Collapsin response mediator protein 2 (CRMP2) interacts with N-methyl-D-aspartate (NMDA) receptor and Na+/Ca2+ exchanger and regulates their functional activity

Tatiana Brustovetsky, Jessica J. Pellman, Xiao Fang Yang, Rajesh Khanna, Nickolay Brustovetsky

Research output: Contribution to journalArticlepeer-review

61 Scopus citations


Collapsin response mediator protein 2 (CRMP2) is traditionally viewed as an axonal growth protein involved in axon/dendrite specification. Here, we describe novel functions of CRMP2. A 15-amino acid peptide from CRMP2, fused to the TAT cell-penetrating motif of the HIV-1 protein, TAT-CBD3, but not CBD3 without TAT, attenuated N-methyl-D-aspartate receptor (NMDAR) activity and protected neurons against glutamate-induced Ca2+ dysregulation, suggesting the key contribution of CRMP2 in these processes. In addition, TAT-CBD3, but not CBD3 withoutTATor TAT-scramble peptide, inhibited increases in cytosolic Ca2+ mediated by the plasmalemmal Na+/Ca 2+ exchanger (NCX) operating in the reverse mode. Coimmunoprecipitation experiments revealed an interaction between CRMP2 and NMDAR as well as NCX3 but not NCX1. TAT-CBD3 disrupted CRMP2-NMDAR interaction without change in NMDAR localization. In contrast, TAT-CBD3 augmented theCRMP2-NCX3co-immunoprecipitation, indicating increased interaction or stabilization of a complex between these proteins. Immunostaining with an anti-NCX3 antibody revealed that TAT-CBD3 induced NCX3 internalization, suggesting that both reverse and forward modes of NCX might be affected. Indeed, the forward mode of NCX, evaluated in experiments with ionomycin-induced Ca2+ influx into neurons, was strongly suppressed by TAT-CBD3. Knockdown of CRMP2 with short interfering RNA (siRNA) prevented NCX3 internalization in response to TAT-CBD3 exposure. Moreover, CRMP2 down-regulation strongly attenuated TAT-CBD3-induced inhibition of reverse NCX. Overall, our results demonstrate that CRMP2 interacts with NCX and NMDAR and that TAT-CBD3 protects against glutamate-induced Ca2+ dysregulation most likely via suppression of both NMDAR and NCX activities. Our results further clarify the mechanism of action of TAT-CBD3 and identify a novel regulatory checkpoint for NMDAR and NCXfunction based on CRMP2 interaction with these proteins.

Original languageEnglish (US)
Pages (from-to)7470-7482
Number of pages13
JournalJournal of Biological Chemistry
Issue number11
StatePublished - Mar 14 2014

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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