TRPV1 corneal neuralgia mutation: Enhanced pH response, bradykinin sensitization, and capsaicin desensitization

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 121; no. 37; p. e2406186121
• Main Authors: Gualdani, Roberta, Barbeau, Solène, Yuan, Jun-Hui, Jacobs, Deborah S., Gailly, Philippe, Dib-Hajj, Sulayman D., Waxman, Stephen G.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 10.09.2024
• Subjects: Animals; Arachidonic acid; Biological Sciences; Bradykinin; Bradykinin - metabolism; Bradykinin - pharmacology; Calcium imaging; Calcium ions; Capsaicin; Capsaicin - pharmacology; Capsaicin receptors; Channel gating; Channels; Cornea; Cornea - metabolism; Cornea - pathology; Desensitization; Eye diseases; HEK293 Cells; Humans; Hydrogen-Ion Concentration; Metabolites; Mutation; Neuralgia; Neuralgia - etiology; Neuralgia - genetics; Neuralgia - metabolism; Pain; Pathogenesis; pH effects; Photorefractive Keratectomy - adverse effects; Photorefractivity; Proton damage; Protons; Rats; TRPV Cation Channels - genetics; TRPV Cation Channels - metabolism; human mutation; TRP channels; corneal neuralgia
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2406186121

The factors that contribute to pain after nerve injury remain incompletely understood. Laser-assisted in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK) are common surgical techniques to correct refractive errors. After LASIK or PRK, a subset of patients suffers intense and persistent pain, of unknown origin, described by patients as feeling like shards of glass in their eye. Here, we evaluated a TRPV1 variant, p.V527M, found in a 49-y-old woman who developed corneal pain after LASIK and subsequent PRK enhancement, reporting an Ocular Surface Disease Index score of 100. Using patch-clamp and Ca 2+ imaging, we found that the V527M mutation enhances the response to acidic pH. Increasing proton concentration induced a stronger leftward shift in the activation curve of V527M compared to WT, resulting in channel activity of the mutant in acidic pH at more physiological membrane potentials. Finally, comparing the responses to consecutive applications of different agonists, we found in V527M channels a reduced capsaicin-induced desensitization and increased sensitization by the arachidonic acid metabolite 12-hydroxyeicosatetraenoic acid (12-HETE). We hypothesize that the increased response in V527M channels to protons and enhanced sensitization by 12-HETE, two inflammatory mediators released in the cornea after tissue damage, may contribute to the pathogenesis of corneal neuralgia after refractive surgery.