Thyroid iodide efflux: a team effort?

Abstract

The thyroid hormones thyroxine (T(4)) and triiodothyronine (T(3)) play key roles in regulating development, growth and metabolism in pre- and postnatal life. Iodide (I(-)) is an essential component of the thyroid hormones and is accumulated avidly by the thyroid gland. The rarity of elemental iodine and I(-) in the environment challenges the thyroid to orchestrate a remarkable series of transport processes that ultimately ensure sufficient levels for hormone synthesis. In addition to actively extracting circulating I(-), thyroid follicular epithelial cells must also translocate I(-) into a central intrafollicular compartment, where thyroglobulin is iodinated to form the protein precursor to T(4) and T(3). In the last decade, several bodies of evidence render questionable the notion that I(-) exits thyrocytes solely via the Cl(-)/I(-) exchanger Pendrin (SLC26A4), therefore necessitating reconsideration of several other candidate I(-) conduits: the Cl(-)/H(+) antiporter, CLC-5, the cystic fibrosis transmembrane conductance regulator (CFTR) and the sodium monocarboxylic acid transporter (SMCT1).

Figure 1. Organization of thyroid follicular epithelium and summary of key processes in hormone synthesis

A, haematoxylin and eosin stained section of neonatal pig thyroid tissue showing follicles consisting of epithelial cells and colloid-filled lumina. Scale bar = 50 μm. B, schematic depiction of thyroid follicle showing polarized orientation of epithelial cells (A, apical; BL, basolateral). Arrows indicate directional movements of thyroglobulin (Tg) and I⁻, uptake of iodinated Tg (Tg*) pro-hormone and release of T₃ and T₄. Circulating I⁻ levels in blood range between 10 and 100 μm (Kogai et al. 2006; Shcheynikov et al. 2008). Due to rapid intrafollicular Tg* formation, the colloid can be regarded as essentially devoid of free I⁻. C, basic steps involved in thyroid hormone formation are shown. Left, TSH binds its receptor and promotes thyroid hormone production. Circulating I⁻ is taken up at the basolateral membrane via the sodium-iodide symporter, NIS (Dai et al. 1996). Intracellular I⁻ accumulates and moves across the apical membrane by a process believed at least partially to be mediated by Pendrin, thereby providing this essential element for hormone synthesis. Middle, Tg is produced by the thyroid epithelial cells, processed along the synthetic pathway and released into the follicular lumen. Top, H₂O₂, required for the coupling of I⁻ and Tg, is generated by DUOX2 at the apical membrane. Reaction of these components is catalysed by TPO; I⁻ is coupled to many tyrosine residues within Tg, of which only a select number are hormonogenic. Tyrosine residues can be either mono- or di-iodinated. TPO also facilitates coupling of these residues to form precursor to T₃ (mono- + di-iodinated) and T₄ (2 × di-iodinated). Right, outline of endocytosis and processing of the pro-hormone. Some Tg* is proteolysed at the apical surface by externalized cathepsins prior to uptake (Brix et al. 1996). Internalized Tg* is proteolysed by cathepsins within lysosomes (Dunn et al. 1991; Dunn & Dunn, 2001). T₃ and T₄ exit basolaterally in a process at least partially mediated by MCT8, a monocarboxylic acid transporter of the SLC16 family (Di Cosmo et al. 2010). Un-utilized iodotyrosines are further degraded by iodotyrosine dehalogenases and recycled.

Figure 2. Outline of the perchlorate discharge test

Subjects are infused with radioiodide tracer (*I) prior to perchlorate challenge. A, intact trapping depends on efficient exit of I⁻ (*I) from the cell and into the follicle lumen. On challenge with perchlorate, levels generally remain steady; any decline is <10% below baseline. B, impaired exit of I⁻ (*I) shown in this panel. Trapping cannot proceed without transport of I⁻ (*I) into the follicular lumen. Perchlorate competes for NIS-mediated uptake; untrapped intracellular I⁻ (*I) is released basolaterally into the circulation, resulting in a decrease in thyroid counts. C, this idealized plot illustrates time courses of radioiodide counts measured over the thyroid after perchlorate administration (arrow) in the case of either intact or impaired trapping.

Figure 3. Models showing how CLC-5 and CFTR might directly facilitate I⁻ efflux, as well as indirectly by coupling with Pendrin

Left, direct I⁻ transport via either CLC-5 and/or CFTR. Middle, efflux of Cl⁻ through CLC-5 provides a counter-ion for Pendrin-mediated I⁻ efflux. Note that stoichiometry of CLC-5 is 2 Cl⁻ to 1 H⁺; only one Cl⁻ is shown for simplicity. Right, similarly, CFTR-mediated Cl⁻ efflux also can furnish a counter-ion for driving Pendrin exchange activity.