Swelling-activated chloride channels in aqueous humour formation: on the one side and the other

Aqueous humour is secreted by the ciliary epithelium comprising pigmented and non-pigmented cell layers facing the stroma and aqueous humour respectively. Net chloride secretion likely limits the rate of aqueous humour formation and proceeds in three steps: stromal chloride entry into pigmented cells, diffusion through gap junctions and final non-pigmented cell secretion. Swelling-activated chloride channels function on both epithelial surfaces. At the stromal surface, swelling- and cyclic adenosine monophosphate-activated maxi-chloride channels can recycle chloride, reducing net chloride secretion. At the aqueous-humour surface, swelling- and A3 adenosine receptor-activated chloride channels subserve chloride release into the aqueous humour. The similar macroscopic properties of the two non-pigmented cell chloride currents suggest that both flow through a common conduit. In addition, measurements of intraocular pressure (IOP) in living wild-type and mutant mice have confirmed that A3 adenosine receptor-activated agonists and antagonists increase and lower IOP respectively. Isolated ciliary epithelial cells are commonly perfused with hypotonic solution to probe and characterize chloride channels, but the physiological role of swelling-activated channels has been unclear without knowing their epithelial distribution. Recently, hypotonic challenge has been found to stimulate the chloride-sensitive short-circuit current across the intact bovine ciliary epithelium, suggesting that the net effect of the swelling-activated chloride currents is oriented to enhance aqueous humour formation. Taken together, the results suggest that swelling-activated chloride channels are predominantly oriented to enhance aqueous humour secretion, and these chloride channels at the aqueous surface may be identical with adenosine receptor-activated chloride channels which likely modulate aqueous inflow and IOP in the living mouse.