Corneal surface and stromal hydration is maintained by the movement of Na + , K + , and Cl" across the apical and basolateral membranes of the epithelium and the corneal endothelium (Fig. 4). The active transport of these ions is responsible for the tear-side negative potential difference of the corneal epithelial cells. The ouabain-sensitive Na + /K + -ATPase on the basolateral side of the epithelium actively transports Na+ out of the cells
in exchange for K+ (Green, 1970). CP entry across the basolateral membrane of the epithelium is mediated by a loop diuretic-sensitive Na + /K + / CP cotransporter (Klyce, 1972; Marshall and Klyce, 1983). This CP entry occurs against an electrochemical potential and is ouabain sensitive, suggesting that CP entry is coupled to the Na + /K + -ATPase activity. The Na + / K + /CP cotransporter elevates the intracellular CP concentration to three to four times greater than that expected from simple equilibrium, enabling the passive transport of CP through CP channels located on the apical side. K+ has low paracellular permeability, and it enters the cells through Na + / K + -ATPase (Marshall and Klyce, 1983) and exits through K+ channels located on the basolateral side.
In endothelial cells, the Na + /K + -ATPase is located on the basolateral side (Whikehart and Soppet, 1981; Whikehart et al., 1987). Inhibition of this pump with ouabain stops sodium transport, causes corneal swelling, and eliminates the transendothelial potential difference. Stromal CP concentration is in part determined by CP entry through a CP/HCO^ exchanger located on the apical membrane of the endothelial cells and exit through CP channel on the basolateral membrane of the endothelium (Bonanno et al., 1998). Also, Na + /K + /CP cotransporter present on the lateral membrane of the corneal endothelium contributes to the transendothelial CP flux (Jelamskii et al., 2000).
In corneal epithelial and endothelial cells, Na + /H+ exchanger, Na + -HCO^ symport, and CP /HCO^ exchanger are involved in the regulation of intracellular pH (Jentsch et al., 1985; Bonanno et al., 1999). Na + /H + exchanger is present in the basolateral membranes of both epithelial and endothelial cells. Na + /HCO^ transporter is predominantly localized on the basolateral side of the corneal endothelium and is weakly expressed in the corneal epithelium (Sun et al., 2000).
H + -lactate cotransport is present on the baslolateral side of the rabbit corneal epithelium (Bonanno, 1990) and on both sides of the rabbit corneal endothelium (Giasson and Bonanno, 1994). In addition, the corneal endothelium has a Na + -lactate cotransport process on the basolateral side (Giasson and Bonanno, 1994). These transport processes efficiently remove lactate from the highly glycolytic cornea, thereby preventing lac-tate-mediated corneal swelling.
The corneal epithelium is relatively impermeable to water-soluble compounds such as amino acids derived from tears (Thoft and Friend, 1972). The limbal blood supplies less than 20% of the corneal nutrients, with the aqueous humor being the primary source of amino acids (Thoft and Friend, 1972). Indeed, corneal endothelium, the principal barrier between the aqueous humor and the corneal epithelium, transports amino acids from the aqueous humor to the extracellular fluid of the stroma against a concentration gradient in the rabbit cornea (Riley, 1977). Consistent with this, the steady-state concentrations of most free amino acids in the stroma of the rabbit cornea are higher than those in the aqueous humor (Thoft and Friend, 1972; Riley et al., 1973; Riley and Yates, 1977). Similarly, the high glucose requirements of the corneal epithelium are met in part by the facilitated glucose transporter, GLUT 1, present on the basolateral side of the epithelium (Takahashi et al., 1996).
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