)| PMID |
10627601 ( ) |
|---|---|
| Title | AMPA exposures induce mitochondrial Ca(2+) overload and ROS generation in spinal motor neurons in vitro. |
| Abstract | The reason for the selective vulnerability of motor neurons in amyotrophic lateral sclerosis (ALS) is primarily unknown. A possible factor is the expression by motor neurons of Ca(2+)-permeable AMPA/kainate channels, which may permit rapid Ca(2+) influx in response to synaptic receptor activation. However, other subpopulations of central neurons, most notably forebrain GABAergic interneurons, consistently express large numbers of these channels but do not degenerate in ALS. Indeed, when subjected to identical excitotoxic exposures, motor neurons were more susceptible than GABAergic neurons to AMPA/kainate receptor-mediated neurotoxicity. Microfluorimetric studies were performed to examine the basis for the difference in vulnerability. First, AMPA or kainate exposures appeared to trigger substantial mitochondrial Ca(2+) loading in motor neurons, as indicated by a sharp increase in intracellular Ca(2+) after addition of the mitochondrial uncoupler carbonyl cyanide p-(trifluoromethoxy)phenyl hydrazone (FCCP) after the agonist exposure. The same exposures caused little mitochondrial Ca(2+) accumulation in GABAergic cortical neurons. Subsequent experiments examined other measures of mitochondrial function to compare sequelae of AMPA/kainate receptor activation between these populations. Brief exposure to either AMPA or kainate caused mitochondrial depolarization, assessed using tetramethylrhodamine ethylester, and reactive oxygen species (ROS) generation, assessed using hydroethidine, in motor neurons. However, these effects were only seen in the GABAergic neurons after exposure to the nondesensitizing AMPA receptor agonist kainate. Finally, addition of either antioxidants or toxins (FCCP or CN(-)) that block mitochondrial Ca(2+) uptake attenuated AMPA/kainate receptor-mediated motor neuron injury, suggesting that the mitochondrial Ca(2+) uptake and consequent ROS generation are central to the injury process. 92697-4292, USA. Neuroscience |
NOTE: Color highlight is limited to the abstract and SciMiner text-mining mode. If you see much more identified targets below from "Targets by SciMiner Summary" and "Targets by SciMiner Full list", they may have been identified from the full text.
Targets by SciMiner Summary
| HUGO ID | Symbol | Target Name | #Occur | ActualStr |
|---|---|---|---|---|
| 4092 | GAD1 | glutamate decarboxylase 1 (brain, 67kDa) | 4 | GAD | |
| 4571 | GRIA1 | glutamate receptor, ionotropic, AMPA 1 | 3 | glutamate receptor | |
| 4572 | GRIA2 | glutamate receptor, ionotropic, AMPA 2 | 2 | GluR2 | |
| 9704 | PVALB | parvalbumin | 1 | parvalbumin | |
| 3229 | EGF | epidermal growth factor (beta-urogastrone) | 1 | epidermal growth factor | |
Targets by SciMiner Full list
| HUGO ID | Symbol | Name | ActualStr | Score | FlankingText |
|---|---|---|---|---|---|
| 4092 | GAD1 | glutamate decarboxylase 1 (brain, 67kDa) | GAD | 0.6 | GABAergic cortical neurons were labeled using glutamic acid decarboxylase (GAD; GAD Developmental Studies Hybridoma Bank at the University of Iowa Iowa |
| 4092 | GAD1 | glutamate decarboxylase 1 (brain, 67kDa) | GAD | 0.6 | solution at 1 6000 for SMI-32 and 1 500 for GAD were performed for 48-72 hr at 4degreeC |
| 4092 | GAD1 | glutamate decarboxylase 1 (brain, 67kDa) | GAD | 0.6 | for either SMI-32 (for for identifying spinal motor neurons or GAD (for for identifying GABAergic cortical neurons |
| 4572 | GRIA2 | glutamate receptor, ionotropic, AMPA 2 | GluR2 | 1.9 | Yin et al. 1994 may express low levels of the GluR2 AMPA subunit (which which confers Ca impermeability to heteromeric AMPA |
| 4572 | GRIA2 | glutamate receptor, ionotropic, AMPA 2 | GluR2 | 1.9 | both of these populations are comprised of AMPA subunits lacking GluR2 |
| 4092 | GAD1 | glutamate decarboxylase 1 (brain, 67kDa) | GAD | 0.6 | for SMI-32 GABAergic cortical neurons were identified by staining for GAD |
| 4571 | GRIA1 | glutamate receptor, ionotropic, AMPA 1 | glutamate receptor | 1.0 | considerable evidence supports a link between ca influx and glutamate receptor mediated neurodegeneration. |
| 3229 | EGF | epidermal growth factor (beta-urogastrone) | epidermal growth factor | 1.0 | glial cultures were prepared similarly except that tissue was obtained from early postnatal 1 3 d mice and plating media was supplemented with epidermal growth factor 10 ng/ml . |
| 4571 | GRIA1 | glutamate receptor, ionotropic, AMPA 1 | glutamate receptor | 1.0 | exposures were terminated by replacing the exposure solution with mem + glucose along with the ionotropic glutamate receptor antagonists mk 801 and nbqx both at 10 micro m and returning the cultures to the 37degreec 5% co 2 incubator. |
| 9704 | PVALB | parvalbumin | parvalbumin | 1.0 | indeed gabaergic interneurons are characterized by the strong expression of cbps including parvalbumin celio 1986 calretinin rogers 1992 and calbindin d28k hendry and jones 1991 . |
| 4571 | GRIA1 | glutamate receptor, ionotropic, AMPA 1 | glutamate receptor | 1.0 | although one must be careful in extrapolating findings in murine cultures to human disease it is notable that even across species motor neurons in vitro and in vivo seem to express similar glutamate receptor profiles and vulnerabilities to ampa/kainate receptor mediated injury. |