Disruption of NMDAR-CRMP-2 signaling protects against focal cerebral ischemic damage in the rat middle cerebral artery occlusion model

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dc.contributor.authorPan, Rui
dc.contributor.authorYou, Haitao
dc.contributor.authorBrustovetsky, Tatiana
dc.contributor.authorKhanna, Rajesh
dc.contributor.authorBrittain, Joel M.
dc.contributor.authorBrustovetsky, Nickolay N.
dc.contributor.authorZamponi, Gerald W.
dc.contributor.authorLee, Weihua
dc.date.accessioned2018-05-29T14:44:35Z
dc.date.available2018-05-29T14:44:35Z
dc.date.issued2012-01-01
dc.description.abstractCollapsin response mediator protein 2 (CRMP-2), traditionally viewed as an axon/dendrite specification and axonal growth protein, has emerged as nidus in regulation of both pre- and post-synaptic Ca ( 2+) channels. Building on our discovery of the interaction and regulation of Ca ( 2+) channels by CRMP-2, we recently identified a short sequence in CRMP-2 which, when appended to the transduction domain of HIV TAT protein, suppressed acute, inflammatory and neuropathic pain in vivo by functionally uncoupling CRMP-2 from the Ca ( 2+) channel. Remarkably, we also found that this region attenuated Ca ( 2+) influx via N-methylD-Aspartate receptors (NMDARs) and reduced neuronal death in a moderate controlled cortical impact model of traumatic brain injury (TBI). Here, we sought to extend these findings by examining additional neuroprotective effects of this peptide (TAT-CBD3) and exploring the biochemical mechanisms by which TAT-CBD3 targets NMDARs. We observed that an intraperitoneal injection of TAT-CBD3 peptide significantly reduced infarct volume in an animal model of focal cerebral ischemia. Neuroprotection was observed when TAT-CBD3 peptide was given either prior to or after occlusion but just prior to reperfusion. Surprisingly, a direct biochemical complex was not resolvable between the NMDAR subunit NR2B and CRMP-2. Intracellular application of TAT-CBD3 failed to inhibit NMDAR current. NR2B interactions with the post synaptic density protein 95 (PSD-95) remained intact and were not disrupted by TAT-CBD3. Peptide tiling of intracellular regions of NR2B revealed two 15-mer sequences, in the carboxyl-terminus of NR2B, that may confer binding between NR2B and CRMP-2 which supports CRMP-2's role in excitotoxicity and neuroprotection.en_US
dc.identifier.citationBrittain, J. M., Pan, R., You, H., Brustovetsky, T., Brustovetsky, N., Zamponi, G. W., … Khanna, R. (2012). Disruption of NMDAR-CRMP-2 signaling protects against focal cerebral ischemic damage in the rat middle cerebral artery occlusion model. Channels (Austin, Tex.), 6(1), 52–59. https://doi.org/10.4161/chan.6.1.18919en_US
dc.identifier.doihttp://dx.doi.org/10.4161/chan.18919en_US
dc.identifier.urihttp://hdl.handle.net/1880/106696
dc.identifier.urihttps://doi.org/10.11575/PRISM/43764
dc.language.isoenen_US
dc.publisherLandes Bioscienceen_US
dc.publisher.departmentPhysiology & Pharmacologyen_US
dc.publisher.facultyCumming School of Medicineen_US
dc.publisher.institutionUniversity of Calgaryen_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0en_US
dc.titleDisruption of NMDAR-CRMP-2 signaling protects against focal cerebral ischemic damage in the rat middle cerebral artery occlusion modelen_US
dc.typeunknown
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