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

缺乏激酶结构域的截断Trk受体同工型在发育和成人中大量表达；然而，它们的功能和信号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BDNF在独立于神经系统支配的心脏收缩力调节中具有新的意想不到的作用。这个功能是由截断的TrkB介导的。T1受体在心肌细胞中的表达。TrkB丢失。这些细胞中的T1损害钙信号并引起心肌病。TrkB。T1被心肌细胞产生的BDNF激活，提示自分泌/旁分泌循环。这些发现揭示了BDNF在心脏激活的一种新的信号传导机制，并为这种神经营养因子通过不同的TrkB受体亚型信号传导在生物体稳态中的全局作用提供了证据。此外，我们报道了内源性TrkB的缺失和体内标记。胰岛β细胞中TrkB亚型的表达增加了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。总之，这些研究是最终提供TrkB介导的强大而明确的生理功能的关键。T1信号独立于其在TrkB上的经典显性/负性作用。FL或BDNF的隔离活性。此外，它们为下一阶段旨在确定TrkB.T1激活的尚未表征的分子通路铺平了道路。到目前为止，我们和其他人已经证明TrkB。T1调节星形细胞、心肌细胞和胰腺β细胞中的Ca++信号，但不清楚它与哪些蛋白结合来诱导信号传导。这仍然是神经营养因子生物学中主要的开放性问题之一。很可能是小的TrkB。T1胞内结构域无法与蛋白质形成稳定的相互作用，妨碍了质谱法对其进行分离和鉴定。

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.