Down-regulation of the neurotrophin receptor TrkB following ligand binding- Evidence for an involvement of the proteasome and differential regulation of TrkA and TrkB

This study examines the mechanisms by which the tyrosine kinase receptor Tr kB is down-regulated following binding of brain-derived neurotrophic factor (BDNF). In primary cultures of cerebellar granule neurons, BDNF-induced re duction of TrkB receptors was largely prevented by the addition of specific proteasome inhibitors. HN10 cells, a neuronal cell line that can be readil y transfected, also showed a marked down-regulation of cell surface TrkB fo llowing BDNF exposure. In addition, me observed that prolonged exposure to nerve growth factor of TrkA-transfected cells did not lead to the down-regu lation seen with BDNF and TrkB. TrkA and TrkB chimeric molecules were there fore expressed in HN10 cells and tested for ligand-induced regulation. Thes e experiments led to the conclusion that the motives responsible for down-r egulation are contained in the cytoplasmic domain of TrkB, and a short sequ ence in the juxtamembrane domain of TrkB was identified that confers nerve growth factor-induced down-regulation when inserted into TrkA.