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Cardiac effects of 3-iodothyronamine: a new aminergic system modulating cardiac function

Grazia Chiellini^*, Sabina Frascarelli^*, Sandra Ghelardoni^*, Vittoria Carnicelli^*, Sandra C. Tobias, Andrea DeBarber, Simona Brogioni, Simonetta Ronca-Testoni^*, Elisabetta Cerbai, David K. Grandy, Thomas S. Scanlan and Riccardo Zucchi^*,1

^* Dipartimento di Scienze dell’Uomo e dell’Ambiente, University of Pisa, Pisa, Italy;

Departments of Pharmaceutical Chemistry and Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California, USA;

Departments of Physiology and Pharmacology and Cell and Developmental Biology, Oregon Health and Science University, Portland, Oregon, USA; and

Dipartimento di Farmacologia, University of Florence, Florence, Italy

¹Correspondence: Dip. di Scienze dell’Uomo e dell’Ambiente, via Roma 55, 56126 Pisa, Italy. E-mail: r.zucchi{at}med.unipi.it

3-iodothyronamine T₁AM is a novel endogenous thyroid hormone derivative that activates the G protein-coupled receptor known as trace anime-associated receptor 1 (TAAR1). In the isolated working rat heart and in rat cardiomyocytes, T₁AM produced a reversible, dose-dependent negative inotropic effect (e.g., 27±5, 51±3, and 65±2% decrease in cardiac output at 19, 25, and 38 µM concentration, respectively). An independent negative chronotropic effect was also observed. The hemodynamic effects of T₁AM were remarkably increased in the presence of the tyrosine kinase inhibitor genistein, whereas they were attenuated in the presence of the tyrosine phosphatase inhibitor vanadate. No effect was produced by inhibitors of protein kinase A, protein kinase C, calcium-calmodulin kinase II, phosphatidylinositol-3-kinase, or MAP kinases. Tissue cAMP levels were unchanged. In rat ventricular tissue, Western blot experiments with antiphosphotyrosine antibodies showed reduced phosphorylation of microsomal and cytosolic proteins after perfusion with synthetic T₁AM; reverse transcriptase-polymerase chain reaction experiments revealed the presence of transcripts for at least 5 TAAR subtypes; specific and saturable binding of [¹²⁵I]T₁AM was observed, with a dissociation constant in the low micromolar range (5 µM); and endogenous T₁AM was detectable by tandem mass spectrometry. In conclusion, our findings provide evidence for the existence of a novel aminergic system modulating cardiac function.—Chiellini, G., Frascarelli, S., Ghelardoni, S., Carnicelli, V., Tobias, S. C., DeBarber, A., Brogioni, S., Ronca-Testoni, S., Cerbai, E., Grandy, D. K., Scanlan, T. S., Zucchi, R. Cardiac effects of 3-iodothyronamine: a new aminergic system modulating cardiac function.

Key Words: thyronamines • signal transduction • G protein-coupled receptors • myocardial function

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