Supplemental Digital Content is Available in the Text. Severe acute respiratory syndrome coronavirus 2's spike protein promotes analgesia by interfering with vascular endothelial growth factor-A/NRP1 pathway, which may affect disease transmission dynamics.

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.

Global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues unabated. Binding of SARS-CoV-2's Spike protein to host angiotensin converting enzyme 2 triggers viral entry, but other proteins may participate, including neuropilin-1 receptor (NRP-1). As both Spike protein and vascular endothelial growth factor-A (VEGF-A) - a pro-nociceptive and angiogenic factor, bind NRP-1, we tested if Spike could block VEGF-A/NRP-1 signaling. VEGF-A-triggered sensory neuronal firing was blocked by Spike protein and NRP-1 inhibitor EG00229. Pro-nociceptive behaviors of VEGF-A were similarly blocked via suppression of spontaneous spinal synaptic activity and reduction of electrogenic currents in sensory neurons. Remarkably, preventing VEGF-A/NRP-1 signaling was antiallodynic in a neuropathic pain model. A 'silencing' of pain via subversion of VEGF-A/NRP-1 signaling may underlie increased disease transmission in asymptomatic individuals.

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...

Collapsin response mediator proteins (CRMPs) are ubiquitously expressed phosphoproteins that coordinate cytoskeletal formation and regulate cellular division, migration, polarity, and synaptic connection. CRMP2, the most studied of the five family members, is best known for its affinity for tubulin heterodimers and function in regulating the microtubule network. Accumulating evidence has also demonstrated a key role for CRMP2 in trafficking of voltage- and ligand-gated ion channels. These functions are tightly regulated by post-translational modifications including phosphorylation and SUMOylation (addition of a small ubiquitin like modifier). Over the past decade, it has become increasingly clear that dysregulated post-translational modifications of CRMP2 contribute to the pathomechanisms of diverse diseases, including cancer, neurodegenerative diseases, chronic pain, and bipolar disorder. Here, we review the discovery, functions, and current putative preclinical and clinical therapeutics targeting CRMP2. These potential therapeutics include CRMP2-based peptides that inhibit protein–protein interactions and small-molecule compounds. Capitalizing on the availability of structural information, we identify druggable pockets on CRMP2 and predict binding modes for five known CRMP2-targeting compounds, setting the stage for optimization and de novo drug discovery targeting this multifunctional protein.

No abstract

No abstract

Collapsin response mediator protein 2 is a key regulator of glutamatergic sensory neurotransmission that contributes to the initiation and maintenance of chronic neuropathic pain.