Ligand-induced down-regulation of trkmessenger RNA, protein and tyrosine phosphorylation in rat cortical neurons

Chronic exposure of brain neurons to nerve growth factor in vitroand in vivoresults in increased levels of the nerve growth factor receptor TrkA. In contrast, in the present study, we have found that chronic exposure of rat embryonic cortical neurons to brain-derived neurotrophic factor leads to a pronounced reduction of the levels of protein and messenger RNA for the full-length but not the truncated brain-derived neurotrophic factor receptor TrkB. Similar effects were observed with the other TrkB ligands neurotrophin-3 and neurotrophin-4/5. After pretreatment with brain-derived neurotrophic factor, neurotrophin-3 or neurotrophin-4/5, subsequent tyrosine phosphorylation responses of the remaining Trks to the same factors were greatly reduced. Three days exposure of rat embryonic cortical neurons to brain-derived neurotrophic factor induced an absolute refractory period of several hours, with no subsequent response to the same factor. Similar but less pronounced refractory effects were observed with neurotrophin-3 and neurotrophin-4/5. Our results suggest a negative regulatory effect of brain-derived neurotrophic factor and other TrkB ligands on TrkB receptors. Down-regulation of the TrkB response by its ligands might play a role in the control of brain-derived neurotrophic factor action during early development, when brain-derived neurotrophic factor levels significantly increase.