Sodium-coupled nonelectrolyte transport across epithelia: emerging concepts and directions

Since the proposal of the sodium-gradient hypothesis, research efforts have focused on two major areas: 1) establishing the thermodynamic efficacy of the electrochemical gradient for sodium as a driving force for uphill solute accumulation, and 2) determining the mechanism of energy coupling in cotransport systems. On the whole it is now reasonably well established that the Na+ electrochemical gradient can indeed energize the uphill accumulation of various nonelectrolytes in epithelia. This conclusion is substantiated by electrophysiological studies on intact epithelia using both conventional and Na+-selective microelectrodes and has been repeatedly verified in studies using brush-border membrane vesicles. One important additional concept that has emerged from these studies is that the overall transport process is intimately associated with, and perhaps controlled by, the electrical properties of leaky epithelia. The mechanism of energy coupling, as deduced from kinetic studies and modeling, has proven to be more elusive. Interpretations of earlier kinetic measurements on intact epithelia are complicated by unstirred layer effects and varying electrochemical Na+ gradients. Even more recent studies using brush-border membrane vesicles have failed to provide a unified mechanism, even for Na+-glucose transport, because of the various methods used to extract kinetic parameters and the variety of assumptions underlying different kinetic models. The common assumption that a translocation step rate limits the coupled entry process has been recently challenged, leading to novel proposals that are not based on mobile carriers. Future mechanistic studies will undoubtedly rely on recent advances in the isolation and purification of Na+-dependent proteins and their subsequent reconstitution into well-defined artificial membranes.