Biology subjects

Gomez, K.

Publications and source records attributed to Gomez, K..

At least 19 recordsLinked to original sources

bioRxiv2026

A mouse model of myotonic dystrophy type 1 exhibits pain-like behavior and peripheral nociceptor hyperexcitability

Pain is a prevalent and disabling symptom of myotonic dystrophy type 1 (DM1), yet its underlying mechanisms remain poorly understood. Using HSA LR20b transgenic mice, we found multimodal mechanical and thermal hypersensitivity. Whole-cell electrophysiological recordings demonstrated depolarized resting membrane potentials and increased action potential firing selectively in small- and medium-diameter dorsal root ganglion neurons. These findings identify peripheral nociceptor sensitization as a potential mechanism contributing to pain in DM1.

neuroscience↗

bioRxiv2026

NaV1.7-dependent peripheral sensitization drives chronic pain in Parkinson's disease

Pain is among the most prevalent and disabling nonmotor symptoms of Parkinson's disease (PD), yet its mechanisms remain poorly defined and effective treatments are limited. Safinamide is one of the few drugs reported to improve pain in PD, but the mechanism underlying this effect is unknown. Here, we show that nigrostriatal neurodegeneration produces persistent hyperexcitability of primary sensory neurons associated with dysregulation of the voltage-gated sodium channel NaV1.7. In a brain-restricted 6-hydroxydopamine (6-OHDA) model, small-diameter dorsal root ganglion (DRG) neurons exhibited increased sodium current density and altered voltage-dependent inactivation, with the excess current eliminated by selective NaV1.7 blockade. Safinamide directly inhibited a NaV1.7-dependent component of sensory neuron sodium current and reversed established pain-like behaviors. Pharmacological disruption of NaV1.7 regulation by collapsin response mediator protein 2 (CRMP2) normalized DRG hyperexcitability and reversed mechanical and thermal hypersensitivity, whereas genetic disruption of the NaV1.7 CRMP2 regulatory sequence prevented the development of 6-OHDA-induced pain-like behaviors for up to 30 weeks despite preservation of the Parkinsonian motor phenotype. Transcriptomic profiling of human PD DRGs revealed limited global transcriptional remodeling with selective alterations in genes associated with sensory neuron excitability. Together, these findings demonstrate that dopaminergic neurodegeneration initiated within the brain is sufficient to drive persistent peripheral sensory neuron dysfunction and identify CRMP2-dependent regulation of NaV1.7 as a therapeutic target for Parkinsonian pain.

neuroscience↗

bioRxiv2026

Looking beyond stereotyped neuron structures reveals links between beading and morphological rearrangements in aging phenotypes.

1Understanding how neuronal morphology changes during aging and acute stress is essential for elucidating mechanisms of neurodegeneration. The highly branched PVD neuron of Caenorhabditis elegans provides a powerful model for studying dendritic remodeling and degeneration-associated phenotypes such as dendritic beading. However, the complexity of this arbor presents substantial challenges for automated segmentation and quantitative analysis. In this study, we adapted a convolutional neural network (CNN)-guided region growing framework for automated dendrite tracing, coupled with two topology-based algorithms for categorizing dendritic segments by branching degree. The segmentation algorithm achieved high accuracy relative to manual tracing, with a median Dice coefficient of 0.82, while reducing analysis time by approximately tenfold. Automated dendrite categorization demonstrated strong agreement with manual annotations across branching orders, though position-based mapping performance declined with age due to progressive morphological distortion. Leveraging this platform, we investigated mechanistic differences in dendritic beading patterns observed during aging and cold shock. Consistent with prior work, aging was associated with decreased inter-bead spacing, whereas cold shock produced increased bead dispersion with stress severity. Structural analysis revealed that these trends were not driven by dendritic pruning or reduced arbor complexity. Instead, while a traditional anatomically unflexible paradigm falsely implicated lower-degree dendrites as highly vulnerable, our branching-informed framework revealed that age-dependent beading is fundamentally dictated by a segments history of successive branching events. Conversely, acute cold shock triggered systemic beading that expanded across all dendritic orders in a severity-dependent manner. Together, these findings demonstrate that chronic aging and acute stress engage distinct degenerative pathways (compartment-specific lineage vulnerability versus global architectural collapse) rather than gross morphological loss, as well as highlighting the need for paradigms that enable reliable analysis of changing morphologies.

