Trace amine-associated receptors (TAAR) as targets for thyronamines

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3-iodothyronamine (T1AM), an endogenous derivative and degradation product of thyroid hormones, exerts several biological functions, like reduction of body temperature, heart rate, and metabolism, and is an agonist at trace amine-associated receptor 1 (TAAR1). TAAR1 was first deorphanized as receptor activated by trace amines, namely β-phenylethylamine, p-tyramine and tryptamine, but also by psychoactive compounds like MDMA, amphetamine and LSD. TAAR1 is a Gαs protein-coupled receptor and a member of the TAAR family consisting of nine subtypes in mammals. Here we test the hypothesis that the entire TAAR family may be activated by metabolites of thyroid hormones. Specifically, T1AM action at all TAAR family members, the evolutionary conservation of T1AM function at TAAR1, the molecular basis of ligand specificity and the functional relevance of TAAR redundancy will be studied. Further, the concept of an exclusive intracellular (not plasma membrane bound) signalling as well as non-G protein-mediated signalling of T1AM will be specifically addressed. As an outcome of this study we will fundamentally extent our knowledge of the molecular mechanisms and consequences of T1AM action.