Identification of a nonselective cation channel in isolated lens fiber cells that is activated by cell shrinkage

Abstract

The initiation of lens cataract has long been associated with the development of a membrane "leak" in lens fiber cells that depolarizes the lens intracellular potential and elevates intracellular Na(+) and Ca(2+) concentrations. It has been proposed that the leak observed in cataractous lenses is due to the activation of a nonselective cation (NSC) conductance in the normal electrically tight fiber cells. Studies of the membrane properties of isolated fiber cells using the patch-clamp technique have demonstrated a differentiation-dependent shift in membrane permeability from K(+)-dominated in epithelial and short fiber cells toward larger contributions from anion and NSC conductances as fiber cells elongate. In this study, the NSC conductances in elongating lens fiber cells are demonstrated to be due to at least two distinct classes: a Gd(3+)-sensitive, mechanosensitive channel whose blockade is essential for obtaining viable isolated fiber cells, and a second Gd(3+)-insensitive, La(3+)-sensitive conductance that appears to be activated by cell shrinkage. This second conductance was eliminated by the replacement of extracellular Na(+) with the impermeant cation N-methyl-d-glucamine and was potentiated by both hypertonic stress and isosmotic cell shrinkage evoked by the replacement of extracellular Cl(-) with the impermeant anion gluconate. This additional cation conductance may play a role in normal lens physiology by mediating regulatory volume increase under osmotic or other physiological challenges. Since the inappropriate activation of NSC channels is implicated in the initiation of lens cataract, they represent potential targets for the development of novel anticataract therapies.