Hierarchical CRMP2 posttranslational modifications control NaV1.7 function

SignificanceThe voltage-gated sodium channel NaV1.7 is important for electrogenesis in sensory neurons. Insertion within the membrane is required for function of NaV1.7. However, the mechanisms determining how NaV1.7 is trafficked to neuronal cell membranes are poorly understood. Here, we elucidate a signaling program involving a complex and intriguing posttranslational modification regime of collapsin response mediator protein 2 (CRMP2), an NaV1.7-binding protein. NaV1.7 surface localization and currents are controlled by CRMP2 modifications. Activity of NaV1.7 is thought to modulate neuronal excitability that codes for several sensory modalities, including chronic pain, as inferred from human pain disorders caused by mutations in NaV1.7 channels. Understanding the role of cross-talk between CRMP2 modifications in modulation of NaV1.7 activity opens routes to exploit this system for pain.