Figure 1.

CRMP-2 signaling cascade: a novel role for CRMPs in Ca²⁺ channel regulation and transmitter release. Extracellular signals, such as extracellular matrix, growth factors and guidance cues (semaphorin 3A) activate Neuropilin-1/Plexin A receptors on membranes.⁷ A battery of kinases, including RhoK, Cdk5 and GSK-3β phosphorylate CRMPs. Phosphorylated CRMPs have a reduced affinity to tubulin and other interacting molecules and lose their positive effect on axon elongation, thereby causing growth arrest and growth cone collapse. In contrast, non-phosphorylated CRMPs bind strongly to tubulin heterodimers to promote microtubule assembly and Numb-mediated endocytosis³⁰ thereby promoting axon elongation and branching.⁷ In addition to these classically defined roles for CRMPs, our results suggest that CRMPs (assuming both phosphorylated and non-phosphorylated forms) bind to cytoplasmic loops of the Ca²⁺ channel and increase their insertion into the membrane, resulting in an increased current density.¹ This increase culminates into an increase in the release of the excitatory transmitter glutamate.¹ Interestingly, CRMP-2 overexpression increases synapse size not number.¹ This suggests that CRMP-2 regulation of transmitters may occur via a direct effect on Ca_V2.2 or through an effect on changes in synaptic vesicle machinery and release probabilities. Increased synaptic transmission is likely to contribute to synaptic plasticity.