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

Division Of Basic Sciences - Nci

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Abstract

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.