SIGNAL-TRANSDUCTION MEDIATED BY THE TRUNCATED TRKB RECEPTOR ISOFORMS,TRKB.T1 AND TRKB.T2

The trkB family of transmembrane proteins serves as receptors for BDNF and NT-4/5. The family is composed of a tyrosine kinase-containing is oform as well as several alternatively spliced ''truncated receptors'' with identical extracellular ligand-binding domains but very small in tracellular domains. The two best-characterized truncated trkB recepto rs, designated as trkB.T1 and trkB.T2, contain intracellular domains o f only 23 and 21 amino acids, respectively. Although it is known that the tyrosine kinase isoform (trB.FL) is capable of initiating BDNF and NT-4/5-induced signal transduction, the functional role or roles of t he truncated receptors remain enigmatic. At the same time, the potenti al importance of the truncated receptors in the development, maintenan ce, and regeneration of the nervous system has been highlighted by rec ent developmental and injury paradigm investigations. Here we have use d trkB cDNA transfected cell lines to demonstrate that both trkB.T1 an d trkB.T2 are capable of mediating BDNF-induced signal transduction. M ore specifically, BDNF activation of either trkB.T1 or trkB.T2 increas es the rate of acidic metabolite release from the cell, a common physi ological consequence of many signaling pathways. Further, these trkB.T 1- and trkB.T2-mediated changes occur with kinetics distinct from chan ges mediated by trkB.FL, suggesting the participation of at least some unique rate-limiting component or components. Mutational analysis dem onstrates that the isoform-specific sequences within the intracellular domains of each receptor are essential for signaling capability. Fina lly, inhibitor studies suggest that kinases are likely to be involved in the trkB.T1 and trkB.T2 signaling pathways.