Mechano- and Glucocorticoid-Sensitive TREK-1 Channels Regulate Conventional Outflow and Intraocular Pressure.

1. Invest Ophthalmol Vis Sci. 2025 Nov 3;66(14):57. doi: 10.1167/iovs.66.14.57. Mechano- and Glucocorticoid-Sensitive TREK-1 Channels Regulate Conventional Outflow and Intraocular Pressure. Redmon SN(1), Yarishkin O(1), Rudzitis CN(1)(2), Lakk M(1), Bertrand J(3), van Batenburg-Sherwood J(3), Nicou CM(2), Passaglia CL(2), Overby DR(3), Križaj D(1)(4)(5). Author information: (1)Department of Ophthalmology and Visual Sciences, University of Utah School of Medicine, Salt Lake City, Utah, United States. (2)Department of Medical Engineering, University of South Florida, Tampa, Florida, United States. (3)Department of Bioengineering, Imperial College London, London, United Kingdom. (4)Department of Bioengineering, University of Utah, Salt Lake City, Utah, United States. (5)Department of Neurobiology, University of Utah, Salt Lake City, Utah, United States. 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. DOI: 10.1167/iovs.66.14.57 PMCID: PMC12663879 PMID: 41268978 [Indexed for MEDLINE] Conflict of interest statement: Disclosure: S.N. Redmon, None; O. Yarishkin, None; C.N. Rudzitis, None; M. Lakk, None; J. Bertrand, None; J. van Batenburg-Sherwood, None; C.M. Nicou, None; C.L. Passaglia, None; D.R. Overby, None; D. Križaj, TMclear (F, O, P, S)