BDNF TrkB plays an important role in most neuronal effects mediated by BDNF. When binding to BDNF, BDNF TrkB is induced to dimerize, phosphorylate and activate the intracellular tyrosine kinase domain. These events initiate several complex intracellular signal transduction cascades which subsequently induce biological responses. There are three forms of BDNF TrkB by alternative splicing of trkB mRNA. They are the full-length catalytic receptor (TrkB.FL) and two truncated forms (TrkB.T1 and TrkB.T2). TrkB receptors are highly glycosylated proteins possessing 12 potential N-linked glycosylation sites in the extracellular domain. The truncated forms of BDNF TrkB lack intracellular tyrosine kinase activity and contain different short cytoplasmatic tails. Nevertheless, the truncated forms are also biologically active since they trigger transduction signals, and short isoform-specific intracellular sequences are required for this induction. Analysis of the human TrkB gene recently revealed a novel isoform, TrkB-T-Shc, which seems to be expressed predominantly in the human brain. This truncated form contains a Shc-binding site in the juxtamembrane domain similar to TrkB.FL, but it lacks the kinase domain and has a unique truncated C terminus.
Interestingly, full-length and truncated forms of TrkB likely have different functions. TrkB.T1 is abundantly expressed in non-neuronal cells lacking TrkB.FL in adult brain. The physiological functions of TrkB.T1 and TrkB.T2 isoform receptors remain unclear, but it has been suggested that they may have at least two main functions, i.e., acting as ligand trapping molecules to regulate the local availability of neurotrophins or functioning as dominant negative receptors of neurotrophin responsiveness by heterodimerization. Recent studies have highlighted the potential importance of the truncated receptors in several cellular functions related to development, memory, and injury paradigms. In neuroblastoma cells or primary hippocampal neurons, BDNF rapidly increases TrkB surface expression levels in seconds. Nevertheless, longer treatments (minutes to hours) lead to decreased TrkB surface levels. In addition, coexpression of the TrkB.FL together with the truncated TrkB.T1 isoform results in decreased levels of TrkB.FL on the cell surface. This indicates that increased expression of the TrkB.T1 isoform may lead to increased internalization of the receptor complex from the cell surface, thus reducing the availability of the receptor to exert its biological action.