bioinformatics↗

bioRxiv2025

Assessing PDMS Biocompatibility in Microfluidic Applications: Toxicity and Survival Outcomes in C. elegans

Polydimethylsiloxane (PDMS), often assumed to be biocompatible, is widely used in microfluidic devices and biomedical research. Here, we systematically assess the organismal effects of PDMS network components and their leachates using Caenorhabditis elegans as a whole-animal model. We demonstrate that uncrosslinked vinyl-terminated PDMS (v-PDMS) chains, which comprise the majority of a PDMS network and are known to diffuse into aqueous environments, exhibit acute, environmentally-dependent toxicity. Low-molecular-weight v-PDMS (6 kDa) caused mild lethality in nutrient-rich S-Medium but significantly higher mortality in minimal S-Buffer, showing that media composition strongly influences toxic effects. Adding cholesterol, calcium, or magnesium notably reduced v-PDMS-induced lethality, whereas trace metals increased it. Using a DAF-16::GFP reporter strain, we show that cholesterol influences organismal stress responses to v-PDMS exposures. Progeny from starved parents showed full resistance to v-PDMS, suggesting transgenerational stress memory plays a role in reducing PDMS toxicity. We also find that linear siloxanes cause modest but significant lethality, whereas cyclic siloxanes do not. The PDMS crosslinker TDSS, however, provides partial protection when present with v-PDMS, revealing diverse biological effects among PDMS network precursors. Overall, these results show that PDMS-derived components are not universally harmless and that susceptibility depends greatly on environmental conditions, sterol levels, and physiological history. Our findings emphasize the importance of carefully evaluating PDMS formulations for biomedical use and offer a framework for assessing polymer leachate toxicity in living organisms.

pharmacology and toxicology↗

bioRxiv2025

Uncovering Ant Diversity Across Forest Successional Stages in the Yangambi Biosphere Reserve (DRC): Insights from Winkler and Pitfall Trap Sampling

Litter ant communities are an important component of biodiversity in tropical regions. They are currently used in several ecosystem management programmes to assess forest health. The aim of this study was to uncover the ant diversity across forest successional stages (fallow, secondary forest and primary forest) in the Yangambi Biosphere Reserve, The Democratic Republic of the Congo. These three forest habitats were sampled in six localities with pitfall traps and Winkler extractions. The discovered ant communities, the species typical of each habitat and the effectiveness of both sampling methods are discussed. The results showed that 190 species belonging to 50 genera and 8 sub-families of Formicidae were sampled in the Yangambi region. Ant diversity was lowest in fallow land, higher in secondary forests, and highest in primary forests, reflecting a clear pattern along the successional gradient. A relatively small proportion of ant species were shared among all three habitats, while each habitat also supported a distinct set of species. Primary forests hosted the highest number of exclusive species, followed by secondary forests and fallow land. Winkler extractors captured substantially more ant species than pitfall traps, with nearly 50% greater species richness observed. However, a significant portion of the ant fauna in Yangambi likely remains undocumented, and additional sampling methods could help provide a more complete picture of its biodiversity.

ecology↗

bioRxiv2025

High-throughput phenomics of global ant biodiversity

The big data era in biology is underway, but the study of organismal form has been slow to capitalize on advances in imaging and computation. Modern imaging can digitize whole organisms, but low throughput has limited the effort to document morphological diversity. Within the open science initiative Antscan, we applied high-throughput synchrotron X-ray microtomography to capture phenotypes across a diverse and ecologically dominant insect group -- ants. We provide 2193 whole-body 3D ant datasets from 792 species to broadly cover the ant phylogeny with a global scope, also pairing phenomic data with genome sequencing projects. Scans acquired with standardized parameters facilitate automated analysis and free access to data can broaden the audience and incentivize methods development. Antscan presents a scalable approach to create libraries of diverse anatomies, heralding a new era of studies on the evolution, structure, and function of organismal phenotypes.

