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

Joel M. Brittain, Rui Pan, Haitao You, Tatiana Brustovetsky, Nickolay Brustovetsky, Gerald W. Zamponi, Wei Hua Lee, Rajesh Khanna

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Collapsin 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 Ca2+ channels. Building on our discovery of the interaction and regulation of Ca2+ 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 Ca2+ 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'sw role in excitotoxicity and neuroprotection.

Original languageEnglish (US)
JournalChannels
Volume6
Issue number1
DOIs
StatePublished - 2012

Keywords

  • CRMP-2
  • Focal cerebral ischemia
  • MCAO model
  • N-methylD-aspartate receptor
  • Peptide

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry

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