Exploring the Non-Transcriptional Activity of Thyroid Hormone Derivatives
This work is premised on the hypothesis that thyroid hormone may be a substrate for the aromatic L-amino acid decarboxylase (AADC) and that the resulting iodothyronamines would have significant structural and perhaps functional similarity with several biogenic amines including the classical monoamine neurotransmitters. Previous reports have shown that several thyronamines are rapid and potent agonists of the trace amine-associated receptor 1 (TAAR1), a G protein-coupled receptor (GPCR). We hypothesized that thyronamines might function physiologically as classical neurotransmitters or neuromodulators. As such, we sought to screen thyronamines for activity with a variety of known monoamine transporters. Additionally we attempted to clone, express and screen the rat TAAR family of GPCRs for activity with thyronamines and a variety of phenethylamine (PEA), thyroid hormone, and amino acid derivatives.
Using our previously reported synthesis of these presumed thyroid hormone metabolites and a radioactive derivative of T1AM, we found that T1AM inhibits plasma membrane transport of norepinephrine and dopamine in synaptosomes, and also inhibits biogenic amine vesicular packaging in synaptic vesicles. We further demonstrate that T1AM is an inhibitor of the plasma membrane neurotransmitter transporters DAT and NET, and an inhibitor of the vesicular transporter VMAT2. This is a novel and exciting result, because T1AM is the first example of an endogenous substance that inhibits these transporters and suggests that T1AM may play a physiological role in regulating synaptic transmission with catecholamine neurons. In addition, we report that several PEA derivatives act as agonists of rTAAR4, both confirming previously identified compounds and discovering several additional agonists. Lastly, we show that a class of clinically used thyroid hormone derivatives act as agonists of TAAR1 with potential therapeutic relevance. Significantly, we expand on our understanding of trace amine-associated receptor ligand recognition and the physiological relevance of thyronamine/GPCR interactions.