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The sodium channel NaV1.7 is a master regulator of nociceptive neuronal firing. Mutations in this channel can result in painful conditions as well as produce insensitivity to pain. Despite being recognized as a "poster child" for nociceptive signaling and human pain, targeting NaV1.7 has not yet produced a clinical drug. Recent work has illuminated the NaV1.7 interactome, offering insights into the regulation of these channels and identifying potentially new druggable targets. Amongst the regulators of NaV1.7 is the cytosolic collapsin response mediator protein 2 (CRMP2). CRMP2, modified at Lysine 374 (K374) by addition of a small ubiquitin-like modifier (SUMO), bound NaV1.7 to regulate its membrane localization and function. Corollary to this, preventing CRMP2 SUMOylation was sufficient to reverse mechanical allodynia in rats with neuropathic pain. Notably, loss of CRMP2 SUMOylation did not compromise other innate functions of CRMP2. To further elucidate the in vivo role of CRMP2 SUMOylation in pain, we generated CRMP2 K374A knock-in (CRMP2 K374A/K374A ) mice in which Lys374 was replaced with Ala. CRMP2 K374A/K374A mice had reduced NaV1.7 membrane localization and function in female, but not male, sensory neurons. Behavioral appraisal of CRMP2 K374A/K374A mice demonstrated no changes in depressive or repetitive, compulsive-like behaviors, and a decrease in noxious thermal sensitivity. No changes were observed in CRMP2 K374A/K374A mice to inflammatory, acute, or visceral pain. In contrast, in a neuropathic model, CRMP2 K374A/K374A mice failed to develop persistent mechanical allodynia. Our study suggests that CRMP2 SUMOylation-dependent control of peripheral NaV1.7 is a hallmark of chronic, but not physiological, neuropathic pain. IntroductionThe voltage-gated sodium channel NaV1.7 is a "poster child" target in pain signaling: gain-of-function mutations in the human NaV1.7 gene SCN9A can produce sensory neuron hyperexcitability associated with severe pain as well as insensitivity to pain [16]. While other sodium channels regulate the propagation of action potentials along nerves, NaV1.7 is upstream and defines the threshold at which an action potential will be elicited [44].Alterations of NaV1.7 trafficking are important in the etiology of neuropathic pain. Mapping the NaV1.7 interactome has shed light on novel proteins involved in regulation of trafficking and degradation of NaV1.7 [10; 35]. In neuropathic pain, the expression of proteins regulating trafficking of voltage gated sodium channels (VGSCs) is dysregulated [4; 38]. In particular, upregulation of the VGSC β-subunits [4] and downregulation of Nedd4-2 (an E3 ubiquitin ligase)[38] following a spared nerve injury (SNI) [15], converge to functionally upregulate NaV1.7.We identified the collapsin response mediator protein 2 (CRMP2) as a regulator of NaV1.7 function [17-19; 22; 48]. Our laboratory uncovered the logical coding of CRMP2's cellular actions [11; 51]. The argument path underlying NaV1.7 regulation is defined by "IF CRMP2 is phosphorylated by cycli...

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