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.