Ion Transport Regulation by TRPV4 and TRPV1 in Lens and Ciliary Epithelium.

Nicholas A Delamere,Mohammad Shahidullah

doi:10.3389/fphys.2021.834916

Abstract

Aside from a monolayer of epithelium at the anterior surface, the lens is formed by tightly compressed multilayers of fiber cells, most of which are highly differentiated and have a limited capacity for ion transport. Only the anterior monolayer of epithelial cells has high Na, K-ATPase activity. Because the cells are extensively coupled, the lens resembles a syncytium and sodium-potassium homeostasis of the entire structure is largely dependent on ion transport by the epithelium. Here we describe recent studies that suggest TRPV4 and TRPV1 ion channels activate signaling pathways that play an important role in matching epithelial ion transport activity with needs of the lens cell mass. A TRPV4 feedback loop senses swelling in the fiber mass and increases Na, K-ATPase activity to compensate. TRPV4 channel activation in the epithelium triggers opening of connexin hemichannels, allowing the release of ATP that stimulates purinergic receptors in the epithelium and results in the activation of Src family tyrosine kinases (SFKs) and SFK-dependent increase of Na, K-ATPase activity. A separate TRPV1 feedback loop senses shrinkage in the fiber mass and increases NKCC1 activity to compensate. TRPV1 activation causes calcium-dependent activation of a signaling cascade in the lens epithelium that involves PI3 kinase, ERK, Akt and WNK. TRPV4 and TRPV1 channels are also evident in the ciliary body where Na, K-ATPase is localized on one side of a bilayer in which two different cell types, non-pigmented and pigmented ciliary epithelium, function in a coordinated manner to secrete aqueous humor. TRPV4 and TRPV1 may have a role in maintenance of cell volume homeostasis as ions and water move through the bilayer.

Highlights

The lens is a deceptively simple tissue, but its transparency and optical properties are the result of many complex cellular specializations
The functional role of TRPV4 and TRPV1 in the lens led us to examine the ciliary epithelium which is a bilayer structure formed by two different epithelial cell types in which one cell type, the non-pigmented ciliary epithelium (NPE), is specialized for Na, K-ATPase activity (Riley and Kishida, 1986; Usukura et al, 1988; Ghosh et al, 1991)
Responses do not occur when calcium is omitted from the bathing medium, which suggests that even though TRPV1 and TRPV4 are nonselective cation channels (White et al, 2016), their functional role appears to be calcium entry

Summary

INTRODUCTION

The lens is a deceptively simple tissue, but its transparency and optical properties are the result of many complex cellular specializations. Our studies in porcine lens suggest that when the lens is subjected to osmotic swelling, TRPV4 channels in the epithelium are activated to open by the mechanical stimulus This permits Ca2+ entry and triggers a complex chain of signaling events that stimulates Na, K-ATPase activity (Figure 2) (Shahidullah et al, 2012b). The channels that open permit ATP release from the lens This stimulates purinergic receptors in the epithelium and results in the activation of Src family tyrosine kinases (SFKs) and SFK-dependent increase of Na, K-ATPase activity (Figure 2; Shahidullah et al, 2012a,b). TRPV1 activation causes calcium-dependent activation of a signaling cascade in the lens epithelium that involves PI3 kinase, ERK, Akt and WNK (Figure 3; Shahidullah et al, 2018) This leads to increased NKCC1 activity which, by loading solute into the cells, has the effect of reversing osmotic shrinkage. TRPV1 in neurons is activated by compressive forces caused by cell shrinkage (Prager-Khoutorsky et al, 2014)

LENS CIRCULATION

CILIARY EPITHELIUM

Findings

DISCUSSION