Potential conflict of interest: Nothing to report.
Glutamate receptors on myelinated spinal cord axons: II. AMPA and GluR5 receptors†
Article first published online: 17 FEB 2009
Copyright © 2009 American Neurological Association
Annals of Neurology
Volume 65, Issue 2, pages 160–166, February 2009
How to Cite
Ouardouz, M., Coderre, E., Zamponi, G. W., Hameed, S., Yin, X., Trapp, B. D. and Stys, P. K. (2009), Glutamate receptors on myelinated spinal cord axons: II. AMPA and GluR5 receptors. Ann Neurol., 65: 160–166. doi: 10.1002/ana.21539
- Issue published online: 3 MAR 2009
- Article first published online: 17 FEB 2009
- Manuscript Accepted: 29 AUG 2008
- Manuscript Revised: 25 AUG 2008
- Manuscript Received: 5 AUG 2008
- NIH (National Institute of Neurological Disorders and Stroke)
- Canadian Institutes of Health Research. Grant Numbers: #FRN 37858, #MOP 14172
- Heart and Stroke Foundation of Ontario Center for Stroke Recovery
- Heart and Stroke Foundation of Ontario Career Investigator Award
- Alberta Heritage Foundation for Medical Research Scientist Award
- private donors
- Canada Research Chairs (Tier 1)
Glutamate receptors, which play a major role in the physiology and pathology of central nervous system gray matter, are also involved in the pathophysiology of white matter. However, the cellular and molecular mechanisms responsible for excitotoxic damage to white matter elements are not fully understood. We explored the roles of AMPA and GluR5 kainate receptors in axonal Ca2+ deregulation.
Dorsal column axons were loaded with a Ca2+ indicator and imaged in vitro using confocal microscopy.
Both AMPA and a GluR5 kainate receptor agonist increased intraaxonal Ca2+ in myelinated rat dorsal column fibers. These responses were inhibited by selective antagonists of these receptors. The GluR5-mediated Ca2+ increase was mediated by both canonical (ie, ionotropic) and noncanonical (metabotropic) signaling, dependent on a pertussis toxin–sensitive G protein/phospholipase C–dependent pathway, promoting Ca2+ release from inositol triphosphate–dependent stores. In addition, the GluR5 response was reduced by intraaxonal NO scavengers. In contrast, GluR4 AMPA receptors operated via Ca2+-induced Ca2+ release, dependent on ryanodine receptors, and unaffected by NO scavengers. Neither pathway depended on L-type Ca2+ channels, in contrast with GluR6 kainate receptor action.1 Immunohistochemistry confirmed the presence of GluR4 and GluR5 clustered at the surface of myelinated axons; GluR5 coimmunoprecipitated with nNOS and often colocalized with neuronal nitric oxide synthase clusters on the internodal axon.
Central myelinated axons express functional AMPA and GluR5 kainate receptors, and can directly respond to glutamate receptor agonists. These glutamate receptor–dependent signaling pathways promote an increase in intraaxonal Ca2+ levels potentially contributing to axonal degeneration. Ann Neurol 2009