Tags

Type your tag names separated by a space and hit enter

AMPA exposures induce mitochondrial Ca(2+) overload and ROS generation in spinal motor neurons in vitro.
J Neurosci. 2000 Jan 01; 20(1):240-50.JN

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.

Authors+Show Affiliations

Department of Neurobiology and Behavior, University of California, Irvine, 92697-4292, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

10627601

Citation

Carriedo, S G., et al. "AMPA Exposures Induce Mitochondrial Ca(2+) Overload and ROS Generation in Spinal Motor Neurons in Vitro." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 20, no. 1, 2000, pp. 240-50.
Carriedo SG, Sensi SL, Yin HZ, et al. AMPA exposures induce mitochondrial Ca(2+) overload and ROS generation in spinal motor neurons in vitro. J Neurosci. 2000;20(1):240-50.
Carriedo, S. G., Sensi, S. L., Yin, H. Z., & Weiss, J. H. (2000). AMPA exposures induce mitochondrial Ca(2+) overload and ROS generation in spinal motor neurons in vitro. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 20(1), 240-50.
Carriedo SG, et al. AMPA Exposures Induce Mitochondrial Ca(2+) Overload and ROS Generation in Spinal Motor Neurons in Vitro. J Neurosci. 2000 Jan 1;20(1):240-50. PubMed PMID: 10627601.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - AMPA exposures induce mitochondrial Ca(2+) overload and ROS generation in spinal motor neurons in vitro. AU - Carriedo,S G, AU - Sensi,S L, AU - Yin,H Z, AU - Weiss,J H, PY - 2000/1/11/pubmed PY - 2000/1/11/medline PY - 2000/1/11/entrez SP - 240 EP - 50 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J Neurosci VL - 20 IS - 1 N2 - 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. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/10627601/AMPA_exposures_induce_mitochondrial_Ca_2+__overload_and_ROS_generation_in_spinal_motor_neurons_in_vitro_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=10627601 DB - PRIME DP - Unbound Medicine ER -