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

Abstract

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-<smlcap>L</smlcap>-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.

Dissecting thyroid hormone transport and metabolism in dendritic cells

“…Results of the study of T 3 transport in DCs in the presence of selective MCT10 and LAT2 inhibitors strengthen the main role of MCT10 in T 3 transport in DCs. In agreement, it was reported that LATs exhibit lower affinity than MCTs to transport THs (Friesema et al 2005) and a recent report revealed that LAT2 exhibits favored affinity for 3,3′-diiodothyronine (T 2 ), less for T 3 and no affinity for T 4 (Kinne et al 2015), reinforcing the evidence that LAT2 is not compelling for T 3 crossing through DC's membrane. Noteworthy, it was reported that MCT10 transports T 3 and T 4 in and out of cells (Friesema et al 2008), but it was suggested that it plays a prominent role in T 3 efflux (Muller et al 2014).…”

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

“…In recent studies we showed that Lat2 is involved in 3,3Ј-T 2 and to lower extent in T 3 uptake (36).…”

“…It has been reported that LAT1 transports 3,3Ј-diiodothyronine (3,3Ј-T 2 ), T 3 , and rT 3 (7,(33)(34)(35). We have recently shown that Lat2 transports 3,3Ј-T 2 ; transport of T 3 is less effective and rT 3 and T 4 are not transported at all (36).…”

Differential regulation of monocarboxylate transporter 8 expression in thyroid cancer and hyperthyroidism

“…Secondary TH transporters, i.e. the large neutral amino acid transporters LAT2 and LAT4 facilitate in and efflux of TH and other substrates (8,9,10). Thus, while the preferred TH substrate of LAT2 is 3,3′-T2 (4), LAT2 also transports large neutral amino acids, amino acid-related compounds and small amino acids (11).…”