Potential conflict of interest: Nothing to report.
Glutamate receptors on myelinated spinal cord axons: I. GluR6 kainate receptors†
Article first published online: 17 FEB 2009
Copyright © 2009 American Neurological Association
Annals of Neurology
Volume 65, Issue 2, pages 151–159, February 2009
How to Cite
Ouardouz, M., Coderre, E., Basak, A., Chen, A., Zamponi, G. W., Hameed, S., Rehak, R., Yin, X., Trapp, B. D. and Stys, P. K. (2009), Glutamate receptors on myelinated spinal cord axons: I. GluR6 kainate receptors. Ann Neurol., 65: 151–159. doi: 10.1002/ana.21533
- Issue published online: 3 MAR 2009
- Article first published online: 17 FEB 2009
- Manuscript Accepted: 21 AUG 2008
- Manuscript Revised: 5 AUG 2008
- Manuscript Received: 17 JUN 2008
- NIH (National Institute of Neurological Diseases and Stroke)
- Canadian Institutes of Health Research
- Heart and Stroke Foundation of Ontario Center for Stroke Recovery
- Canadian Stroke Network
- HSFO (Heart and Stroke Foundation of Ontario) Career Investigator Award
- AHFMR (Alberta Heritage Foundation for Medical Research) Scientist Award
- CCRI (Center for Catalysis Research and Innovation collaborative fund
- Canada Research Chairs (Tier I)
The deleterious effects of glutamate excitotoxicity are well described for central nervous system gray matter. Although overactivation of glutamate receptors also contributes to axonal injury, the mechanisms are poorly understood. Our goal was to elucidate the mechanisms of kainate receptor–dependent axonal Ca2+ deregulation.
Dorsal column axons were loaded with a Ca2+ indicator and imaged in vitro using confocal laser-scanning microscopy.
Activation of glutamate receptor 6 (GluR6) kainate receptors promoted a substantial increase in axonal [Ca2+]. This Ca2+ accumulation was due not only to influx from the extracellular space, but a significant component originated from ryanodine-dependent intracellular stores, which, in turn, depended on activation of L-type Ca2+ channels: ryanodine, nimodipine, or nifedipine blocked the agonist-induced Ca2+ increase. Also, GluR6 stimulation induced intraaxonal production of nitric oxide (NO), which greatly enhanced the Ca2+ response: quenching of NO with intraaxonal (but not extracellular) scavengers, or inhibition of neuronal NO synthase with intraaxonal Nω-nitro-L-arginine methyl ester, blocked the Ca2+ increase. Loading axons with a peptide that mimics the C-terminal PDZ binding sequence of GluR6, thus interfering with the coupling of GluR6 to downstream effectors, greatly reduced the agonist-induced axonal Ca2+ increase. Immunohistochemistry showed GluR6/7 clusters on the axolemma colocalized with neuronal NO synthase and Cav1.2.
Myelinated spinal axons express functional GluR6-containing kainate receptors, forming part of novel signaling complexes reminiscent of postsynaptic membranes of glutamatergic synapses. The ability of such axonal “nanocomplexes” to release toxic amounts of Ca2+ may represent a key mechanism of axonal degeneration in disorders such as multiple sclerosis where abnormal accumulation of glutamate and NO are known to occur. Ann Neurol 2009