Cardiac effects of trace amines: Pharmacological characterization of trace amine-associated receptors
Introduction
We have recently reported that 3-iodotyhyronamine (T1AM), a novel endogenous metabolite of thyroid hormone, produces negative inotropic and chronotropic actions in the isolated rat heart (Scanlan et al., 2004, Chiellini et al., 2007). T1AM can activate trace amine-associated receptor 1 (TAAR1) (Scanlan et al., 2004), one member of a novel family of G-protein coupled receptors, whose name reflects the fact that it interacts with trace amines (i.e. p-tyramine, β-phenylethylamine, octopamine, and tryptamine), but not with classical biogenic amines.
After TAAR1 was identified (Borowsky et al., 2001, Bunzow et al., 2001) a comprehensive search for TAAR1-like sequences in several nucleotide sequence databases led to the identification of several additional mammalian TAAR genes (Lindemann et al., 2005, Zucchi et al., 2006, Grandy, 2007). Due to the lack of selective ligands or antibodies, subtype differentiation has been achieved on the basis of the pharmacological effects produced in cells expressing mRNAs that code for specific TAARs. Since we have recently reported at least 5 TAAR subtypes to be expressed in rat heart (Chiellini et al., 2007), in the present work we compare the response to T1AM and to trace amines in order to obtain a pharmacological characterization of cardiac TAAR-mediated effects.
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Chemicals and radionuclides
T1AM and thyronamine (T0AM) were synthesized as described elsewhere (Hart et al., 2006). All other reagents were from Sigma-Aldrich (St. Louis, MO), or by Invitrogen Life Technologies (Paisley, UK). [3H]-p-tyramine was obtained from Biotrend (Cologne, Germany), [125I]-T1AM was synthesized as described elsewhere (Chiellini et al., 2007), using [125I]-NaCl obtained from New England Nuclear (Milan, Italy).
Animals and perfusion technique
This investigation conforms to the Declaration of Helsinki and the Guiding Principles in the
Results
Baseline values of the hemodynamic variables averaged as follows, without any significant difference between groups: cardiac output 62.6 ± 1.2 ml/min, aortic flow 43.0 ± 0.8 ml/min coronary flow 19.6 ± 0.7 ml/min, peak systolic aortic pressure 177 ± 7 mm Hg, heart rate 274 ± 9 bpm. The effects of p-tyramine, β-phenylethylamine, octopamine and tryptamine, each used at 100 μM concentration, are reported in Table 1. The time course of the effects on cardiac output is shown in Fig. 1. A significant reduction
Discussion
TAARs are a family of G-protein coupled receptors that respond to trace amines, i.e. p-tyramine, β-phenylethylamine, octopamine, and tryptamine, but not to classical biogenic amines, e.g. adrenaline, dopamine or serotonin (Borowsky et al., 2001, Bunzow et al., 2001). Several TAAR genes have been identified, e.g. 17 different genes in rat, and they are expressed in several tissues, but their functional role is still largely unknown (Lindemann et al., 2005, Zucchi et al., 2006). Based on in vitro
Acknowledgement
This work was supported by Ministero dell'Università, dell'Istruzione e della Ricerca Scientifica e Tecnologica (MIUR, PRIN 2005).
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2017, Molecular and Cellular EndocrinologyCitation Excerpt :The receptor originally identified as the target of T1AM is trace amine associated receptor-1 (TAAR1) (Scanlan et al., 2004). However, it is unclear whether T1AM produces its cardiac effects through TAAR1, since at least five diverse TAAR subtypes are expressed in the rat heart, with RT-PCR revealing TAAR8a to be the main subtype (Chiellini et al., 2007), and the pharmacological characterization of other trace amines showed that the rank of potency did not correspond to the affinity for TAAR1 (Frascarelli et al., 2008). As reviewed elsewhere (Hoefig et al., 2016; Zucchi et al., 2014) additional targets have been recently identified for T1AM, including other TAAR subtypes (particularly TAAR5), α-2A-adrenergic receptor (Regard et al., 2007), and membrane transporters.
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