Studies on CRMP2 SUMOylation–deficient transgenic mice identify sex-specific Na_v1.7 regulation in the pathogenesis of chronic neuropathic pain

The sodium channel Na_v1.7 is a master regulator of nociceptive input into the central nervous system. Mutations in this channel can result in painful conditions and produce insensitivity to pain. Despite being recognized as a “poster child” for nociceptive signaling and human pain, targeting Na_v1.7 has not yet produced a clinical drug. Recent work has illuminated the Na_v1.7 interactome, offering insights into the regulation of these channels and identifying potentially new druggable targets. Among the regulators of Na_v1.7 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 Na_v1.7 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 Na_v1.7 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. By 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 Na 1.7 is a hallmark of chronic but not physiological neuropathic pain.