zoology↗

bioRxiv2025

Enabling wider access to human molecular neuroscience research in pain: A simple preservation method for human dorsal root ganglion neurons in Hibernate A media

The use of human dorsal root ganglion (DRG) from organ donors opens the door for research into the molecular biology and physiology of human nociceptors; however, there are barriers to working with this tissue including logistical difficulties and limited access. We present an approach using Hibernate media to temporarily store either whole DRGs or dissociated DRG neurons prior to culturing and functional testing. Dissociation of DRGs following temporary storage (4-16hrs) in Hibernate media resulted in similar neuronal and immune cell yield as acutely dissociated DRGs. Neurons derived from DRGs stored in Hibernate media prior to dissociation exhibited similar electrophysiological properties and capsaicin responses as acutely dissociated DRG neurons. Similarly, neurons from acutely dissociated DRGs stored in Hibernate media (>24hrs) and shipped to geographically distant laboratories produced neuronal cultures displaying comparable electrophysiological properties as acutely cultured neurons. This approach overcomes insurmountable logistical burdens and increases access to freshly recovered human DRGs.

neuroscience↗

bioRxiv2024

Mouse models of non-dystrophic and dystrophic myotonia exhibit nociplastic pain-like behaviors

Pain is a common and disabling feature of myotonic disorders, yet its biological basis remains poorly understood and no targeted analgesic therapies currently exist. Here, we demonstrate that skeletal muscle hyperexcitability is sufficient to initiate a persistent pain state independent of inflammation, nerve injury, or overt tissue damage. Using complementary pharmacological and genetic models of myotonia resulting from loss of the voltage-gated skeletal muscle chloride channel ClC-1 function, we show that transient and chronic myotonia produce robust mechanical, thermal, and cold hypersensitivity, as well as spontaneous pain-like behavior. Notably, pain-like behaviors induced by transient myotonia persist long after overt motor symptoms have resolved, suggesting that a transient episode of muscle hyperexcitability is sufficient to trigger prolonged alterations in nociceptive processing. Physiological recordings revealed altered excitability of dorsal root ganglion and superficial dorsal horn neurons and enhanced sensory-evoked activity in the parabrachial nucleus, indicating altered nociceptive processing across multiple levels of the pain neuraxis. Transient myotonia increased total sodium current density in sensory neurons, with a shift toward a greater tetrodotoxin-resistant current fraction. Pharmacological inhibition with the NaV1.8-directed analgesic Suzetrigine markedly attenuated pain-like behaviors in both models of myotonia. Together, these findings establish a link between myotonia and persistent alterations in nociceptive processing and identify NaV1.8-directed analgesia as a promising therapeutic strategy for myotonia-associated pain.

neuroscience↗

bioRxiv2024

Mechanism, and treatment of anti-CV2/CRMP5 autoimmune pain

Paraneoplastic neurological syndromes arise from autoimmune reactions against nervous system antigens due to a maladaptive immune response to a peripheral cancer. Patients with small cell lung carcinoma or malignant thymoma can develop an autoimmune response against the CV2/collapsin response mediator protein 5 (CRMP5) antigen. For reasons that are not understood, approximately 80% of patients experience painful neuropathies. Here, we investigated the mechanisms underlying anti-CV2/CRMP5 autoantibodies (CV2/CRMP5-Abs)-related pain. We found that patient-derived CV2/CRMP5-Abs can bind to their target in rodent dorsal root ganglia (DRG) and superficial laminae of the spinal cord. CV2/CRMP5-Abs induced DRG neuron hyperexcitability and mechanical hypersensitivity in rats that were abolished by preventing binding to their cognate autoantigen CRMP5. The effect of CV2/CRMP5-Abs on sensory neuron hyperexcitability and mechanical hypersensitivity observed in patients was recapitulated in rats using genetic immunization providing an approach to rapidly identify possible therapeutic choices for treating autoantibody-induced pain including the repurposing of a monoclonal anti-CD20 antibody that selectively deplete B-lymphocytes. These data reveal a previously unknown neuronal mechanism of neuropathic pain in patients with paraneoplastic neurological syndromes resulting directly from CV2/CRMP5-Abs-induced nociceptor excitability. CV2/CRMP5-Abs directly sensitize pain responses by increasing sensory neuron excitability and strategies aiming at either blocking or reducing CV2/CRMP5-Abs can treat pain as a comorbidity in patients with paraneoplastic neurological syndromes.

neuroscience↗

bioRxiv2023

Neuropilin-1 is a co-receptor for NGF and TrkA-evoked pain

Nerve growth factor (NGF) monoclonal antibodies inhibit chronic pain yet, failed to gain approval due to worsened joint damage in osteoarthritis patients. We report that neuropilin-1 (NRP1) is a co-receptor for NGF and tropomyosin-related kinase A (TrkA) pain signaling. NRP1 is coexpressed with TrkA in human and mouse nociceptors. NRP1 inhibitors suppress NGF-stimulated excitation of human and mouse nociceptors and NGF-evoked nociception in mice. NRP1 knockdown inhibits NGF/TrkA signaling, whereas NRP1 overexpression enhances signaling. NGF binds NRP1 with high affinity and interacts with and chaperones TrkA from the biosynthetic pathway to the plasma membrane and endosomes, enhancing TrkA signaling. Molecular modeling suggests that C-terminal R/KXXR/K NGF motif interacts with extracellular "b" NRP1 domain within a plasma membrane NGF/TrkA/NRP1 of 2:2:2 stoichiometry. G Alpha Interacting Protein C-terminus 1 (GIPC1) scaffolds NRP1 and TrkA to myosin VI and colocalizes in nociceptors with NRP1/TrkA. GIPC1 knockdown abrogates NGF-evoked excitation of nociceptors and pain-like behavior. NRP1 is a nociceptor-enriched co-receptor that facilitates NGF/TrkA pain signaling. NRP binds NGF and chaperones TrkA to the plasma membrane and signaling endosomes via the GIPC1 adaptor. NRP1 and GIPC1 antagonism in nociceptors offers a long-awaited non-opioid alternative to systemic antibody NGF sequestration for the treatment of chronic pain. SummaryNeuropilin-1 and G Alpha Interacting Protein C-terminus 1 are necessary for nerve growth factor-evoked pain and are non-opioid therapeutic targets for chronic pain.

neuroscience↗

bioRxiv2023

Intranasal CRMP2-Ubc9 Inhibitor Regulates NaV1.7 to Alleviate Trigeminal Neuropathic Pain

Dysregulation of voltage-gated sodium NaV1.7 channels in sensory neurons contributes to chronic pain conditions, including trigeminal neuropathic pain. We previously reported that chronic pain results in part from increased SUMOylation of collapsin response mediator protein 2 (CRMP2), leading to an increased CRMP2/NaV1.7 interaction and increased functional activity of NaV1.7. Targeting this feed-forward regulation, we developed compound 194, which inhibits CRMP2 SUMOylation mediated by the SUMO-conjugating enzyme Ubc9. We further demonstrated that 194 effectively reduces the functional activity of NaV1.7 channels in dorsal root ganglia neurons and alleviated inflammatory and neuropathic pain. Here, we employed a comprehensive array of investigative approaches, encompassing biochemical, pharmacological, genetic, electrophysiological, and behavioral analyses, to assess the functional implications of NaV1.7 regulation by CRMP2 in trigeminal ganglia (TG) neurons. We confirmed the expression of Scn9a, Dpysl2, and UBE2I within TG neurons. Furthermore, we found an interaction between CRMP2 and NaV1.7, with CRMP2 being SUMOylated in these sensory ganglia. Disrupting CRMP2 SUMOylation with compound 194 uncoupled the CRMP2/NaV1.7 interaction, impeded NaV1.7 diffusion on the plasma membrane, and subsequently diminished NaV1.7 activity. Compound 194 also led to a reduction in TG neuron excitability. Finally, when intranasally administered to rats with chronic constriction injury of the infraorbital nerve (CCI-ION), 194 significantly decreased nociceptive behaviors. Collectively, our findings underscore the critical role of CRMP2 in regulating NaV1.7 within TG neurons, emphasizing the importance of this indirect modulation in trigeminal neuropathic pain.

