Role of Trk Receptors in the Development and Function of Non-neuronal Structures

缺乏激酶结构域的截短的Trk受体亚型在发育过程中和成人中大量表达;然而，它们的功能和信号传导能力在很大程度上是未知的。最近，我们研究了TrkB受体是否在神经系统外具有其他功能。我们发现了一种新的意想不到的作用，脑源性神经营养因子在调节心脏收缩力的神经系统无关。该功能由心肌细胞中表达的截短的TrkB. T1受体介导。这些细胞中TrkB.T1的缺失会损害钙信号传导并导致心肌病。TrkB.T1被心肌细胞产生的BDNF激活，表明自分泌/旁分泌回路。这些发现揭示了心脏中由BDNF激活的一种新的信号传导机制，并通过不同的TrkB受体亚型的信号传导，为这种神经营养因子在生物体内稳态中的全球作用提供了证据。此外，我们通过内源性TrkB. T1的缺失和体内标记报道了该TrkB同种型在胰腺β细胞中的表达增加葡萄糖诱导的胰岛素分泌。重要的是，我们发现这种途径在人类中是保守的。总而言之，这些研究是最终提供由TrkB.T1信号传导介导的强大和确定的生理功能的关键，这些功能独立于其对TrkB.FL或BDNF螯合活性的经典显性/负性作用。此外，他们为下一阶段铺平了道路，旨在确定TrkB.T1激活的尚未表征的分子途径。到目前为止，我们和其他人已经表明TrkB.T1调节星形胶质细胞，心肌细胞和胰腺β细胞中的Ca++信号传导，但尚不清楚它结合哪些蛋白质来诱导信号传导。这仍然是神经营养因子生物学中的主要开放问题之一。很可能小的TrkB.T1胞内结构域不能与蛋白质形成稳定的相互作用，从而妨碍了它们的分离和质谱鉴定。

Truncated Trk receptor isoforms lacking the kinase domain are abundantly expressed during development and in the adult; however, their function and signaling capacity is largely unknown. Recently, we have investigated whether TrkB Receptors have other functions outside the nervous system. We found that a novel unexpected role of BDNF in regulating the cardiac contraction force independent of the nervous system innervation. This function is mediated by the truncated TrkB.T1 receptor expressed in cardiomyocytes. Loss of TrkB.T1 in these cells impairs calcium signaling and causes cardiomyopathy. TrkB.T1 is activated by BDNF produced by cardiomyocytes suggesting an autocrine/paracrine loop. These findings unveil a novel signaling mechanism in the heart that is activated by BDNF and provide evidence for a global role of this neurotrophin in the homeostasis of the organism by signaling through different TrkB receptor isoforms. Moreover, we reported by deletion and in vivo tagging of endogenous TrkB.T1 that expression of this TrkB isoform in pancreatic beta-cells increases glucose-induced insulin secretion. Importantly, we showed that this pathway is conserved in humans. Altogether, these studies were key to finally providing strong and definitive physiological functions mediated by TrkB.T1 signaling that are independent of its classic dominant/negative role on TrkB.FL or BDNF sequestering activity. In addition, they pave the way for the next phase aimed at identifying the still uncharacterized molecular pathway/s activated by TrkB.T1. So far, we and others have shown that TrkB.T1 regulates Ca++ signaling in astrocytes, cardiomyocytes and pancreatic beta-cells but it is unclear as to which proteins it binds to induce signaling. This is still one of the major open questions in neurotrophin biology. It is likely that the small TrkB.T1 intracellular domain is unable to form stable interactions with proteins precluding their isolation and identification by mass-spectrometry.