more current into the cell than out of it in response to voltage steps of the same magnitude, and the opposite is true for outward rectifiers. Both delayed (Lang et al., 1998) and Ca2þ activated outward rectifiers (Va´zquez et al., 2001; Ferna´ndez-Ferna´ndez et al., 2002) have been thought to provide exit pathways for Kþ in parallel with Cl channels in mediating swelling activated release of KCl from other cells. The physiological delivery of fluid from the PE cell layer to the NPE cells may sustain the activity of these Kþ channels and thus be particularly relevant to Kþ secretion into the aqueous humor.

4. Transfer of Water from Stroma to Aqueous Humor

The pathways for water secretion across the ciliary epithelium are incompletely understood (Fig. 1A). The specialized AQP water channels (Agre and Kozono, 2003; King et al., 2004) are thought to play a major role (Nielsen et al., 1993; Hasegawa et al., 1994; Stamer et al., 1994; Frigeri et al., 1995; Hamann et al., 1998; Zhang et al., 2002; Yamaguchi et al., 2006). AQP1 has been localized to the apical and basolateral membranes (Stamer et al., 1994; Hamann et al., 1998; Yamaguchi et al., 2006) and AQP4 to the basolateral surfaces of the NPE cells (Hamann et al., 1998; Yamaguchi et al., 2006). Agreement is incomplete whether AQP4 is (Hamann et al., 1998) or is not (Yamaguchi et al., 2006) also expressed in the NPE cell apical membranes.

In contrast, no AQP has yet been found in the PE cells. Possibly, water is taken from the stroma through unidentified AQPs. Alternatively, water might permeate other transporters, such as sodium glucose symports (Loike et al., 1996). Another possibility is that water might diVuse across the plasma membranes of these cells. In the absence of high contents of sphingomyelin and cholesterol, plasma membranes can display relatively high water permeability (Finkelstein, 1976). The lipid composition of the PE plasma membranes is unknown.

Irrespective of the precise permeating pathway, water is thought to follow uptake of solute from the stroma into the PE cells, cross the gap junctions into the NPE cells, and be released by local osmosis through AQP1 and AQP4 channels into the aqueous humor (Fig. 1A). This hypothesis is consistent with the observation that double knockout of AQP1 and AQP4 reduced IOP in mice (Zhang et al., 2002).

It is increasingly recognized that AQPs not only provide a conduit for water, and in some cases glycerol or gases, but may interact with other transporters in the plasma membranes with which they are clustered. In particular, proteins incorporating PDZ domains can interact with AQP1 and AQP2 (Cowan et al., 2000) and with AQP9 (Cowan et al., 2000; Pietrement et al., 2008). The full significance of this clustering is not yet clear. The eye’s AQPs and their regulation are considered more fully in Chapter 2 (Stamer et al., 2008).