Species-specific influence of lithium on the activity of SLC13A5 (NACT)

Lithium-induced activation is specific for the transporter in primates

Elangovan Gopal, Ellappan Babu, Sabarish Ramachandran, Yangzom D. Bhutia, Puttur D Prasad, Vadivel Ganapathy

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)17-26
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume353
Issue number1
DOIs
StatePublished - Apr 1 2015

Fingerprint

Lithium
Primates
Citric Acid Cycle
Human Activities
Tryptophan
Amino Acids
Pan troglodytes
Caenorhabditis elegans
Zebrafish
Citric Acid
Haplorhini
Dogs
Mutation
Liver

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Species-specific influence of lithium on the activity of SLC13A5 (NACT) : Lithium-induced activation is specific for the transporter in primates. / Gopal, Elangovan; Babu, Ellappan; Ramachandran, Sabarish; Bhutia, Yangzom D.; Prasad, Puttur D; Ganapathy, Vadivel.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 353, No. 1, 01.04.2015, p. 17-26.

Research output: Contribution to journalArticle

Gopal, Elangovan ; Babu, Ellappan ; Ramachandran, Sabarish ; Bhutia, Yangzom D. ; Prasad, Puttur D ; Ganapathy, Vadivel. / Species-specific influence of lithium on the activity of SLC13A5 (NACT) : Lithium-induced activation is specific for the transporter in primates. In: Journal of Pharmacology and Experimental Therapeutics. 2015 ; Vol. 353, No. 1. pp. 17-26.
@article{39999e1833d544deb1869f378ca95c84,
title = "Species-specific influence of lithium on the activity of SLC13A5 (NACT): Lithium-induced activation is specific for the transporter in primates",
abstract = "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.",
author = "Elangovan Gopal and Ellappan Babu and Sabarish Ramachandran and Bhutia, {Yangzom D.} and Prasad, {Puttur D} and Vadivel Ganapathy",
year = "2015",
month = "4",
day = "1",
doi = "10.1124/jpet.114.221523",
language = "English (US)",
volume = "353",
pages = "17--26",
journal = "The Journal of pharmacology and experimental therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "1",

}

TY - JOUR

T1 - Species-specific influence of lithium on the activity of SLC13A5 (NACT)

T2 - Lithium-induced activation is specific for the transporter in primates

AU - Gopal, Elangovan

AU - Babu, Ellappan

AU - Ramachandran, Sabarish

AU - Bhutia, Yangzom D.

AU - Prasad, Puttur D

AU - Ganapathy, Vadivel

PY - 2015/4/1

Y1 - 2015/4/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84923323840&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84923323840&partnerID=8YFLogxK

U2 - 10.1124/jpet.114.221523

DO - 10.1124/jpet.114.221523

M3 - Article

VL - 353

SP - 17

EP - 26

JO - The Journal of pharmacology and experimental therapeutics

JF - The Journal of pharmacology and experimental therapeutics

SN - 0022-3565

IS - 1

ER -