Investigations of 3-iodothyronamine as a novel regulator of thyroid endocrinology
3-iodothyronamine (T1AM) is an endogenous thyroid hormone metabolite with distinct, acute biological effects that are largely opposite those of thyroid hormone. Administration of T1AM to rodents results in rapid and profound reduction in body temperature, heart rate, and metabolism. Since its discovery only five years ago, T1AM is emerging as a potentially key signaling molecule involved in thyroid hormone endocrinology. The structural similarities between T1AM and monoamine neurotransmitters as well as its parent compound, thyroid hormone, suggest an intriguing role for T1AM as both a neuromodulator and a hormone-like molecule that complements or regulates thyroid hormone action.
The known molecular targets of T1AM include both plasma membrane and intracellular proteins, suggesting that intracellular transport of T1AM may be an important component of its action. Using various cell lines, we show that, indeed, specific T1AM uptake occurs in multiple cell types. An RNAi screen targeting the SLC superfamily of transporter genes identifies eight transporters that may contribute to T1AM uptake in HeLa cells. Moreover, we demonstrate that T1AM is taken up into the nucleus of HepG2 cells, suggesting that T1AM might play a role in transcriptional regulation.
We also investigate the effect of T1AM on cellular entry of thyroid hormones. Transport inhibition studies reveal that T1AM displays differential inhibition of T3 and T4 cellular uptake by the specific thyroid hormone transporter MCT8 and by the multispecific organic anion transporting polypeptides (OATPs) 1A2 and 1C1, but does not affect thyroid hormone transport by OATP1B3. Given that OATP1A2, OATP1C1, and MCT8 are present in the brain, T1AM may modulate thyroid hormone delivery and activity in specific target regions in the central nervous system.
Finally, we identify α2-Macroglobulin (α2M) as a serum binding protein for T1AM. α2M is known for various functions in the body, including its unique role as a pan-protease inhibitor, as well as its potential significance in immune defense and modulation of neurotransmitter metabolism. In addition to the possible role of α2M as a carrier protein for T1AM, the discovery of α2M interaction with T1AM opens another interesting area of investigation into this thyroid hormone derivative and its mechanisms of action.