3,5-T2 is an alternative ligand for the thyroid hormone receptor β1

Area of Science:

• Endocrinology
• Molecular Biology
• Genetics

Background:

• Nuclear receptors often exhibit tissue-specific ligand interactions.
• Thyroid hormone metabolites, like 3,5-diiodothyronine (T(2)), are products of deiodination from active hormones such as triiodothyronine (T(3)).

Purpose of the Study:

• To investigate 3,5-diiodothyronine (T(2)) as an alternative ligand for thyroid hormone receptor beta1 (TRβ1).
• To explore the differential activation of TRβ1 isoforms by T(2) and T(3) and their functional relevance.

Main Methods:

• Cloning of two tilapia TRβ isoforms.
• Ligand binding and transactivation assays using human and tilapia TRβ1 isoforms.
• Analysis of chimeric TRβ1 receptors.
• Evaluation of mRNA expression and regulation by T(2) and T(3) in vivo.

Main Results:

• T(2) activates human and long tilapia TRβ1, but not the short tilapia isoform.
• A specific 9-amino acid insert in the ligand-binding domain of tilapia TRβ1 is crucial for T(2) activation.
• The N-terminus of TRβ1 is essential for T(2)-mediated transactivation, suggesting interaction with the ligand-binding domain.
• Long TRβ1 expression is significantly higher than the short isoform, with differential regulation by T(2) and T(3).

Conclusions:

• T(2) functions as an alternative ligand for TRβ1, impacting tissue-specific receptor activity.
• Thyroid hormone metabolites previously considered inactive may play significant biological roles.
• Nuclear receptors can interact with alternative ligands, expanding their known functional mechanisms and tissue-specific actions.