 40 hrs of treatment. However, GluR2 mRNA level as shown by in situ hybridization was already up-regulated above controls after 10 hrs of KCl treatment (P < 0.01) and remained elevated with longer periods of depolarization. TTX blockade, on the other hand, induced a significant down-regulation of GluR2 immunoreactivity, GluR2 gene expression as well as CO activity (P < 0.01 for all). Our results indicate that both protein and mRNA expressions of GluR2 in cultured visual cortical neurons are tightly controlled by neuronal activity.
 ...
PMID:Neuronal activity regulates protein and gene expressions of GluR2 in postnatal rat visual cortical neurons in culture. 1461 2