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The increased association between Cdk5-phosphorylated CRMP2 and CaV2.2 was reduced by ( S)-LCM in vitro and in vivo. Cross-linking experiments and analytical ultracentrifugation showed no effect of ( S)-LCM on the oligomerization state of CRMP2. Using an in vitro luminescent kinase assay, we observed that ( S)-LCM specifically inhibited Cdk5-mediated phosphorylation of CRMP2. Saturation transfer difference nuclear magnetic resonance (STD NMR) and differential scanning fluorimetry (DSF) experiments demonstrated direct binding of ( S)-LCM to CRMP2. Mechanistically, ( S)-LCM increased CRMP2 binding to both Cdk5- and GSK-3β without affecting binding of CRMP2 to its canonical partner tubulin. ( S)-LCM application to embryonic cortical neurons resulted in reduced levels of Cdk5- and GSK-3β-phosphorylated CRMP2. Here, we investigated the mechanism by which ( S)-LCM affects CRMP2 phosphorylation by two key kinases, cyclin-dependent kinase 5 (Cdk5) and glycogen synthase kinase 3β (GSK-3β). We also identified ( S)-LCM, an inactive stereoisomer of the clinically used antiepileptic drug ( R)-LCM (Vimpat®), as a novel tool for preferentially targeting CRMP2-mediated neurite outgrowth. We recently reported that alterations in the phosphorylation state of an axon specification/guidance protein, the collapsin response mediator protein 2 (CRMP2), play a major role in the activity-dependent regulation of neurite outgrowth. Neurite outgrowth is an obligatory step in these events. The neuronal circuit remodels during development as well as in human neuropathologies such as epilepsy.