Trabecular Meshwork TREK-1 Channels Function as Polymodal Integrators of Pressure and pH

Area of Science:

• Ophthalmology
• Cell Physiology
• Ion Channel Function

Background:

• Aqueous humor (AH) pH is critical for vertebrate eye physiology, normally near blood pH.
• Pathologic conditions and surgical interventions can drastically alter AH pH.
• Trabecular meshwork (TM) cells regulate AH outflow and are potential targets for pH-related dysfunction.

Purpose of the Study:

• To investigate the effects of extracellular and intracellular pH changes on TM cell physiology and function.
• To determine the role of pH in regulating transmembrane currents and mechanotransduction in TM cells.

Main Methods:

• Utilized electrophysiology, pharmacology, gene knockdown (shRNA), and optical recording.
• Examined primary and immortalized human TM cells.
• Assessed pH dependence of transmembrane currents and mechanotransduction.

Main Results:

• Extracellular acidification depolarized TM cells by inhibiting K+ currents; alkalinization had the opposite effect.
• Intracellular acidification hyperpolarized cells, while alkalinization depolarized them.
• TREK-1 (a K2P channel) mediated these pH-dependent effects, with acidosis suppressing and alkalosis facilitating pressure-evoked currents.

Conclusions:

• TM cell mechanotransduction via TREK-1 channels is highly sensitive to extracellular and intracellular pH shifts.
• Intracellular acidification may influence AH outflow and intraocular pressure (IOP) by modulating TREK-1 channel activity.