Mechanisms of thyroid hormone action (original) (raw)
Thyroid hormone is produced by the thyroid gland, which consists of follicles in which thyroid hormone is synthesized through iodination of tyrosine residues in the glycoprotein thyroglobulin (6, 7). Thyroid stimulating hormone (TSH), secreted by the anterior pituitary in response to feedback from circulating thyroid hormone, acts directly on the TSH receptor (TSH-R) expressed on the thyroid follicular cell basolateral membrane (8). TSH regulates iodide uptake mediated by the sodium/iodide symporter, followed by a series of steps necessary for normal thyroid hormone synthesis and secretion (9). Thyroid hormone is essential for normal development, growth, neural differentiation, and metabolic regulation in mammals (2, 3, 10) and is required for amphibian metamorphosis (11). These actions are most apparent in conditions of thyroid hormone deficiency during development, such as maternal iodine deficiency or untreated congenital hypothyroidism, manifesting as profound neurologic deficits and growth retardation (6). More subtle and reversible defects are present when ligand deficiency occurs in the adult (12).
There are two TR genes, _TR_α and _TR_β, with different patterns of expression in development and in adult tissues (2, 13). _TR_α has one T3-binding splice product, TR_α_1, predominantly expressed in brain, heart, and skeletal muscle, and two non–T3-binding splice products, TR_α_2 and TR_α_3, with several additional truncated forms. _TR_β has three major T3-binding splice products: TR_β_1 is expressed widely; TR_β_2 is expressed primarily in the brain, retina, and inner ear; and TR_β_3 is expressed in kidney, liver, and lung (2). Human genetics, animal models, and the use of selective pharmacologic agonists have been informative about the role and specificity of the two major isoforms (2, 14, 15). The selective actions of thyroid hormone receptors are influenced by local ligand availability (1, 16); by transport of thyroid hormone into the cell by monocarboxylate transporter 8 (MCT8) or other related transporters (17); by the relative expression and distribution of the TR isoforms (13) and nuclear receptor corepressors and coactivators (18); and, finally, by the sequence and location of the thyroid hormone response element (TRE; refs. 19, 20) (Figure 1). In addition, nongenomic actions of thyroid hormone, those actions not involving direct regulation of transcription by TR, have been increasingly recognized (21). Membrane receptors, consisting of specific integrin αv/β3 receptors, have been identified (22) and found to mediate actions at multiple sites, including blood vessels and the heart (23). Several studies have identified direct actions of TR on signal transduction systems (2, 24), which may be especially significant in relation to actions in cell proliferation and cancer.
Nuclear action of thyroid hormone. Shown are the key components required for thyroid hormone action, as demonstrated by a range of clinical observations. (A) The TR gene has 2 major isoforms, _TR_β and _TR_α; the structures of TR_α_1 and TR_α_2 (non–T3-binding) and TR_β_1 and TR_β_2 are shown. (B) The major thyroid hormone forms, T4, T3, and rT3. (C) Circulating T4 is converted locally in some tissues by membrane-bound D2 to the active form, T3. D3 converts T3 to the inactive rT3. (D) In specific tissues, such as brain, transporters such as MCT8 transport T4 and T3 into the cell. Unliganded TR heterodimerizes with RXR and binds to a TRE and then to a corepressor, such as NCoR or SMRT, repressing gene expression. T3 binding to the ligand-binding domain results in movement of the carboxyterminal helix 12, disruption of corepressor binding, and promotion of coactivator binding, which then leads to recruitment of polymerase III and initiation of gene transcription.
The broad range of genes whose expression is modified by thyroid hormone status makes studying the effect of thyroid hormone action a daunting challenge (25). Many of the actions of thyroid hormone are the result of potentiation or augmentation of other signal transduction pathways (Table 2 and ref. 5). In metabolic regulation, this includes potentiation of adrenergic signaling (26–29) as well as direct interaction with metabolic-sensing nuclear receptors (30–32). Similar direct receptor-to-receptor interactions and competition for overlapping DNA response elements are seen in neural differentiation, as TR interacts with chicken ovalbumin upstream transcription factor 1 (COUP-TF1) and retinoic acid receptor (RAR) (3, 33).
Thyroid signaling cross-talk with other pathways from in vitro and in vivo models and TR isoform preference
TR isoforms differ in length at both amino and carboxy termini and are differentially expressed developmentally and spatially (Figure 1). The structure of _TR_α and _TR_β are similar in the DNA and ligand domains and differ most in the amino terminus, and it is thought that the increased potency of _TR_α is related to its amino terminus (34). Fundamental differences in the ligand-binding pocket have permitted the design of ligands that specifically interact with _TR_α or _TR_β (35), and these have been important tools in the dissection of isoform-specific actions.
TR isoform selectivity for TRE sequences in genes that mediate thyroid hormone response have been seen in some studies, but not all. TRE sequences influence TR isoform interaction with ligand (36) and may influence coactivator recruitment (37). TR interaction with TREs is not static; as has been reported with other nuclear receptors, there is variation in the pattern of binding that may be influenced by the TRE (37). In vitro studies have shown some TR isoform preferences for specific TREs (38), although the ability to translate these findings to in vivo observations are likely limited. Liver gene profiling in _TR_α and _TR_β gene knockouts demonstrates little in the way of specific genes linked to a TR isoform (25). A recent study, however, suggests that the relative potency of activation may be controlled more by the relative expression of _TR_α or _TR_β in a tissue, rather than by TR isoform specificity for a specific TRE (39).