neuroscience↗

bioRxiv2022

Identification and targeting of a unique NaV1.7 domain driving chronic pain

Despite identification of several small molecules directly targeting the voltage-gated sodium channel NaV1.7, none has been clinically successful. We reported that preventing addition of a small ubiquitin-like modifier (SUMO) on the NaV1.7-interacting cytosolic collapsin response mediator protein 2 (CRMP2) blocked NaV1.7 functions and was antinociceptive in rodents. Here, we discovered a 15 amino acid CRMP2 regulatory sequence (CRS) unique to NaV1.7 that is essential for this regulatory coupling. CRMP2 preferentially bound to the NaV1.7 CRS over other isoforms. Substitution of the NaV1.7 CRS with the homologous domains from the other eight voltage-gated sodium channel isoforms decreased tetrodotoxin-sensitive NaV1.7 currents in rodent sensory neurons. A cell-penetrant version of NaV1.7-CRS reduced NaV1.7 currents and trafficking, decreased presynaptic NaV1.7 localization, reduced spinal neurotransmitter release, and reversed mechanical allodynia in a rat spared nerve injury model of neuropathic pain. Interfering with NaV1.7-CRMP2 coupling did not produce motor impairment and spared thermal, inflammatory, and post-surgical nociception. As proof-of-concept for NaV1.7-targeted gene therapy, we found that NaV1.7-CRS packaged into an adeno-associated virus recapitulated the effects on NaV1.7 function in both rodent and rhesus macaque sensory neurons and both reversed and prevented the development of mechanical allodynia in a neuropathic pain model in male and female rodents. One Sentence SummaryA novel regulatory domain on the voltage gated sodium channel NaV1.7 that can be targeted to produce analgesia.

neuroscience↗

bioRxiv2021

A single shot of a hybrid hAdV5-based anti-COVID-19 vaccine induces a long-lasting immune response and broad coverage against VOC

Most approved vaccines against COVID-19 have to be administered in a prime/boost regimen. We engineered a novel vaccine based on a chimeric hAdV5 vector. The vaccine (named CoroVaxG.3) is based on three pillars: i) high expression of Spike to enhance its immunodominance by using a potent promoter and a mRNA stabilizer; ii) enhanced infection of muscle and dendritic cells by replacing the fiber knob domain of hAdV5 by hAdV3; iii) use of Spike stabilized in a prefusion conformation. Transduction with CoroVaxG.3 expressing Spike (D614G) dramatically enhanced Spike expression in human muscle cells, monocytes and dendritic cells compared to CoroVaxG.5 that expressed the native fiber knob domain. A single dose of CoroVaxG.3 induced potent humoral immunity with a balanced Th1/Th2 ratio and potent T-cell immunity, both lasting for at least 5 months. Sera from CoroVaxG.3 vaccinated mice was able to neutralize pseudoviruses expressing B.1 (wild type D614G), B.1.117 (alpha) and P.1 (gamma) Spikes, as well as an authentic WT and P.1 SARS-CoV-2 isolates. Neutralizing antibodies did not wane even after 5 months making this kind of vaccine a likely candidate to enter clinical trials

immunology↗

bioRxiv2021

Lipocalin 2 promotes inflammatory breast cancer tumorigenesis and skin invasion

Inflammatory breast cancer (IBC) is an aggressive form of primary breast cancer characterized by rapid onset and high risk of metastasis and poor clinical outcomes. The biological basis for the aggressiveness of IBC is still not well understood and no IBC-specific targeted therapies exist. In this study we report that lipocalin 2 (LCN2), a small secreted glycoprotein belonging to the lipocalin superfamily, is expressed at significantly higher levels in IBC versus non-IBC tumors, independently of molecular subtype. LCN2 levels were also significantly higher in IBC cell lines and in their culture media than in non-IBC cell lines. High expression was associated with poor-prognosis features and shorter overall survival in IBC patients. Depletion of LCN2 in IBC cell lines reduced proliferation, colony formation, migration, and cancer stem cell populations in vitro, and inhibited tumor growth, skin invasion, and brain metastasis in mouse models of IBC. Analysis of our proteomics data showed reduced expression of proteins involved in cell cycle and DNA repair in LCN2-silenced IBC cells. Our findings support that LCN2 promotes IBC tumor aggressiveness and offer a new potential therapeutic target for IBC.

