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I. Glur6 Kainate Receptors

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I. Glur6 Kainate Receptors University of Calgary PRISM: University of Calgary's Digital Repository Cumming School of Medicine Cumming School of Medicine Research & Publications 2009-02 Glutamate receptors on myelinated spinal cord axons: I. GluR6 kainate receptors Ouardouz, Mohamed; Basak, Ajoy; Chen, Andrew; Rehak, Renata; Yin, Xinghua; Coderre, Elaine M.; Zamponi, Gerald W.; Hameed, Shahid; Trapp, Bruce D. T.; Stys, Peter K.... Wiley-Liss, Inc. Ouardouz, M., Coderre, E., Basak, A., Chen, A., Zamponi, G. W., Hameed, S., … Stys, P. K. (2009). Glutamate receptors on myelinated spinal cord axons: I. glur6 kainate receptors. Annals of Neurology, 65(2), 151–159. https://doi.org/10.1002/ana.21533 http://hdl.handle.net/1880/106670 unknown https://creativecommons.org/licenses/by/4.0 Downloaded from PRISM: https://prism.ucalgary.ca Glutamate Receptors on Myelinated Spinal Cord Axons: I. GluR6 Kainate Receptors Mohamed Ouardouz, PhD,1 Elaine Coderre,1 Ajoy Basak, PhD,2 Andrew Chen, BSc,2 Gerald W. Zamponi, PhD,3 Shameed Hameed, PhD,3 Renata Rehak, MSc,3 Xinghua Yin, MD,4 Bruce D. Trapp, PhD,4 and Peter K. Stys, MD5 Objective: 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 ϩ elucidate the mechanisms of kainate receptor–dependent axonal Ca2 deregulation. ϩ Methods: Dorsal column axons were loaded with a Ca2 indicator and imaged in vitro using confocal laser-scanning micros- copy. ϩ Results: Activation of glutamate receptor 6 (GluR6) kainate receptors promoted a substantial increase in axonal [Ca2 ]. This ϩ Ca2 accumulation was due not only to influx from the extracellular space, but a significant component originated from ϩ ryanodine-dependent intracellular stores, which, in turn, depended on activation of L-type Ca2 channels: ryanodine, nimodip- ϩ ine, or nifedipine blocked the agonist-induced Ca2 increase. Also, GluR6 stimulation induced intraaxonal production of nitric ϩ oxide (NO), which greatly enhanced the Ca2 response: quenching of NO with intraaxonal (but not extracellular) scavengers, ϩ or inhibition of neuronal NO synthase with intraaxonal N␻-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 ϩ 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. Interpretation: 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 ϩ 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;65:151–159 Glutamate is the main excitatory neurotransmitter in glutamate receptors. ␣-amino-3-hydroxy-5-methyl-4- the mammalian central nervous system, playing a sig- isoxazole propionic acid (AMPA)/kainate receptor an- nificant role in gray matter injury in many neurode- tagonists are protective both in vitro6–10 and in generative diseases.1 Prevalent and devastating disorders vivo,11–14 in ischemic, traumatic, and autoimmune such as stroke, multiple sclerosis, and trauma to the models of white matter injury. Conversely, activating brain and spinal cord invariably affect afferent and ef- AMPA/kainate receptors, but not N-methyl-D-aspartate ferent white matter tracts, though much less is known (NMDA) receptors, or increasing extracellular gluta- about mechanisms of injury to myelinated white mate levels by blocking glutamate transport either in ϩ ϩ matter axons. Voltage-gated Na and Ca2 channels, vitro15–17 or in vivo17–19 is injurious to axons. ϩ ϩ together with reverse Na -Ca2 exchange, play impor- The precise mechanisms of injury to white matter tant roles2–4 (for review, see Stys5). Perhaps counterin- elements induced by non-NMDA glutamate receptor tuitive, given the nonsynaptic nature of central nervous activation are unknown. Both astrocytes and oligoden- system white matter, are observations of functional drocytes express AMPA and kainate receptors (for re- protection of this tissue by antagonists of ionotropic view, see Matute and colleagues20), and more recently, From the 1Division of Neuroscience and 2Hormones, Growth and Potential conflict of interest: Nothing to report. Development Program, Ottawa Health Research Institute, Univer- sity of Ottawa, Ottawa, Ontario; 3Department of Physiology and Received Jun 17, 2008, and in revised form Aug 5. Accepted for Biophysics, Hotchkiss Brain Institute, University of Calgary, Cal- publication Aug 21, 2008. gary, Alberta, Canada; 4Department of Neurosciences, Cleveland Clinic Foundation, Cleveland, OH; and 5Department of Clinical Published online in Wiley InterScience (www.interscience.wiley.com). Neurosciences, Hotchkiss Brain Institute, University of Calgary, DOI: 10.1002/ana.21533 Calgary, Alberta, Canada. Additional Supporting Information may be found in the online ver- Address correspondence to Dr Stys, Department of Clinical Neuro- sion of this article. sciences, HRIC 1AA22, 3330 Hospital Drive NW, AB, Canada, T2N 4N1. E-mail: [email protected] © 2009 American Neurological Association 151 Published by Wiley-Liss, Inc., through Wiley Subscription Services NMDA receptors have been detected on mature oligo- Peptide Synthesis and Purification 21 22 dendrocytes, their processes, and even the myelin Two peptides (NH2-Cys-Ahx-Arg-Leu-Pro-Gly-Lys-Glu- 23 2ϩ ϭ sheath. These receptors are permeable to Ca ions; Thr-Met-Ala-CONH2 (I), [molecular weight 1,218] and therefore, it is reasonable to conclude that receptor- NH2-Cys-Ahx-Cys-Ahx-Cys-Ahx-Cys-Ahx-Arg-Leu-Pro-Gly- 2ϩ ϭ mediated Ca overload is responsible for excitotoxic Lys-Glu-Thr-Met-Ala-CONH2 (II) [molecular weight glial injury.15,24,25 What is so far unexplained is the 1,864]) were designed that contain the C-terminal of GluR6 observation that central axons per se are damaged by PDZ1 binding motif, a single or multiple N-terminal Cys 18,19 residues (for dye conjugation via free SH groups), and one or activation of AMPA/kainate receptors and, in turn, more Ahx (ε-amino-hexanoic acid) moieties as spacers (for protected by blockers of these receptors in various in- 9,13,26 steric reasons). Active and sham dextropeptides were synthe- jury models. These latter observations raise the sized using standard methods. The peptides were dissolved to possibility that central myelinated axons themselves ex- a concentration of 0.1 to 1mM in the loading pipette yield- press AMPA/kainate receptors, whose overactivation re- ing approximately 1 to 10␮M in the axons. sults in damage to the fibers directly. Indeed, antago- nists of AMPA/kainate receptors, but not NMDA receptors, were protective against spinal cord dorsal Results column injury,6–8 and bath application of AMPA, kai- Activation of GluR6-Containing Receptors Increases ϩ nate, or glutamate, but not NMDA, induced irrevers- Axonal Ca2 ϩ ible reduction of compound action potential.6,16 In We measured [Ca2 ] changes in live adult rat dorsal this report, we tested the hypothesis that myelinated column axons in vitro using laser-scanning confocal axons from rat spinal cord express functional kainate microscopy (see Fig 1). Activation of kainate receptors receptors capable of mediating a potentially deleterious (kainate 200␮M), at concentrations that significantly ϩ axonal Ca2 increase. We found that GluR6- reduced compound action potentials (see later), caused ϩ containing kainate receptors reside along the internodal a progressive increase of intraaxonal [Ca2 ]. Axoplas- 2ϩ axolemma in “nanocomplexes” together with neuronal mic Ca -dependent fluorescence (FCa.ax) showed a ro- nitric oxide synthase (nNOS), exerting control over bust increase after drug application (mean increase after ϩ ϩ L-type Ca2 channels and causing Ca2 release from 30 minutes: kainate, 110 Ϯ 67%; n ϭ 54 axons) that ϩ intraaxonal Ca2 stores. These signaling molecules are was strongly reduced by the AMPA/kainate receptor an- organized in a surprisingly intricate arrangement (see tagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX Fig 6) reminiscent of what is found at the postsynaptic 50␮M) (12 Ϯ 15%; n ϭ 35; p Ϸ 0). The AMPA re- membrane of conventional glutamatergic synapses. ceptor antagonists 1-naphtyl acetyl spermine (25␮M) or 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H- 2,3-benzodiazepine (GYKI52466 100␮M) did not sig- Materials and Methods nificantly blunt kainate-induced F increase (kai- All experiments were performed in accordance with institu- Ca.ax nate ϩ spermine: 97 Ϯ 64%, n ϭ 54, p ϭ 0.98; tional guidelines for the care and use of experimental ani- ϩ Ϯ ϭ ϭ mals. Additional details can be found in the supplementary kainate GYKI52466: 79 65%, n 40, p 0.24). material. In contrast, 3-(hydroxyamino)-6-nitro-6,7,8,9- tetrahydrobenzo[g]indol-2-one (NS-102 10␮M), an an- 27 2ϩ tagonist of GluR6-containing kainate receptors, Ca Imaging strongly reduced the response induced by kainate (kai- Dorsal columns from deeply anesthetized adult Long-Evans nate ϩ NS-102: 35 Ϯ 25%; n ϭ 37; p Ϸ 0). (S)-1-(2- male rats were removed from the thoracic region and placed 2ϩ amino-2-carboxyethyl)-3-(2-carboxybenzyl)pyrimidine-
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