The ability of thyroid hormone receptors to sense T₄ as an agonist depends on receptor isoform and on cellular cofactors

T₄ (3,5,3',5'-tetraiodo-L-thyronine) is classically viewed as a prohormone that must be converted to the T₃ (3,5,3'-triiodo-L-thyronine) form for biological activity. We first determined that the ability of reporter genes to respond to T₄ and to T₃ differed for the different thyroid hormone receptor (TR) isoforms, with TRα1 generally more responsive to T₄ than was TRα1. The response to T₄ vs T₃ also differed dramatically in different cell types in a manner that could not be attributed to differences in deiodinase activity or in hormone affinity, leading us to examine the role of TR coregulators in this phenomenon. Unexpectedly, several coactivators, such as steroid receptor coactivator-1 (SRC1) and thyroid hormone receptor-associated protein 220 (TRAP220), were recruited to TRα1 nearly equally by T₄ as by T₃ in vitro, indicating that TRα1 possesses an innate potential to respond efficiently to T₄ as an agonist. In contrast, release of corepressors, such as the nuclear receptor coreceptor NCoRω, from TRα1 by T₄ was relatively inefficient, requiring considerably higher concentrations of this ligand than did coactivator recruitment. Our results suggest that cells, by altering the repertoire and abundance of corepressors and coactivators expressed, may regulate their ability to respond to T₄, raising the possibility that T₄ may function directly as a hormone in specific cellular or physiological contexts.