Mechanism of Action of Thyroid Hormone

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Chapter: Essential pharmacology : Thyroid Hormones And Thyroid Inhibitors

Both T3 and T4 penetrate cells by active transport and produce majority of their actions by combining with a nuclear thyroid hormone receptor (TR) which belongs to the steroid and retinoid superfamily of intracellular receptors.


MECHANISM OF ACTION

 

Both T3 and T4 penetrate cells by active transport and produce majority of their actions by combining with a nuclear thyroid hormone receptor (TR) which belongs to the steroid and retinoid superfamily of intracellular receptors.

 

Two TR isoform families (TRα and TRβ) have been identified. Both bind T3 and function in similar manner, but their tissue distribution differs, which may account for quantitative differences in the sensitivity of different tissues to T3.

 

In contrast to the steroid receptor, the TR resides in the nucleus even in the unliganded inactive state. It is bound to the ‘thyroid hormone response element’ (TRE) in the enhancer region of the target genes along with corepressors (Fig. 18.4). This keeps gene transcription suppressed. When T3 binds to the ligand binding domain of TR, it heterodimerizes with retinoid X receptor (RXR) and undergoes a conformation change releasing the corepressor and binding the coactivator. This induces gene transcription production of specific mRNA and a specific pattern of protein synthesis various metabolic and anatomic effects.

 

Many of the effects, e.g. tachycardia, arrhythmias, raised BP, tremor, hyperglycaemia are mediated, at least partly, by sensitization of adrenergic receptors to catecholamines. Induction of adenylyl cyclase, proliferation of β adrenoceptors and a better coupling between these two has been demonstrated.

 

Apart from the nuclear T3 receptor, other sites of thyroid hormone action have been described. It acts on cell membrane to enhance amino acid and glucose entry and on mitochondria to increase oxygen consumption. At these sites T4 appears to be equipotent to T3, while at the nuclear receptor T4 has much lower affinity, and even when bound to the TR, T4 does not promote gene transcription.

 


 

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