Thyroid hormone – an iodinated molecule synthesized and secreted by the thyroid gland – plays a role in a number of processes in all vertebrates, including development, growth, energy homeostasis, cardiovascular and muscle-skeleton systems, and cognitive function. Thyroid hormone is secreted into the circulation and enters virtually all cells through membrane transporters, reaching the cell nucleus and interacting with thyroid hormone receptors (TR) to modulate gene expression. At the same time, thyroid hormone action can be modified on a cell-specific fashion through the controlled expression of the deiodinase group of enzymes. These are homodimeric Type I integral membrane selenoproteins composed of a single N-terminal trans-membrane segment connected to a larger globular domain with a Selenocysteine-containing active center embedded in a thioredoxin-like fold. Deiodinases modify the biological activity of thyroid hormone while it is diffusing from the cell membrane to the nucleus, both activating (type II deiodinase, D2) or inactivating (type III deiodinase, D3) thyroid hormone molecules. Intracellular and extracellular compartments tend to equilibrate and T3 molecules eventually leave the cells and slowly equilibrate with the general pool of T3 in the circulation. Therefore, D2-expressing tissues constitute sources of T3 to the general circulation. In fact, in healthy adult individuals, about 80–90% of the circulating T3 is produced by deiodination of T4, most of it via the D2 pathway; only 10-20% is directly secreted by the thyroid gland. In contrast, D3-expressing tissues function as metabolic sinks for thyroid hormones, mediating most of the daily thyroid hormone clearance. The type I deiodinase, D1, has lower affinity for both T4 and T3. However, given the very high D1 expression in liver and kidney, the D1 pathway also contributes to the general pool of circulating T3, although to a lesser extent when compared to D2. D1 has much higher affinity for conjugated thyroid hormone molecules, and thus could play a role in preserving iodine homeostasis.

The hypothalamus-pituitary-thyroid (HPT) axis is wired to preserve and defend the constancy of the general pool of circulating T3. Serum T3 concentration is remarkably stable throughout the life os an healthy adult individual, only to rapidly decrease in the event of starvation or systemic illness. Thus, the general pool of circulating T3 provides a steady supply of T3 to target cells. T3 enters cells through specific thyroid hormone transporters and diffuse to the cell nucleus to interact with nuclear receptors (TR). The T3-TR complex controls the expression of specific sets of T3-responsive genes, thus promoting T3-dependent biological effects. However, deiodinases modify thyroid hormone signaling on a cell-specific fashion. While on its way from the cell membrane to the nucleus, the flow of T3 molecules can be increased by the additional T3 supplied by the D2 pathway, which locally converts T4 to T3, or it can be decreased by the D3 pathway, which terminally inactivates T3 to T2. D2 is a short-lived endoplasmic-reticulum-resident protein that generates T3 in a cell compartment that is adjacent to the nucleus. This probably explains why D2 activity results in higher TR occupancy with locally generated T3. In contrast, D3 is long-lived and sorts to the plasma membrane, where it undergoes endocytosys and recycling via early endosomes; in neurons, D3 is also found incorporated into neurosecretory vesicles. Under hypoxic and/or ischemic conditions, D3 is redirected from the endoplasmic reticulum to the nuclear envelope, where it inactivates T3 and slows down cellular metabolism. The D1 pathway is not thought to affect intracellular thyroid hormone signaling other than by contributing to the general pool of circulating T3.