Neurotrophins (NGF, BDNF, NT-3, NT-4/5, and NT-6) are essential for many aspects of neuronal development, survival, maintenance, and regeneration. This family of molecules uses the trk family of receptors (trkA, trkB and trkC) to transduce their signals to the inside of the cell. Alternative splicing of trkB mRNA generates five known trkB isoforms, each possessing the same extracellular and transmembrane domains but varying intracellularly. The """"""""full length"""""""" trkB isoform (trkB.FL) has an intracellular signal transducing tyrosine kinase domain, while the """"""""truncated"""""""" trkB isoforms (trkB.T1, trkB.T2, trkB.T3S, trkB.T3L) have relatively small, unique intracellular domains. Based upon available data, the hypothesis being tested is that the truncated trkB receptors, and specifically trkB.T1, serve important functions in neuronal cell biology. This proposal aims to assess this hypothesis by testing the ability of trkB.T1 to serve several candidate functions, including signal transduction, sequestration or presentation of ligand, or as dominant negatives. First, I will investigate the internalization and binding kinetics of trkB.T1. Next, I will establish how coexpression of trkB.T1 and trkB.FL, in adjacent cells or the same cells, modifies the response of the full length receptor. Finally, I will determine if trkB.T1 interacts with other cytosolic proteins. These studies will promote our knowledge of neurotrophin action, which is fundamental to neuronal development and maintenance. In addition, these studies may be relevant in development of therapeutic procedures for the treatment of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and retinal degeneration.
