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Modulation of cardiac inotropic state by 3‐iodothyronamine: evidence for a novel signalling pathway mediated by trace amine‐associated receptors
Author(s) -
Zucchi Riccardo,
Chiellini Grazia,
Frascarelli Sabina,
Carnicelli Vittoria,
Brogioni Simona,
Ghelardoni Sandra,
Testoni Simonetta,
Grandy David K,
Cerbai Elisabetta,
Scanlan Thomas S
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a246-d
Subject(s) - signal transduction , endocrinology , receptor , medicine , protein tyrosine phosphatase , phosphorylation , biology , chemistry , biochemistry
3‐iodothyronamine (T1AM) is a thyroid hormone derivative, which binds to a new class of plasma membrane receptors known as trace amine‐associated receptors (TAARs). In the isolated heart, micromolar concentrations of T1AM produce a dose‐dependent negative inotropic effect. This work was aimed at determining the expression of TAARs in heart, and the transduction pathway involved in the response to T1AM. RT‐PCR experiments showed expression of at least 5 TAAR isoforms in rat heart, the major being TAAR8a. Pharmacological experiments performed in the isolated working rat heart confirmed that T1AM decreased cardiac output, with IC50 = 28 microM. The response to T1AM was remarkably increased in the presence of the tyrosine kinase inhibitor genistein, while it was reduced by the tyrosine phosphatase inhibitor vanadate. Western blots with anti‐phosphotyrosine antibodies showed that phosphorylation of 74 KDa cytosolic proteins and of >100 KDa microsomal proteins was reduced in the presence of T1AM. In rat cardiac cardiomyocytes T1AM had no effect on basal I CaL amplitude, while it reduced the amplitude and duration of calcium transients. In conclusion, we obtained evidence of a signalling pathway associated with reduced contractility, triggered by T1AM through TAARs, and possibly mediated by decreased phosphorylation of critical tyrosine residues and modulation of sarcoplasmic reticulum calcium release.