{"doi":"10.1167/iovs.66.14.57","title":"Mechano- and Glucocorticoid-Sensitive TREK-1 Channels Regulate Conventional Outflow and Intraocular Pressure","abstract":"Purpose: The purpose of this study was twofold: to determine the molecular link between corticosteroid exposure and mechanosensation and to establish the role of mechanosensitive TWIK-related potassium channel-1 (TREK-1) in the regulation of aqueous humor outflow and corticosteroid-induced ocular hypertension (OHT). Methods: Real-time PCR was used to determine the corticosteroid dexamethasone (DEX) dependence of expression of tandem-pore potassium (K2P), transient receptor potential vanilloid (TRPV), Piezo channel, extracellular matrix (ECM), and fibrotic marker genes in mouse trabecular meshwork (mTM) cells. Immunohistochemistry was employed to assess TREK-1 localization, iPerfusion to determine the TREK-1 dependence of conventional outflow, and tonometry to track intraocular pressure (IOP) in mouse eyes. Telemetry additionally tested TREK-1 dependence of OHT in rat. Steroid-induced transcriptional suppression of mTM Kcnk2 was validated by whole-cell recording in primary human trabecular meshwork (TM) cells. Results: The tandem pore K+ channel transcriptome in mTM cells was dominated by Trek-1 (Kcnk2) mRNA; with residual levels of Traak and Thik-2 transcripts; and low levels of Trek-2, Twik3, and Task1 expression. DEX upregulated Fsp1 and suppressed Kcnk2 expression without affecting Trpv4, Piezo1, or Trpc1 mRNA content. The TREK-1 agonist ML-402 doubled outflow facility in mouse eyes and reduced IOP in the mouse model of DEX-induced OHT and in rat eyes with spontaneously elevated IOP. Chronic DEX exposure depolarized human primary TM (pTM) cells and reduced the amplitude of the ML-402-evoked current. Conclusions: Ocular overexposure to corticosteroids may compromise IOP homeostasis by impairing TM expression and function of TREK-1. Pharmacological activation of TREK-1 facilitates conventional outflow and could help lower IOP in eyes with steroid-induced ocular hypertension.","journal":"Investigative Ophthalmology & Visual Science","year":2025,"id":548780,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9675,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":292177,"name":"Oleg Yarishkin","orcid":"0000-0002-8215-7444","position":1,"is_corresponding":false},{"id":292180,"name":"Christopher N. Rudzitis","orcid":"0000-0002-7271-5609","position":2,"is_corresponding":false},{"id":292182,"name":"Mónika Lakk","orcid":"0000-0001-5660-2623","position":3,"is_corresponding":false},{"id":523036,"name":"Jacques Bertrand","orcid":null,"position":4,"is_corresponding":false},{"id":364105,"name":"Joseph M. Sherwood","orcid":"0000-0002-4402-9767","position":5,"is_corresponding":false},{"id":709175,"name":"Christina M. Nicou","orcid":"0000-0002-4706-9369","position":6,"is_corresponding":false},{"id":443793,"name":"Christopher L. Passaglia","orcid":"0000-0001-5902-9818","position":7,"is_corresponding":false},{"id":364107,"name":"Darryl R. Overby","orcid":"0000-0001-9894-7515","position":8,"is_corresponding":false},{"id":292184,"name":"David Križaj","orcid":"0000-0003-4468-3029","position":9,"is_corresponding":false},{"id":832783,"name":"Sarah N. Redmon","orcid":null,"position":0,"is_corresponding":true}],"reference_count":61,"raw_metadata":null,"created_at":"2026-07-19T02:54:03.053965Z","pmid":"41268978","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}