Translational downregulation of the noncatalytic growth factor receptor TrkB.T1 by ischemic preconditioning of primary neurons.
Short episodes of ischemia can protect neuronal cells and tissue against a subsequent lethal ischemia by a phenomenon called ischemic preconditioning. The development of this tolerance depends on protein synthesis and takes at least 1 day. It therefore seems reasonable that preconditioning leads to upregulation and translation of protective genes or posttranslational modification of pro- or antiapoptotic proteins. We recently used suppression subtractive hybridization to identify transcripts upregulated in rat primary neuronal cultures preconditioned by oxygen glucose deprivation. In this contribution, we describe the previously unknown 7-kb full-length sequence of an upregulated expressed sequence tag and show that it constitutes the 3' end of the large untranslated region of the noncatalytic "truncated" growth factor receptor TrkB.T1. TrkB.T1 is expressed most prominently in the adult brain and its mRNA was found to be 2.1-fold upregulated by ischemic preconditioning. At the protein level, however, TrkB.T1 was clearly downregulated, possibly by increased degradation in preconditioned cultures. TrKB.T1 can act as a dominant-negative inhibitor of its catalytic counterpart TrkB, which is the receptor for brain-derived neurotrophic factor (BDNF), a factor induced by ischemia that can protect from ischemia-induced neuron loss. We hypothesize that the downregulation of TrkB.T1 at the protein level can prolong BDNF-mediated protective signaling via the catalytic receptor and thus participates in the development of ischemic preconditioning.
Steinbeck
Julius A
JA
Research Group Protective Signaling, Zentrum für Molekulare Neurobiologie and Klinik und Poliklinik für Neurologie, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany.
Methner
Axel
A
D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D002545:Brain Ischemia / Q000378:metabolism* / Q000503:physiopathology; D019208:Brain-Derived Neurotrophic Factor; D015536:Down-Regulation; D005333:Fetus; D005799:Genes, Dominant; D019194:Ischemic Preconditioning; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism*; D014018:Tissue Distribution
D019208:Brain-Derived Neurotrophic Factor; D012333:RNA, Messenger; D020813:Receptor, trkB