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

• 成果类型: Article
• 署名作者: Gualdani, Roberta; Barbeau, Solene; Yuan, Jun - Hui; Jacobs, Deborah S.; Gailly, Philippe; Dib-Hajj, Sulayman D.; Waxman, Stephen G.
• 署名单位: Universite Catholique Louvain; Yale University; Yale University; US Department of Veterans Affairs; Veterans Health Administration (VHA); VA Connecticut Healthcare System; Harvard University; Harvard University Medical Affiliates; Massachusetts Eye & Ear Infirmary
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10884
• DOI: 10.1073/pnas.2406186121
• 发表日期: 2024-09-10
• 关键词: platelet-activating-factor; linoleic-acid metabolites; potential vanilloid 1; sensing ion channels; molecular-basis; receptor vr1; chronic pain; temperature; mechanisms; target

摘要

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 tion 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.