MECHANISMS OF ACTION OF THYROID HORMONES
Thyroid hormone mechanisms of action can be classi-fied into two types: (1) genomic or nuclear and (2) nongenomic, including effects at the plasma mem-brane and mitochondria. Genomic effects involve modi-fication of gene transcription, are mediated only by T3, and require at least several hours to detect. Nongenomic actions are generally rapid in onset and occur in response to T4 and some T4 metabolites (e.g., rT3, T3, and T2).
Thyroid hormone receptors are members of a super-family of nuclear receptors that includes receptors for estrogen, glucocorticoid, mineralocorticoid, retinoic acid, 9-cis-retinoic acid (retinoid X), and vitamin D. Similar to the mechanism of action of lipophilic steroid hormones, the lipophilic T3 binds to a protein receptor to form a complex and the hormone–receptor complex binds to an appropriate hormone response el-ement on DNA to alter the transcription of specific genes. The current view of the mechanism of thyroid hormone action differs from that for steroid hor-mones, however, in three major ways: (1) There are ap-parently no cytosolic receptors for thyroid hormones. (2) The nuclear TRs can bind to DNA nucleotide se-quences in the regulatory region of thyroid hormone– responsive genes in the absence of thyroid hormone binding. (3) In the absence of T3 binding, TR bound to these specific areas of DNA may repress or promote the transcription of the associated thyroid hormone-responsive gene.
The nongenomic actions of thyroid hormone are in-creasingly recognized as physiologically significant. Nongenomic actions may be observed within minutes of stimulation and respond to a range of thyroid hormone metabolites (T4, T3, rT3, T2). The magnitude of nonge-nomic actions is usually only a few fold in contrast to the multifold genomic actions. The nongenomic actions (Table 65.2) may involve interactions with components of the cellular signal transduction pathways, such as cyclic adenosine monophosphate (cAMP), phos-phatidyl inositol, and protein kinases. Examples include effects on cellular respiration, cell morphology, vascular tone, and ion homeostasis. Possible nongenomic targets of thyroid hormone include the plasma membrane, cy- toskeleton, sarcoplasmic reticulum, mitochondria, and contractile elements of vascular smooth muscle.