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。我们发现脑源性神经营养因子在调节心脏收缩力方面发挥了一种新的意想不到的作用，与神经系统的神经支配无关。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被心肌细胞产生的脑源性神经营养因子激活，表明存在自分泌/旁分泌循环。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，我们正在研究BDNF激活TrkB.T1是否在遗传或药物诱导的心脏损伤中具有保护作用。例如，我们将TrkB.T1缺陷小鼠与营养不良小鼠模型杂交，以研究TrkB.T1的缺失是否会加重由突变型肌营养不良蛋白基因引起的心脏缺陷。此外，我们正在测试多柔比星诱导的心脏毒性是否受到TrkB.T1/BDNF信号转导丢失的影响。下丘脑神经元回路中的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β-细胞TrkB.T1的结合触发细胞内钙储存的释放，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表型模仿β细胞中TrkB.T1缺失引起的代谢损伤。BDNF还通过TrkB.T1诱导人类胰岛中的胰岛素分泌的发现，鉴定了BDNF对代谢的新的意想不到的调节功能，其独立于CNS活性。我们的数据表明，肌肉来源的BDNF可能是一个关键因素，介导增加葡萄糖代谢的运动，与糖尿病和相关代谢疾病的治疗的影响。

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.