An understanding of TR subtypes is crucial because mutations that inactivate TR have been found to cause thyroid hormone resistance syndromes. The most common mutations occur in the TRβ2 subtype, resulting in incomplete negative feedback at the hypothalamic-pituitary level. This leads to elevated T4 levels but no suppression of TSH. When resistance is primarily at the hypothalamic-pituitary level, the patient may exhibit signs of hyperthyroidism due to the effects of elevated thyroid hormone levels on peripheral tissues, particularly the heart, mediated by TRα1. TR isoforms also present potential therapeutic targets. For instance, research is underway to develop TRβ-specific agonists that have beneficial effects on lipid and cholesterol metabolism without the risk of adverse cardiovascular side effects.

Emerging evidence suggests that T3 and T4 can have non-genomic actions mediated by receptors acting in the plasma membrane, mitochondria, or cytoplasm. In some cases, these receptors are modified versions of the nuclear thyroid receptors. Truncated isoforms of TRα1, for example, have been reported to bind T3 in the plasma membrane to mediate non-genomic effects in bone or bind T4 in the cytoplasm to regulate microfilament organization. It has also been reported that an integrin, αvβ3, can act as a T4 receptor at the cell surface to regulate cellular proliferation and angiogenesis through a non-genomic mechanism. The interplay between the classical genomic and non-genomic actions of thyroid hormones is likely to be another active area of future research.

1. The thyroid gland is located in the front part of the neck and consists of right and left lobes on the sides of the trachea, connected by an isthmus.
2. The thyroid gland produces tetraiodothyronine (thyroxine, T4) and triiodothyronine (T3).
3. The follicle is the fundamental unit of the gland, composed of a single spherical layer of epithelial cells surrounding a central lumen filled with colloid or stored hormone.
4. Iodide is transported into thyroid cells through a sodium-iodide symporter in the basolateral plasma membrane.
5. The enzyme complex of dual oxidase and thyroid peroxidase synthesizes T4 and T3 from tyrosine and iodide. Iodination of tyrosine residues in thyroglobulin is followed by coupling of two iodotyrosine molecules to produce the iodothyronines.
6. Stored T4 and T3 are released by endocytosis of thyroglobulin from the follicle lumen. Thyroglobulin is subsequently broken down in endolysosomes to release T4 and T3. Iodide is conserved by recycling any iodotyrosine molecules that were not coupled within thyroglobulin.
7. TSH stimulates all stages of T4 and T3 production in the thyroid gland through its plasma membrane receptor. These stages include iodide uptake, iodination and coupling, and retrieval from thyroglobulin. TSH also promotes glucose oxidation, protein synthesis, and growth of epithelial cells.
8. More than 99.5% of T4 and T3 circulate bound to proteins such as thyroid-binding globulin.
Bernal J, et al. Thyroid hormone transporters–functions and clinical implications. Nat Rev Endocrinol. 2015;11:406-417.
AnunderstandingofTRsubtypesisimportantbecauseinactivatingTRmutationshavebeenfoundtocausethyroid hormone resistance syndromes.ThemostcommonmutationsoccurintheTRβ2subtype,resultinginincompletenegativefeedbackatthehypothalamic-pituitarylevel.ThusT4levelsareelevated,butTSHisnotsuppressed.Whenresistanceispredominantlyatthehypothalamic-pituitarylevel,thepatientmayexhibitsignsofhyperthyroidismduetoeffectsofelevatedthyroidhormonelevelsonperipheraltissues,particularlyontheheart,mediatedbyTRα1.TRisoformsmayalsoofferpotentialtherapeutictargets.Forexample,researchisunderwaytodevelopTRβ-specificagoniststhathavebeneficialeffectsonlipidandcholesterolmetabolismwithouttheriskofadversecardiovascularsideeffects.
ThereisemergingevidencefornongenomicactionsofT3andT4thataremediatedbyreceptorsactingintheplasmamembrane,mitochondria,orcytoplasm.Insomecasesthesearemodifiedversionsofthenuclearthyroidreceptors.Forexample,truncatedisoformsofTRα1havebeenreportedthatbindT3intheplasmamembranetomediatenongenomiceffectsinboneorthatbindT4inthecytoplasmtoregulatemicrofilamentorganization.Ithasalsobeenreportedthatanintegrin,αvβ3,canactasaT4receptoratthecellsurfacetoregulatecellularproliferationandangiogenesisbyanongenomicmechanism.Theinterplaybetweentheclassicalgenomicandnongenomicactionsofthyroidhormonesislikelytobeanotheractiveareaoffutureresearch.
1.
The thyroid gland is situated in the ventral aspect of the neck and is composed of right and left lobes anterolateral to the trachea and connected by an isthmus.
2.
The thyroid gland is the source of tetraiodothyronine (thyroxine, T4) and triiodothyronine (T3).
3.
The basic endocrine unit in the gland is a follicle that consists of a single spherical layer of epithelial cells surrounding a central lumen that contains colloid or stored hormone.
4.
Iodide is taken up into thyroid cells by a sodium-iodide symporter in the basolateral plasma membrane.
5.
T4 and T3 are synthesized from tyrosine and iodide by the enzyme complex of dual oxidase and thyroid peroxidase. Tyrosine residues in thyroglobulin undergo iodination, after which two iodotyrosine molecules are coupled to yield the iodothyronines.
6.
Secretion of stored T4 and T3 requires retrieval of thyroglobulin from the follicle lumen by endocytosis. Thyroglobulin is then degraded in endolysosomes to liberate T4 and T3. Iodide is conserved by recycling any iodotyrosine molecules that did not undergo coupling within thyroglobulin.
7.
TSH acts on the thyroid gland via its plasma membrane receptor to stimulate all steps in the production of T4 and T3. These steps include iodide uptake, iodination and coupling, and retrieval from thyroglobulin. TSH also stimulates glucose oxidation, protein synthesis, and growth of epithelial cells.
8.
More than 99.5% of T4 and T3 circulates bound to the following proteins: thyroid-binding globulin,
Bernal J, et al. Thyroid hormone transporters–functions and clinical implications. Nat Rev Endocrinol. 2015;11:406-417.