Extracellular Application of CRMP2 Increases Cytoplasmic Calcium through NMDA Receptors

•CRMP2 is a cytosolic protein that mediates tubulin polymerization.•CRMP2 detected in the CM evokes intracellular Ca2+ increase through NMDAr.•Extracellular antagonist of NMDAr blocked the CM-evoked calcium increase.•Recombinant CRMP2 also evokes intracellular calcium increase through NMDAr.•Prolonged exposure to CRMP2 could induce calcium dysregulation and cell damage. Collapsin Response Mediator Protein 2 (CRMP2) is an intracellular protein involved in axon and dendrite growth and specification. In this study, CRMP2 was identified in a conditioned media derived from degenerated sciatic nerves (CM). On cultured rat hippocampal neurons, acute extracellular application of CM or partially purified recombinant CRMP2 produced an increase in cytoplasmic calcium. The increase in cytoplasmic calcium was mostly mediated through NMDA receptors, with a minor contribution of N-type VDCC, and it was maintained as long as CM was present. By using live-labeling of CRMP2, Ca2+ channel binding domain 3 (CBD3) peptide derived from CRMP2, and recombinant CRMP2, we demonstrated that that this effect was mediated by an action on the extracellular side of the NMDA receptor. This is the first report of an extracellular action of CRMP2. Prolonged exposure to extracellular CRMP2, may contribute to neuronal calcium dysregulation and neuronal damage.