Endocrinology 6 - Thyroid Hormone Signalling How does thyroid hormone signal to its target cells to elicit a physiological response? - Signal transduction pathway activated by thyroid hormone Its neither made in the peptide nor steroid hormone - We start with tyrosine (amino acid) - And through a process of iodisation reactions (adding iodine) it becomes thyroxine So, it's an amino acid hormone Other amino acid hormones include: - Catecholamines/adrenaline o Its derived from tyrosine Thyroid Hormone Signalling Pathway - It's not a peptide hormone so its receptor is not going to be on the cell surface - Thyroid hormones act a little bit like steroid hormones o Because they are able to cross that hydrophobic environment of the bilayer T4 T3 Thyroid hormone transporter Cytoplasm T4 D3 rT3 T3 D1/D2 V T3 Nucleus Corepressor RXR TR Coactivator T3 RXR TR TRE TRE Cell Entry - Can passively diffuse across the cell membrane - There are also specialist transporters that actively transport the thyroid hormones inside o Effgff MCT8 - Adds another level of control o By regulating the expression of these transporters
- Expression of these transporters are both spatially and temporally Extracellular T4 T3 T4 T3 Thyroid hormone transporter Cell membrane Lo Intracellular T4 T3 T4 T3 (D3) into reverse T3 (rT3) o This adds another level of regulation o Regulates the amount of hormone produced - Activity of deiodinases is highly regulated - o ubiquitination (adding a ubiquitin protein to a substance) · will target them for degradation T4 T3 T4 T3 D3 D1/D2 rT3 T3 Receptors Thyronine Receptor - TR - members of the "nuclear hormone receptor" family o steroid is also part of this family - we have a single thyronine receptor gene o multiple isoforms are formed from alternate splicing o share molecular structure - functional domains " all contain conserved DNA binding domain " all share a motif - which allows them to bind to T3 - different isoforms are expressed in different tissues at different DNA binding T3 binding TRa1 TRa2 TRß1 TRß2
TR is slightly unusual within the family as it will be found in its inactive state within the nucleus Even in the absence of its ligand (hormone) it will be localised within the nucleus and already be bound to its target gene Binds to a particular sequence (consensus): TAAGGTCA Wherever we find bases within the genome in this order, there is a high chance that the hormone will bind here Binding site = thyroid hormone response element (TRE) Usually found as a direct repeat; TAAGGTCA TAAGGTCA or everted repeat TAAGGTCA T&AGGTCA Inactive Thyroid Hormone Receptors - no ligand present, target cell is not responding to thyroxine - the receptor is localised at the TRE - but the target gene will be not be transcribed o because the THR forms a complex with some other proteins (RXR and corepressor proteins) - stops the GENERAL TRANSCRIPTION MACHINERY (including rna polymerase) from that target gene promoter - So you cannot get expression