UCSF

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.