Ionic conductance and cataract: Two distinct non-selective cation channels in lens fiber cells

Abstract

Ionic conductance and cataract: Two distinct non-selective cation channels in lens fiber cells. The ocular lens is a dense avascular tissue composed primarily of terminally differentiated elongated fibre cells, layered to create a pseudocrystalline cellular architecture. A unique microcirculatory system exists in order to maintain lens transparency, tissue volume, ionic homeostasis and supply internalised fibre cells with metabolic and antioxidant support. Spatial segregation of transport functions within the lens creates a continuous flux of ions through the tissue structure. Na+ and Cl- enter the lens at both poles via the extracellular space, enter internalized fibre cells via a distributed low level entry pathway and leave the lens via an intracellular route mediated by gap junctions at the equator. This circulating flux of ions creates an extracellular fluid flow by solvent drag that also carries other solutes, including antioxidants and various nutrients. Electrical measurements conducted on whole lenses have shown that K+ permeability is restricted to the surface, while deeper fiber cells contain Na+ and Cl- permeability pathways. As equatorial epithelial cells differentiate into fiber cells a switch in cation permeability from predominately outward K+ conductance to inwardly directed Na+ conductance occurs. Likewise Cl- conductance changes from peripheral efflux to a deeper influx that’s necessary to preserve electroneutrality. Consequently short fiber cells are hyperpolarized, electrically tight and dominated by K+ conductances, while longer fiber cells are dominated by an outwardly rectifying anion channel. Recently by use of whole-cell patch-clamping of isolated rat lens fibre cells, we have discovered two classes of non-selective cation (NSC) channels identified by their sensitivity to trivalent cations. These channels are present in parallel to an anion conductance. As a result the NSC conductances introduce a variable Na+-permeable leak pathway resulting in depolarized reversal potential and a linear component to whole-cell current recordings. While one NSC conductance was inhibited by Gd3+, an additional La3+ sensitive NSC conductance was shown to be active upon isotonic and hypertonic cell shrinkage. NSC conductances therefore play an important role in the regulation of mature fiber cell volume. Given that cataractic lenses show an increased leak conductance, these channels may provide a target for preventative cataract treatment.