Cerebral Cortex Hyperthyroidism of Newborn Mct8-Deficient Mice Transiently Suppressed by Lat2 Inactivation

Núñez, Bárbara; Mena, Raquel Martínez de; Obregón, Marı́a Jesús; Font-Llitjós, Mariona; Nunes, Virginia; Palacı́n, Manuel; Dumitrescu, Alexandra M.; Morte, Beatriz; Bernal, Juan

doi:10.1371/journal.pone.0096915

Cited by 25 publications

(19 citation statements)

References 30 publications

(48 reference statements)

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“…Single loss-of-function mouse models for LAT2 (null knockout) [24][25][26] and TAT1 (premature STOP codon at position Y88) 17 were crossed to obtain double heterozygous mice and backcrossed to get the F2 generation, including dKO LAT2-TAT1 (dKO) mice. Genotype was confirmed by PCR and/or Sanger sequencing.…”

Section: Mouse Model Generation Genotyping and Experimental Dietsmentioning

confidence: 99%

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Cooperation of Antiporter LAT2/CD98hc with Uniporter TAT1 for Renal Reabsorption of Neutral Amino Acids

Vilches

Boiadjieva-Knöpfel

Bodoy

et al. 2018

JASN

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Reabsorption of amino acids (AAs) across the renal proximal tubule is crucial for intracellular and whole organism AA homeostasis. Although the luminal transport step is well understood, with several diseases caused by dysregulation of this process, the basolateral transport step is not understood. In humans, only cationic aminoaciduria due to malfunction of the basolateral transporter yLAT1/CD98hc (SLC7A7/SLC3A2), which mediates the export of cationic AAs, has been described. Thus, the physiologic roles of basolateral transporters of neutral AAs, such as the antiporter LAT2/CD98hc (SLC7A8/SLC3A2), a heterodimer that exports most neutral AAs, and the uniporter TAT1 (SLC16A10), which exports only aromatic AAs, remain unclear. Functional cooperation between TAT1 and LAT2/CD98hc has been suggested by studies but has not been evaluated To study the functional relationship of TAT1 and LAT2/CD98hc , we generated a double-knockout mouse model lacking TAT1 and LAT2, the catalytic subunit of LAT2/CD98hc (dKO LAT2-TAT1 mice). Compared with mice lacking only TAT1 or LAT2, dKO LAT2-TAT1 mice lost larger amounts of aromatic and other neutral AAs in their urine due to a tubular reabsorption defect. Notably, dKO mice also displayed decreased tubular reabsorption of cationic AAs and increased expression of yLAT1/CD98hc. The LAT2/CD98hc and TAT1 transporters functionally cooperate , and yLAT1/CD98hc may compensate for the loss of LAT2/CD98hc and TAT1, functioning as a neutral AA exporter at the expense of some urinary loss of cationic AAs. Cooperative and compensatory mechanisms of AA transporters may explain the lack of basolateral neutral aminoacidurias in humans.

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Section: Mouse Model Generation Genotyping and Experimental Dietsmentioning

confidence: 99%

“…Single ablation mouse models for LAT2 (null knockout) (KO LAT2) 26,25 and TAT1 (premature STOP codon at position Y88; TAT1 Y88*; KO TAT1) 17,24 in pure genetic background C57BL/6J were crossed to obtain the full range of possible genotypes including the double TAT1 and LAT2 knockout…”

Section: General Features Of the Double-knockout Lat2-tat1 Micementioning

confidence: 99%

Cooperation of Antiporter LAT2/CD98hc with Uniporter TAT1 for Renal Reabsorption of Neutral Amino Acids

Vilches

Boiadjieva-Knöpfel

Bodoy

et al. 2018

JASN

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“…Circulating thyroid hormones, thyroid-stimulating hormone and thyroid hormone-responsive genes remained unchanged, possibly because of functional compensation by Mct8 [8]. The role of Lat2 during the early postnatal cerebral cortex development is indicated by the combined Mct8/Lat2 mouse [9]. …”

Section: Introductionmentioning

confidence: 99%

Involvement of the L-Type Amino Acid Transporter Lat2 in the Transport of 3,3′-Diiodothyronine across the Plasma Membrane

