Growth factor-mediated Fyn signaling regulates alpha-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor expression in rodent neocortical neurons.
Src-family protein tyrosine kinases (PTKs) transduce signals to regulate neuronal development and synaptic plasticity. However, the nature of their activators and molecular mechanisms underlying these neural processes are unknown. Here, we show that brain-derived neurotrophic factor (BDNF) and platelet-derived growth factor enhance expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor 1 and 2/3 proteins in rodent neocortical neurons via the Src-family PTK(s). The increase in AMPA receptor levels was blocked in cultured neocortical neurons by addition of a Src-family-selective PTK inhibitor. Accordingly, neocortical cultures from Fyn-knockout mice failed to respond to BDNF whereas those from wild-type mice responded. Moreover, the neocortex of young Fyn mutants exhibited a significant in vivo reduction in these AMPA receptor proteins but not in their mRNA levels. In vitro kinase assay revealed that BDNF can indeed activate the Fyn kinase: It enhanced tyrosine phosphorylation of Fyn as well as that of enolase supplemented exogenously. All of these results suggest that the Src-family kinase Fyn, activated by the growth factors, plays a crucial role in modulating AMPA receptor expression during brain development.
Narisawa-Saito
M
M
Department of Molecular Neurobiology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.
Silva
A J
AJ
Yamaguchi
T
T
Hayashi
T
T
Yamamoto
T
T
Nawa
H
H
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002478:Cells, Cultured; D003433:Crosses, Genetic; D004815:Epidermal Growth Factor / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006133:Growth Substances / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019579:Neocortex / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051076:Proto-Oncogene Proteins c-fyn; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000235:genetics*; D017470:Receptors, Glutamate / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic; D019061:src-Family Kinases / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D006133:Growth Substances; D010982:Platelet-Derived Growth Factor; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D016222:Fibroblast Growth Factor 2; D004815:Epidermal Growth Factor; D011505:Protein-Tyrosine Kinases; C494960:Fyn protein, mouse; C494961:Fyn protein, rat; D051076:Proto-Oncogene Proteins c-fyn; D019061:src-Family Kinases