ArticleProceedings of the National Academy of Sciences of the United States of America2022
Targeted ubiquitination of sensory neuron calcium channels reduces the development of neuropathic pain.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 30 citations in OpenAlex.
- PARP1 rewires neuroinflammatory and redox metabolism associated with reactive neuroglia in neuropathic pain.Redox biology · 2026Article
- Palmitic acid aggravates atopic dermatitis by regulating SGK1/NEDD4L-involved cutaneous neuroimmune inflammation through driving TRPV1 and MRGPRB2 S-palmitoylation.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026Article
- High-throughput multiplex voltage-clamp/current-clamp evaluation of acutely isolated neurons.Nature protocols · 2026Review
- Piezo1 in neuropathic pain: a putative mechanotransduction hub and underlying mechanisms.Frontiers in molecular neuroscience · 2026Review
- Absence of the axon initial segment in sensory neuron enhances resistance to amyotrophic lateral sclerosis.Brain : a journal of neurology · 2025Article
- Degradation of voltage-gated calcium channels: mechanisms and applications in neurological and cardiovascular diseases.Cell communication and signaling : CCS · 2025Review
- Modulating ion channels with nanobodies.Synthetic and systems biotechnology · 2025Review
- Voltage-Gated Ion Channels in Neuropathic Pain Signaling.Life (Basel, Switzerland) · 2025Review
- Similarities and differences in the response and molecular characteristics of peripheral sensory neurons associated with pain and itch.Acta biochimica et biophysica Sinica · 2025Article
- Small molecule-mediated targeted protein degradation of voltage-gated sodium channels involved in pain.bioRxiv : the preprint server for biology · 2025Article
- Engineering spatially-confined conduits to tune nerve self-organization and allodynic responses via YAP-mediated mechanotransduction.Nature communications · 2025Article
- Presynaptic neurons self-tune by inversely coupling neurotransmitter release with the abundance of CaV2 voltage-gated CaProceedings of the National Academy of Sciences of the United States of America · 2024Article
- Functional remodeling of presynaptic voltage-gated calcium channels in superficial layers of the dorsal horn during neuropathic pain.iScience · 2024Article
- Pathology of pain and its implications for therapeutic interventions.Signal transduction and targeted therapy · 2024Review
- Generalized modality responses in primary sensory neurons of awake mice during the development of neuropathic pain.Frontiers in neuroscience · 2024Article
- Communicating pain: emerging axonal signaling in peripheral neuropathic pain.Frontiers in neuroanatomy · 2024Review
- Suberoylanilide Hydroxamic Acid Ameliorates Pain Sensitization in Central Neuropathic Pain After Spinal Cord Injury via the HDAC5/NEDD4/SCN9A Axis.Neurochemical research · 2023Article
- Gene therapy for chronic pain: emerging opportunities in target-rich peripheral nociceptors.Nature reviews. Neuroscience · 2023Review
- A sleep-active basalocortical pathway crucial for generation and maintenance of chronic pain.Nature neuroscience · 2023Article
- Design and Applications of Genetically-Encoded Voltage-Dependent Calcium Channel Inhibitors.Handbook of experimental pharmacology · 2023Review
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Neuropathic pain caused by lesions to somatosensory neurons due to injury or disease is a widespread public health problem that is inadequately managed by small-molecule therapeutics due to incomplete pain relief and devastating side effects. Genetically encoded molecules capable of interrupting nociception have the potential to confer long-lasting analgesia with minimal off-target effects. Here, we utilize a targeted ubiquitination approach to achieve a unique posttranslational functional knockdown of high-voltage-activated calcium channels (HVACCs) that are obligatory for neurotransmission in dorsal root ganglion (DRG) neurons. CaV-aβlator comprises a nanobody targeted to CaV channel cytosolic auxiliary β subunits fused to the catalytic HECT domain of the Nedd4-2 E3 ubiquitin ligase. Subcutaneous injection of adeno-associated virus serotype 9 encoding CaV-aβlator in the hind paw of mice resulted in the expression of the protein in a subset of DRG neurons that displayed a concomitant ablation of CaV currents and also led to an increase in the frequency of spontaneous inhibitory postsynaptic currents in the dorsal horn of the spinal cord. Mice subjected to spare nerve injury displayed a characteristic long-lasting mechanical, thermal, and cold hyperalgesia underlain by a dramatic increase in coordinated phasic firing of DRG neurons as reported by in vivo Ca2+ spike recordings. CaV-aβlator significantly dampened the integrated Ca2+ spike activity and the hyperalgesia in response to nerve injury. The results advance the principle of targeting HVACCs as a gene therapy for neuropathic pain and demonstrate the therapeutic potential of posttranslational functional knockdown of ion channels achieved by exploiting the ubiquitin-proteasome system.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.