Structure, function, and expression pattern of a novel sodium-coupled citrate transporter (NaCT) cloned from mammalian brain

Katsuhisa Inoue, Lina Zhuang, Dennis M. Maddox, Sylvia B Smith, Vadivel Ganapathy

Research output: Contribution to journalArticle

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Abstract

Citrate plays a pivotal role not only in the generation of metabolic energy but also in the synthesis of fatty acids, isoprenoids, and cholesterol in mammalian cells. Plasma levels of citrate are the highest (∼135 μM) among the intermediates of the tricarboxylic acid cycle. Here we report on the cloning and functional characterization of a plasma membrane transporter (NaCT for Na+-coupled citrate transporter) from rat brain that mediates uphill cellular uptake of citrate coupled to an electrochemical Na+ gradient. NACT consists of 572 amino acids and exhibits structural similarity to the members of the Na+-dicarboxylate cotransporter/Na+-sulfate cotransporter (NaDC/NaSi) gene family including the recently identified Drosophila Indy. In rat, the expression of NaCT is restricted to liver, testis, and brain. When expressed heterologously in mammalian cells, rat NaCT mediates the transport of citrate with high affinity (Michaelis-Menten constant, ∼20 μM) and with a Na+:citrate stoichiometry of 4:1. The transporter does interact with other dicarboxylates and tricarboxylates but with considerably lower affinity. In mouse brain, the expression of NaCT mRNA is evident in the cerebral cortex, cerebellum, hippocampus, and olfactory bulb. NaCT represents the first transporter to be identified in mammalian cells that shows preference for citrate over dicarboxylates. This transporter is likely to play an important role in the cellular utilization of citrate in blood for the synthesis of fatty acids and cholesterol (liver) and for the generation of energy (liver and brain). NaCT thus constitutes a potential therapeutic target for the control of body weight, cholesterol levels, and energy homeostasis.

Original languageEnglish (US)
Pages (from-to)39469-39476
Number of pages8
JournalJournal of Biological Chemistry
Volume277
Issue number42
DOIs
StatePublished - Oct 18 2002

Fingerprint

Citric Acid
Brain
Sodium
Liver
Rats
Cholesterol
Cells
Fatty Acids
Citric Acid Cycle
Membrane Transport Proteins
Cloning
Olfactory Bulb
Terpenes
Cell membranes
citrate-binding transport protein
sodium citrate
Stoichiometry
Cerebral Cortex
Cerebellum
Sulfates

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Structure, function, and expression pattern of a novel sodium-coupled citrate transporter (NaCT) cloned from mammalian brain. / Inoue, Katsuhisa; Zhuang, Lina; Maddox, Dennis M.; Smith, Sylvia B; Ganapathy, Vadivel.

In: Journal of Biological Chemistry, Vol. 277, No. 42, 18.10.2002, p. 39469-39476.

Research output: Contribution to journalArticle

Inoue, Katsuhisa ; Zhuang, Lina ; Maddox, Dennis M. ; Smith, Sylvia B ; Ganapathy, Vadivel. / Structure, function, and expression pattern of a novel sodium-coupled citrate transporter (NaCT) cloned from mammalian brain. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 42. pp. 39469-39476.
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