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

doi:10.1124/jpet.114.221523

Cited by 29 publications

(46 citation statements)

References 27 publications

(47 reference statements)

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“…Plasma concentrations of lithium in patients treated with the substance range from 0.8 to 2.0 mM (Sproule, 2002). Our results and the findings reported in the literature Gopal et al, 2015) show that potentiation of human NaCT is optimal at lithium concentrations reached in human plasma of patients treated with lithium. In addition, although human NaCT is not very sensitive to citrate, our results show that lithium potentiates only at relatively low citrate concentrations ( Fig.…”

Section: Discussionsupporting

confidence: 79%

“…The finding that human NaCT is much less sensitive to citrate than its murine counterpart raises questions of whether NaCT is a valid target in humans and about the role NaCT plays in human physiology. Despite previous publications that have suggested that lithium ions potentiate NaCT for humans (and other primates) while NaCT from mice (and other rodents) are not Gopal et al, 2015), we have found that both human and mouse NaCT could be potentiated by lithium ions. we found that human and mouse NaCT could both be potentiated by lithium ions.…”

Section: Discussioncontrasting

confidence: 51%

“…Weight gain is one of the side effects of lithium therapy. As pointed out by Gopal et al (2015), this weight gain is likely caused by an enhanced NaCTmediated uptake of citrate in the liver, which results in an increased synthesis of fatty acids and cholesterol.…”

Section: Discussionmentioning

confidence: 99%

“…It has been deducted that for each trivalent citrate or divalent succinate molecule transported by NaCT, four sodium ions are cotransported, resulting in a net transport of positive charges through the membrane with each substrate molecule passing the membrane (Inoue et al, 2004). Both rodent and human NaCT can be functionally expressed in Xenopus oocytes and, because of the electrogenic nature of NaCT, transport activity can be detected by applying the twomicroelectrode voltage clamp technique (Inoue et al, 2004;Brauburger et al, 2011;Gopal et al, 2015). Studying the functional and pharmacological properties of transporters by this technique has advantages over using radiolabeled substrate uptake assays, because transporter activity can be measured more directly and in real time.…”

Section: Introductionmentioning

confidence: 99%

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Electrophysiological Characterization of Human and Mouse Sodium-Dependent Citrate Transporters (NaCT/SLC13A5) Reveal Species Differences with Respect to Substrate Sensitivity and Cation Dependence

Zwart

Peeva

Rong

et al. 2015

J Pharmacol Exp Ther

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The citric acid cycle intermediate citrate plays a crucial role in metabolic processes such as fatty acid synthesis, glucose metabolism, and b-oxidation. Citrate is imported from the circulation across the plasma membrane into liver cells mainly by the sodium-dependent citrate transporter (NaCT; SLC13A5). Deletion of NaCT from mice led to metabolic changes similar to caloric restriction; therefore, NaCT has been proposed as an attractive therapeutic target for the treatment of obesity and type 2 diabetes. In this study, we expressed mouse and human NaCT into Xenopus oocytes and examined some basic functional properties of those transporters. Interestingly, striking differences were found between mouse and human NaCT with respect to their sensitivities to citric acid cycle intermediates as substrates for these transporters. Mouse NaCT had at least 20-to 800-fold higher affinity for these intermediates than human NaCT. Mouse NaCT is fully active at physiologic plasma levels of citrate, but its human counterpart is not. Replacement of extracellular sodium by other monovalent cations revealed that human NaCT was markedly less dependent on extracellular sodium than mouse NaCT. The low sensitivity of human NaCT for citrate raises questions about the translatability of this target from the mouse to the human situation and raises doubts about the validity of this transporter as a therapeutic target for the treatment of metabolic diseases in humans.

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Section: Discussionsupporting

confidence: 79%

Section: Discussioncontrasting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Electrophysiological Characterization of Human and Mouse Sodium-Dependent Citrate Transporters (NaCT/SLC13A5) Reveal Species Differences with Respect to Substrate Sensitivity and Cation Dependence

Zwart

Peeva

Rong

et al. 2015

J Pharmacol Exp Ther

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“…It was expressed in normal human intestine (Weerachayaphorn and Pajor, 2008); however, mRNA of SLC13A5 was found not to be expressed in normal human intestine by RT-PCR (Arai et al, 2012). Gopal et al (2015) reported that SLC13A5 also was predominantly expressed in the liver.…”

Section: Discussionmentioning

confidence: 99%

Molecular characterization, tissue expression profile, and SNP analysis of porcine SLC13A5

Wang¹,

Jiang²,

Ma³

2015

Genet. Mol. Res.

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ABSTRACT. Solute carrier family 13 (sodium-dependent citrate transporter member 5, SLC13A5) gene has been recently found to play an important role in intramuscular fat content in pigs. In this study, the full-length cDNA of porcine SLC13A5 was obtained from the longissimus dorsi muscle of Shaziling pigs, using the rapid amplification of cDNA ends technique. Full-length porcine SLC13A5 cDNA was 2118 bp, with a 1665-bp open reading frame encoding 554 amino acids. The porcine SLC13A5 protein was analyzed using bioinformatic methodology, and found to include 18 potential phosphorylation sites (including six serine, nine threonine, and three tyrosine) and eight putative transmembrane domains. One single nucleotide polymorphism (SNP) site, A251G, was identified by polymerase chain reaction (PCR)-restriction fragment (2015) length polymorphism and the associations of this SNP with age at 100 kg and corrected back fat thickness were found to be not significant. Expression of SLC13A5 was evaluated in ten tissues from 25-day-old full-sib Yorkshire and Shaziling piglets (both N = 3), using quantitative PCR analysis. Expression levels of SLC13A5 differed significantly between the breeds in cecum, liver and crureus muscle. In each breed, gene expression levels were significantly different in longissimus dorsi muscle, compared to the nine other tissues. This study has laid the foundation for further investigations of the molecular mechanisms of SLC13A5 in pigs.

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Peptide Tags and Domains for Expression and Detection of Mammalian Membrane Proteins at the Cell Surface

Jaramillo-Martinez

Ganapathy

Urbatsch

2022

Methods in Molecular Biology

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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

Cited by 29 publications

References 27 publications

Electrophysiological Characterization of Human and Mouse Sodium-Dependent Citrate Transporters (NaCT/SLC13A5) Reveal Species Differences with Respect to Substrate Sensitivity and Cation Dependence

Electrophysiological Characterization of Human and Mouse Sodium-Dependent Citrate Transporters (NaCT/SLC13A5) Reveal Species Differences with Respect to Substrate Sensitivity and Cation Dependence

Molecular characterization, tissue expression profile, and SNP analysis of porcine SLC13A5

Peptide Tags and Domains for Expression and Detection of Mammalian Membrane Proteins at the Cell Surface

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