LIGAND-INDUCED DOWN-REGULATION OF TRK MESSENGER-RNA, PROTEIN AND TYROSINE PHOSPHORYLATION IN RAT CORTICAL-NEURONS

Chronic exposure of brain neurons to nerve growth factor in vitro and in vivo results in increased levels of the nerve growth factor recepto r TrkA. In contrast, in the present study, we have found that chronic exposure of rat embryonic cortical neurons to brain-derived neurotroph ic factor (BDNF) leads to a pronounced reduction of the levels of prot ein and messenger RNA for the full-length but not the truncated BDNF r eceptor TrkB. Similar effects were observed with the other TrkB ligand s neurotrophin-3 and neurotrophin-4/5. After pretreatment with BDNF, n eurotrophin-3 or neurotrophin-4/5, subsequent tyrosine phosphorylation responses of the remaining Trks to the same factors were greatly redu ced. Three days exposure of rat embryonic cortical neurons to BDNF ind uced an absolute refractory period of several hours, with no subsequen t response to the same factor. Similar but less pronounced refractory effects were observed with neurotrophin-3 and neurotrophin-4/5. Our re sults suggest a negative regulatory effect of BDNF and other TrkB liga nds on TrkB receptors. Down-regulation of the TrkB response by its lig ands might play a role in the control of BDNF action during early deve lopment, when BDNF levels significantly increase. Our findings are als o of potential clinical relevance, since the possibility of ligand-ind uced downregulation of the receptor response needs to be addressed whe n considering BDNF or other neurotrophins for the therapy of neurodege neration. (C) 1997 IBRO.