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，我们正在研究TrkB的激活是否。BDNF介导的T1在遗传性或药物性心脏损伤中具有保护作用。例如，我们越过了TrkB。T1缺陷小鼠与变形小鼠模型探讨TrkB的缺失是否。T1加重由突变型肌营养不良蛋白基因引起的心脏缺陷。此外，我们正在测试阿霉素诱导的心脏毒性是否受到TrkB丢失的影响。T1 / BDNF信号。下丘脑神经回路中的BDNF信号调节哺乳动物的食物摄入。BDNF信号传导是否对外周器官产生代谢作用目前尚不清楚。我们最近发现BDNF受体TrkB。T1由胰腺β细胞表达，它调节胰岛素的释放。因此，缺乏这种受体的小鼠表现出葡萄糖耐量和胰岛素分泌受损。BDNF与细胞TrkB的结合。T1触发细胞内储存的钙释放，增加葡萄糖诱导的胰岛素分泌。此外，BDNF由骨骼肌分泌，敲除小鼠骨骼肌中的BDNF可以表型上反映TrkB引起的代谢损伤。细胞中的T1缺失。BDNF还通过TrkB诱导胰岛胰岛素分泌。T1，发现了BDNF对代谢的一种新的意想不到的调节功能，这种功能独立于中枢神经系统的活性。我们的数据表明，肌肉来源的BDNF可能是运动后葡萄糖代谢增加的关键因素，对糖尿病和相关代谢疾病的治疗具有重要意义。

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 are investigating whether activation of TrkB.T1 by BDNF has a protective role during genetic or drug-induced cardiac injury. For example, we have crossed our TrkB.T1 deficient mice with a distrophic mouse model to investigate whether loss of TrkB.T1 worsen the cardiac deficit caused by the mutant dystrophin gene. Moreover, we are testing whether doxorubicin-induced cardiac toxicity is affected by loss of TrkB.T1/BDNF signaling. BDNF signaling in neuronal hypothalamic circuitries regulates mammalian food intake. Whether BDNF signaling exerts metabolic effects on peripheral organs is currently unclear. We recently found that the BDNF receptor TrkB.T1 is expressed by pancreatic beta-cells where it regulates insulin release. Consequently, mice lacking this receptor show impaired glucose tolerance and insulin secretion. BDNF binding to beta-cells TrkB.T1 triggers calcium release from intracellular stores, increasing glucose-induced insulin secretion. In addition, BDNF is secreted by skeletal muscle and knocking out BDNF in skeletal muscle of mice phenocopies the metabolic impairments caused by TrkB.T1 deletion in beta-cells. The finding that BDNF also induces insulin secretion in human islets via TrkB.T1, identifies a new unexpected regulatory function of BDNF on metabolism that is independent of CNS activity. Our data suggest that muscle derived BDNF may be a key factor mediating increased glucose metabolism in response to exercise, with implications for the treatment of diabetes and related metabolic diseases.