# Hemichannels, TRPV4 and a mechanosensitive form of autocrine regulation in the NPE

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2021 · $433,000

## Abstract

We have evidence that TRPV4 channels in the nonpigmented ciliary epithelium (NPE) interact with
connexin-50 to form a mechanism that responds to mechanical stimuli. Distortion of NPE cells is
capable of causing TRPV4 channel activation which in turn causes hemichannel opening at the
aqueous humor-facing surface of the NPE. What this means is the ciliary body, which secretes
aqueous humor, has a mechanism capable to sensing and responding to distortion caused by an
increase of intraocular pressure. Our working hypothesis is that mechanosensitive hemichannel
opening and ATP release are steps in an autocrine feedback loop that reduces Na,K-ATPase activity
in the NPE. Here, we propose studies on how the hemichannel opening mechanism senses and
responds to a mechanical stimulus (Aim 1). We will characterize how the hemichannel mechanism
pivots on TRPV4 activation, the role of connexin-50 vs pannexin-1, how TRPV4 channels respond to
mechanical stimuli (cell swelling and stretch), and the electrical conductance signal of the
hemichannels. Aim 2 studies will examine how hemichannel opening allows ATP to exit the cell then
activate receptors and signaling pathways that change Na,K-ATPase activity in an autocrine fashion.
We also will study cAMP and melatonin release into the aqueous humor via hemichannels. Studies
in Aim 3 will determine the effect of intraocular pressure on the NPE hemichannel mechanism in an
ex vivo arterially perfused eye preparation and test whether the effect of hemichannel blocking
molecules and TRPV4-interacting drugs on the rate of aqueous humor formation. The concept of
mechanosensitive feedback regulation of Na,K-ATPase activity in the NPE is significant because
Na,K-ATPase activity provides the driving force for aqueous humor secretion. The NPE forms a
cellular barrier between blood and aqueous and so is subjected to altered physical forces when
intraocular pressure changes in relation to hydrostatic pressure in the ciliary process stroma.

## Key facts

- **NIH application ID:** 10115046
- **Project number:** 5R01EY029171-03
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Nicholas A Delamere
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $433,000
- **Award type:** 5
- **Project period:** 2019-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10115046

## Citation

> US National Institutes of Health, RePORTER application 10115046, Hemichannels, TRPV4 and a mechanosensitive form of autocrine regulation in the NPE (5R01EY029171-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10115046. Licensed CC0.

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