PUBLICATION
Species-specific Influence of Lithium on the Activity of SLC13A5 (NaCT): Lithium-induced Activation is Specific for the Transporter in Primates
- Authors
- Gopal, E., Babu, E., Ramachandran, S., Bhutia, Y.D., Prasad, P.D., Ganapathy, V.
- ID
- ZDB-PUB-150127-14
- Date
- 2015
- Source
- The Journal of pharmacology and experimental therapeutics 353(1): 17-26 (Journal)
- Registered Authors
- Keywords
- citric acid, drug transport, hepatic transport, membrane transport, transporters
- MeSH Terms
-
- Animals
- Biological Transport
- Caenorhabditis elegans
- Cell Line
- Citrates/metabolism
- Dogs
- Female
- Humans
- Lithium Compounds/pharmacology*
- Macaca mulatta
- Mice
- Mutation
- Oocytes/metabolism
- Pan troglodytes
- Rats
- Species Specificity
- Symporters/genetics
- Symporters/metabolism*
- Xenopus laevis
- Zebrafish
- PubMed
- 25617245 Full text @ J. Pharmacol. Exp. Ther.
Citation
Gopal, E., Babu, E., Ramachandran, S., Bhutia, Y.D., Prasad, P.D., Ganapathy, V. (2015) Species-specific Influence of Lithium on the Activity of SLC13A5 (NaCT): Lithium-induced Activation is Specific for the Transporter in Primates. The Journal of pharmacology and experimental therapeutics. 353(1):17-26.
Abstract
NaCT (SLC13A5) is a Na+-coupled transporter for Krebs cycle intermediates; it is expressed predominantly in the liver. Human NaCT is relatively specific for citrate compared to other Krebs cycle intermediates. The transport activity of human NaCT is stimulated by Li+ whereas that of rat NaCT is inhibited by Li+. Here 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); in contrast, NaCTs from non-primate species (mouse, rat, dog, and zebrafish) were inhibited by Li+. C. 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 phenylalanine at position 500 in human NaCT was critical for Li+/H+-induced stimuation. 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 Phe-500 with tryptophan in human NaCT converted the transporter from a low-affinity/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 Phe-500 in primate NaCTs is important for the Li+ effect.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping