Activation of Trk neurotrophin receptors by glucocorticoids provides a neuroprotective effect.
Glucocorticoids (GCs) display both protective and destructive effects in the nervous system. In excess, GCs produce neuronal damage after stress or brain injury; however, the neuroprotective effects of adrenal steroids also have been reported. The mechanisms that account for the positive actions are not well understood. Here we report that GCs can selectively activate Trk receptor tyrosine kinases after in vivo administration in the brain and in cultures of hippocampal and cortical neurons. Trk receptors are normally activated by neurotrophins, such as NGF and brain-derived neurotrophic factor, but the activation of Trk receptors by GCs does not depend on increased production of neurotrophins. Other tyrosine kinase receptors, such as EGF and FGF receptors, were not activated by GCs. The ability of GCs to increase Trk receptor activity resulted in the neuroprotection of neurons deprived of trophic support and could be modulated by steroid-converting enzymes. Pharmacological and shRNA experiments indicate that Trk receptor activation by GCs depends on a genomic action of the GC receptor. The ability of GCs to promote Trk receptor activity represents a molecular mechanism that integrates the actions of GCs and neurotrophins.
Jeanneteau
Freddy
F
Molecular Neurobiology Program, Department of Cell Biology, Physiology, Kimmel Center for Biology and Medicine of the Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, USA. jeannete@saturn.med.nyu.edu
Garabedian
Michael J
MJ
Chao
Moses V
MV
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002470:Cell Survival / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D016678:Genome; D005938:Glucocorticoids / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D020239:Receptor Cross-Talk / Q000187:drug effects; D020813:Receptor, trkB / Q000378:metabolism; D020812:Receptor, trkC / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection
D005938:Glucocorticoids; D007527:Isoenzymes; D018696:Neuroprotective Agents; D017475:Receptors, Nerve Growth Factor; D003907:Dexamethasone; D020813:Receptor, trkB; D020812:Receptor, trkC