Species-specific influence of lithium on the activity of SLC13A5 (NACT): Lithium-induced activation is specific for the transporter in primates

NaCT (SLC13A5) is a Na⁺-coupled transporter for Krebs cycle intermediates and is expressed predominantly in the liver. Human NaCT is relatively specific for citrate compared with other Krebs cycle intermediates. The transport activity of human NaCT is stimulated by Li⁺, whereas that of rat NaCT is inhibited by Li⁺. We studied the influence of Li⁺ on NaCTs cloned from eight different species. Li⁺ stimulated the activity of only NaCTs from primates (human, chimpanzee, and monkey); by contrast, NaCTs from nonprimate species (mouse, rat, dog, and zebrafish) were inhibited by Li⁺. Caenorhabditis elegans NaCT was not affected by Li⁺. With human NaCT, the Li⁺-induced increase in transport activity was associated with the conversion of the transporter from a low-affinity/high-capacity type to a high-affinity/low-capacity type. H⁺ was able to substitute for Li⁺ in eliciting the stimulatory effect. The amino acid Phe500 in human NaCT was critical for Li⁺/H⁺-induced stimulation. Mutation of this amino acid to tryptophan (F500W) markedly increased the basal transport activity of human NaCT in the absence of Li⁺, but the ability of Li⁺ to stimulate the transporter was almost completely lost with this mutant. Substitution of Phe500 with tryptophan in human NaCT converted the transporter from a lowaffinity/high-capacity type to a high-affinity/low-capacity type, an effect similar to that of Li⁺ on the wild-type NaCT. These studies show that Li⁺-induced activation of NaCT is specific for the transporter in primates and that the region surrounding Phe500 in primate NaCTs is important for the Li⁺ effect.