Cardiac effects of 3-iodothyronamine: a new aminergic system modulating cardiac function
Cardiac effects of 3-iodothyronamine: a new aminergic system modulating cardiac function
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DOI：
10.1096/fj.06-7474com
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发表时间：
2007-05-01
期刊：
影响因子：
4.8
通讯作者：
Zucchi, Riccardo
中科院分区：
文献类型：
--
作者：
Chiellini, Grazia;Frascarelli, Sabina;Zucchi, Riccardo
3 - 碘甲腺原氨酸T(1)AM是一种新型内源性甲状腺激素衍生物，它能激活一种被称为痕量胺相关受体1（TAAR1）的G蛋白偶联受体。在离体工作的大鼠心脏以及大鼠心肌细胞中，T(1)AM产生一种可逆的、剂量依赖性的负性肌力作用（例如，在浓度分别为19、25和38 μM时，心输出量分别降低27 ± 5%、51 ± 3%和65 ± 2%）。还观察到一种独立的负性变时作用。在酪氨酸激酶抑制剂染料木黄酮存在的情况下，T(1)AM的血流动力学效应显著增强，而在酪氨酸磷酸酶抑制剂钒酸盐存在时则减弱。蛋白激酶A、蛋白激酶C、钙 - 钙调蛋白激酶II、磷脂酰肌醇 - 3 - 激酶或丝裂原活化蛋白激酶的抑制剂均未产生作用。组织环磷腺苷（cAMP）水平未改变。在大鼠心室组织中，用抗磷酸酪氨酸抗体进行的蛋白质印迹实验显示，在用合成的T(1)AM灌注后，微粒体和胞质蛋白的磷酸化降低；逆转录酶 - 聚合酶链反应实验表明存在至少5种TAAR亚型的转录本；观察到[I - 125]T(1)AM有特异性和可饱和性结合，其解离常数在低微摩尔范围（约5 μM）；并且通过串联质谱法可检测到内源性T(1)AM。总之，我们的研究结果为存在一种调节心脏功能的新型胺能系统提供了证据。
3-iodothyronamine T(1)AM 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, T(1)AM 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 mu M concentration, respectively). An independent negative chronotropic effect was also observed. The hemodynamic effects of T(1)AM 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 T(1)AM; reverse transcriptase-polymerase chain reaction experiments revealed the presence of transcripts for at least 5 TAAR subtypes; specific and saturable binding of [I-125] T(1)AM was observed, with a dissociation constant in the low micromolar range ( 5 mu M); and endogenous T(1)AM was detectable by tandem mass spectrometry. In conclusion, our findings provide evidence for the existence of a novel aminergic system modulating cardiac function.