Human sodium-coupled citrate transporter, the orthologue of Drosophila Indy, as a novel target for lithium action.
NaCT (sodium-coupled citrate transporter) is an Na(+)-coupled citrate transporter identified recently in mammals that mediates the cellular uptake of citrate. It is expressed predominantly in the liver. NaCT is structurally and functionally related to the product of the Indy (I'm not dead yet) gene in Drosophila, the dysfunction of which leads to lifespan extension. Here, we show that NaCT mediates the utilization of extracellular citrate for fat synthesis in human liver cells, and that the process is stimulated by lithium. The transport function of NaCT is enhanced by lithium at concentrations found in humans treated with lithium for bipolar disorders. Valproate and carbamazepine, two other drugs that are used for the treatment of bipolar disorder, do not affect the function of NaCT. The stimulatory effect of Li+ is specific for human NaCT, since NaCTs from other animal species are either inhibited or unaffected by Li+. The data also suggest that two of the four Na(+)-binding sites in human NaCT may become occupied by Li+ to produce the stimulatory effect. The stimulation of NaCT in humans by lithium at therapeutically relevant concentrations has potential clinical implications. We also show here that a single base mutation in codon-500 (TTT-->CTT) in the human NaCT gene, leading to the replacement of phenylalanine with leucine, stimulates the transport function and abolishes the stimulatory effect of lithium. This raises the possibility that genetic mutations in humans may lead to alterations in the constitutive activity of the transporter, with associated clinical consequences.
Inoue
Katsuhisa
K
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA 30912, USA.
Zhuang
Lina
L
Maddox
Dennis M
DM
Smith
Sylvia B
SB
Ganapathy
Vadivel
V
D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D017173:Caenorhabditis elegans; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D002460:Cell Line; D002951:Citrates / Q000378:metabolism*; D003001:Cloning, Molecular; D029382:Dicarboxylic Acid Transporters / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008094:Lithium / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D051381:Rats; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D027981:Symporters / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D015027:Zebrafish
D002951:Citrates; D029382:Dicarboxylic Acid Transporters; D029721:Drosophila Proteins; C417606:Indy protein, Drosophila; D011994:Recombinant Proteins; C470492:SLC13A5 protein, human; D027981:Symporters; D008094:Lithium