Figure 10.

Working model for CRMP2-mediated, activity-dependent increase in neurite outgrowth and preferential inhibition by (S)-LCM. In control neurons (black arrows), CRMP2-mediated neurite outgrowth is driven by the binding of CRMP2 and tubulin, as well as, the enhancement of tubulin polymerization. Phosphorylation of CRMP2 by GSK3β and/or Cdk5 impairs its binding to tubulin, leading to neurite outgrowth arrest. Neuronal activity driven by KCl depolarization (blue arrows) leads to reduced priming by Cdk5 (residue S522), which prevents subsequent phosphorylation by GSK3β (residues T509/T514/S518; latter residue not shown). This transition to the unphosphorylated form results in increased binding of CRMP2/tubulin and CRMP2-dependent tubulin polymerization, thereby increasing neurite outgrowth. (S)-Lacosamide (green arrows) interacts with CRMP2 to directly impair its GAP activity, thus preventing the enhancement of tubulin polymerization and, therefore, neurite outgrowth (arrow size denotes the effect of treatment, i.e., increases in size imply a positive effect and decreases in size imply a negative effect).