Kinne¹,

Wittner²,

Wirth³

et al. 2015

Eur Thyroid J

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Thyroid hormones are transported across cell membranes by transmembrane transporter proteins, for example by members of the monocarboxylate transporter (MCT) and the L-type amino acid transporter (LAT) families. LATs consist of a light chain (e.g. LAT2) and a heavy chain (CD98), which is essential for their cell surface expression and functionality. The specificity of Lat2 for thyroid hormones and their metabolites and its role in their transport was not fully clear. This fact motivated us to establish a cell system to elucidate the uptake of thyroid hormones and their metabolites by mouse Lat2. The coinjection of cRNA coding for Lat2 and CD98 into Xenopus laevis oocytes resulted in a markedly increased level of 3,3′-diiodo-L-thyronine (3,3′-T₂) and to some extent also enhanced T₃ transport. To gain insight into properties of thyroid hormones and their metabolites transported by Lat2, we inhibited 3,3′-T₂ uptake by various iodothyronine derivatives. T₁ and T₂ derivatives as well as 2-aminobicyclo-[2,2,1]-heptane-2-carboxylic acid strongly competed with 3,3′-T₂ uptake. In addition, we performed T₂ uptake measurements with the thyroid hormone-specific transporter MCT8. For both Lat2 and MCT8, K_m values in a low micromolar range were calculated. We demonstrated that oocytes are a suitable system for thyroid hormone transport studies mediated by Lat2. Our data indicates that Lat2 compared to other thyroid hormone transporters prefers 3,3′-T₂ as the substrate. Thus, Lat2 might contribute to the availability of thyroid hormone by importing and/or exporting 3,3′-T₂, which is generated either by T₃ inactivation or by rapid deiodinase 1-mediated rT₃ degradation.

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“…Moreover, studies with Mct8-knockout (KO) mice showed its importance for TH transport (10,11), and Lat2 has been suggested to compensate for this defect in TH transport (12). In contrast to single KO mice (MCT8), double KO mice (MCT8/LAT2) did not show increased T 3 levels and expression of T 3 target genes in the cerebral cortex, so that it was assumed that Lat2 is important for the uptake of T 3 in the cerebral cortex (11).…”

mentioning

confidence: 99%

“…Both LAT1 and LAT2 are mainly expressed in brain, spleen, and placenta (28,31,32), and high levels of LAT2 are found in the kidney, with lower levels in the liver (28,29). This expression suggests that LAT2 has a role in the renal reabsorption of neutral amino acids (28), and murine Lat2 is thought to have a role in T 3 delivery to neurons in mice during the perinatal period (11). It has been reported that LAT1 transports 3,3Ј-diiodothyronine (3,3Ј-T 2 ), T 3 , and rT 3 (7,(33)(34)(35).…”

mentioning

confidence: 99%

Structural Insights Into Thyroid Hormone Transport Mechanisms of the L-Type Amino Acid Transporter 2

Hinz

Meyer

Kinne

et al. 2015

Molecular Endocrinology

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Thyroid hormones (THs) are transported across cell membranes by different transmembrane transporter proteins. In previous studies, we showed marked 3,3'-diiodothyronine (3,3'-T2) but moderate T3 uptake by the L-type amino acid transporter 2 (Lat2). We have now studied the structure-function relationships of this transporter and TH-like molecules. Our Lat2 homology model is based on 2 crystal structures of the homologous 12-transmembrane helix transporters arginine/agmatine antiporter and amino acid/polyamine/organocation transporter. Model-driven mutagenesis of residues lining an extracellular recognition site and a TH-traversing channel identified 9 sensitive residues. Using Xenopus laevis oocytes as expression system, we found that side chain shortening (N51S, N133S, N248S, and Y130A) expanded the channel and increased 3,3'-T2 transport. Side chain enlargements (T140F, Y130R, and I137M) decreased 3,3'-T2 uptake, indicating channel obstructions. The opposite results with mutations maintaining (F242W) or impairing (F242V) uptake suggest that F242 may have a gating function. Competitive inhibition studies of 14 TH-like compounds revealed that recognition by Lat2 requires amino and carboxylic acid groups. The size of the adjacent hydrophobic group is restricted. Bulky substituents in positions 3 and 5 of the tyrosine ring are allowed. The phenolic ring may be enlarged, provided that the whole molecule is flexible enough to fit into the distinctly shaped TH-traversing channel of Lat2. Taken together, the next Lat2 features were identified 1) TH recognition site; 2) TH-traversing channel in the center of Lat2; and 3) switch site that potentially facilitates intracellular substrate release. Together with identified substrate features, these data help to elucidate the molecular mechanisms and role of Lat2 in T2 transport.

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Cerebral Cortex Hyperthyroidism of Newborn Mct8-Deficient Mice Transiently Suppressed by Lat2 Inactivation

Cited by 25 publications

References 30 publications

Cooperation of Antiporter LAT2/CD98hc with Uniporter TAT1 for Renal Reabsorption of Neutral Amino Acids

Cooperation of Antiporter LAT2/CD98hc with Uniporter TAT1 for Renal Reabsorption of Neutral Amino Acids

Involvement of the L-Type Amino Acid Transporter Lat2 in the Transport of 3,3′-Diiodothyronine across the Plasma Membrane

Structural Insights Into Thyroid Hormone Transport Mechanisms of the L-Type Amino Acid Transporter 2

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