Brain-derived neurotrophic factor (BDNF) signaling through its receptor TRKB modulates survival, differentiation, and activity of neurons. BDNF activates TRKB on the cell surface, which leads to the initiation of intracellular signaling cascades and different biological responses in neurons. Neuronal activity has been shown to regulate TRKB levels on the plasma membrane of neurons, but little is known about other factors affecting TRKB surface expression levels. We report here that BDNF regulates the cell surface levels of transfected or endogenously expressed full-length TRKB, depending on the exposure time in neuroblastoma cells and primary hippocampal neurons. BDNF rapidly increases TRKB surface expression levels in seconds, whereas treatment of cells with BDNF for a longer time (minutes to hours) leads to decreased TRKB surface levels. Coexpression of the full-length TRKB together with the truncated TRKB.T1 isoform results in decreased levels of fulllength TRKB on the cell surface. This effect is specific to the T1 isoform, because coexpression of a kinase-dead TRKB mutant or another kinase domain-lacking TRKB form, truncated T-Shc, leads to increased TRKB surface levels. Our results suggest that regulation of TRKB surface expression levels by different factors is tightly controlled by complex mechanisms in active neurons. Neurotrophin brain-derived neurotrophic factor (BDNF) 1 is a key regulator of survival and differentiation of specific neuronal populations in the central nervous system (1, 2). In addition, increasing evidence indicates that BDNF plays important roles in regulating neuronal activity and synaptic events related to plasticity (for reviews, see Refs. 3-5). BDNF is released in an activity-dependent manner (6 -10), and it regulates neurotransmitter release and synaptic transmission of neurons (11-17).The biological effects of BDNF are mediated by TRKB transmembrane tyrosine kinase receptors (18 -23). The high affinity full-length TRKB.TKϩ (TKϩ) receptors are exclusively expressed in neurons in the central nervous system (24). Binding of BDNF to TRKB.TKϩ activates it by inducing dimerization and autophosphorylation at specific tyrosine residues in the cytoplasmic kinase domains (25). The phosphorylated tyrosines serve as docking sites to cytoplasmic effector molecules, which activate different signaling pathways that eventually lead to changes in gene expression and different biological responses in neurons (26).BDNF signaling through the TKϩ receptors can be modulated by the low affinity p75 neurotrophin receptor (27-29) but also by truncated TRKB isoforms (TKϪ; see Refs. 20 and 24).Different TRKB isoforms are generated by alternative splicing resulting in the TKϩ form and three TKϪ splice variants: T1, T2, and T-Shc (20,24,30). Truncated T1 lacks the kinase domain but contains short isoform-specific cytoplasmic domain in its place (20,24). Even though T1 is mostly expressed in non-neuronal cells in the central nervous system, it has been shown to colocalize with TKϩ in a subpopulation of hipp...

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