Na+-inhibitory sites of the Na+/H+ exchanger are Li+ substrate sites

Amiloride-inhibitable Li+ influx in dog red blood cells is mediated by the Na+/H+ exchanger, NHE. However, there are substantial differences between the properties of Li+ transport and Na+ transport through the NHE. Li+ influx is activated by cell shrinkage, and Na+ influx is not, as we reported previously (Dunham PB, Kelley SJ, and Logue PJ. Am J Physiol Cell Physiol 287: C336-C344, 2004). Li+ influx is a sigmoidal function of its concentration, and Na+ activation is linear at low Na+ concentrations. Li+ does not inhibit its own influx; in contrast, Na+ inhibits Na+ influx. Li+ prevents this inhibition by Na+. Na+ is a mixed or noncompetitive inhibitor of Li+ influx, implying that both a Na+ and a Li+ can be bound at the same time. In contrast, Li+ is a competitive inhibitor of Na+ influx, suggesting Li+ binding at one class of sites on the transporter. Because the properties of Li+ transport and Na+ transport are different, a simple explanation is that Na+ and Li+ are transported by separate sites. The similarities of the properties of Li+ transport and the inhibition of Na+ transport by Na+ suggest that Li+ is transported by the Na+-inhibitory sites.