cancer biology↗

bioRxiv2020

Studies on CRMP2 SUMOylation-deficient transgenic mice reveal novel insights into the trafficking of NaV1.7 channels

Voltage-gated sodium channels are key players in neuronal excitability and pain signaling. Functional expression of the voltage-gated sodium channel NaV1.7 is under the control of SUMOylated collapsin response mediator protein 2 (CRMP2). If not SUMOylated, CRMP2 forms a complex with the endocytic proteins Numb, the epidermal growth factor receptor pathway substrate 15 (Eps15), and the E3 ubiquitin ligase Nedd4-2 to promote clathrin-mediated endocytosis of NaV1.7. We recently reported that CRMP2 SUMO-null knock-in (CRMP2K374A/K374A) female mice have reduced NaV1.7 membrane localization and currents in their sensory neurons. Preventing CRMP2 SUMOylation was sufficient to reverse mechanical allodynia in CRMP2K374A/K374A female mice with neuropathic pain. Here we report that inhibiting clathrin assembly in nerve-injured male and female CRMP2K374A/K374A mice, increased pain sensitivity in allodynia-resistant animals. Furthermore, Numb, Nedd4-2 and Eps15 expression was not modified in basal conditions in the dorsal root ganglia (DRG) of male and female CRMP2K374A/K374A mice. Finally, silencing these proteins in DRG neurons from female CRMP2K374A/K374A mice, restored the loss of sodium currents. Our study shows that the endocytic complex composed of Numb, Nedd4-2 and Eps15, is necessary for non SUMOylated CRMP2-mediated internalization of sodium channels in vivo.

neuroscience↗

bioRxiv2020

SARS-CoV-2 Spike protein hijacks VEGF-A/Neuropilin-1 receptor signaling to induce analgesia

Global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues unabated. Binding of SARS-CoV-2s 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.

neuroscience↗

bioRxiv2020

Amino acids that are well tolerated in random peptides in E. coli are enriched in young animal but not young plant genes

Proteins are the workhorses of the cell, yet they carry great potential for harm via misfolding and aggregation. Despite the dangers, proteins are sometimes born de novo from non-coding DNA. Proteins are more likely to be born from non-coding regions that produce peptides that do little to no harm when translated than from regions that produce harmful peptides. To investigate which newborn proteins are most likely to "first, do no harm", we estimate fitnesses from an experiment that competed Escherichia coli lineages that each expressed a unique random peptide. A variety of peptide metrics significantly predict lineage fitness, but this predictive power stems from simple amino acid frequencies rather than the ordering of amino acids. Amino acids that are smaller and that promote intrinsic structural disorder have more benign fitness effects. We validate that the amino acids that indicate benign effects in random peptides expressed in E. coli also do so in an independent dataset of random N-terminal tags in which it is possible to control for expression level. The same amino acids are also enriched in young animal proteins. Significance statementProteins are sometimes born de novo. In an experiment to reproduce this process in Escherichia coli, we were able to predict 15% of the variation in random peptide fitness effects from their amino acid frequencies. In contrast, which order the amino acids are in seems to make no difference, adding no predictive power on top of simple amino acid frequencies. Amino acids that are smaller and promote intrinsic structural disorder have more benign fitness effects.

evolutionary biology↗

bioRxiv2020

Studies on CRMP2 SUMOylation-deficient transgenic mice identify sex-specific NaV1.7 regulation in the pathogenesis of chronic neuropathic pain

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 (CRMP2K374A/K374A) mice in which Lys374 was replaced with Ala. CRMP2K374A/K374A mice had reduced NaV1.7 membrane localization and function in female, but not male, sensory neurons. Behavioral appraisal of CRMP2K374A/K374A mice demonstrated no changes in depressive or repetitive, compulsive-like behaviors, and a decrease in noxious thermal sensitivity. No changes were observed in CRMP2K374A/K374A mice to inflammatory, acute, or visceral pain. In contrast, in a neuropathic model, CRMP2K374A/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.

neuroscience↗