ArticleThe Journal of cell biology2021
Depolarization induces nociceptor sensitization by CaV1.2-mediated PKA-II activation.
Article in The Journal of cell biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 35 citations in OpenAlex.
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- Centrally Acting Skeletal Muscle Relaxants Sharing Molecular Targets with Drugs for Neuropathic Pain Management.Brain sciences · 2025Review
- BH4 Oxidation-Derived HJournal of neurochemistry · 2025Article
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- Depression of CaJournal of pharmaceutical analysis · 2024Article
- Enhanced kinase translocation reporters for simultaneous real-time measurement of PKA, ERK, and CabioRxiv : the preprint server for biology · 2024Article
- Sustained nerve growth factor-induced C-nociceptor sensitization to electrical sinusoidal stimulation in humans.Pain reports · 2024Article
- Diversely evolved xibalbin variants from remipede venom inhibit potassium channels and activate PKA-II and Erk1/2 signaling.BMC biology · 2024Article
- Modern venomics-Current insights, novel methods, and future perspectives in biological and applied animal venom research.GigaScience · 2022Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Depolarization drives neuronal plasticity. However, whether depolarization drives sensitization of peripheral nociceptive neurons remains elusive. By high-content screening (HCS) microscopy, we revealed that depolarization of cultured sensory neurons rapidly activates protein kinase A type II (PKA-II) in nociceptors by calcium influx through CaV1.2 channels. This effect was modulated by calpains but insensitive to inhibitors of cAMP formation, including opioids. In turn, PKA-II phosphorylated Ser1928 in the distal C terminus of CaV1.2, thereby increasing channel gating, whereas dephosphorylation of Ser1928 involved the phosphatase calcineurin. Patch-clamp and behavioral experiments confirmed that depolarization leads to calcium- and PKA-dependent sensitization of calcium currents ex vivo and local peripheral hyperalgesia in the skin in vivo. Our data suggest a local activity-driven feed-forward mechanism that selectively translates strong depolarization into further activity and thereby facilitates hypersensitivity of nociceptor terminals by a mechanism inaccessible to opioids.
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