Brain-derived neurotrophic factor signal enhances and maintains the expression of AMPA receptor-associated PDZ proteins in developing cortical neurons.
Postsynaptic molecules with PDZ domains (PDZ proteins) interact with various glutamate receptors and regulate their subcellular trafficking and stability. In rat neocortical development, the protein expression of AMPA-type glutamate receptor GluR1 lagged behind its mRNA expression and rather paralleled an increase in PDZ protein levels. One of the neurotrophins, brain-derived neurotrophic factor (BDNF), appeared to contribute to this process, regulating the PDZ protein expression. In neocortical cultures, BDNF treatment upregulated SAP97, GRIP1, and Pick1 PDZ proteins. Conversely, BDNF gene targeting downregulated these same PDZ molecules. The BDNF-triggered increases in PDZ proteins resulted in the elevation of their total association with the AMPA receptors GluR1 and GluR2/3, which led to the increase in AMPA receptor proteins. When Sindbis viruses carrying GluR1 or GluR2 C-terminal decoys disrupted their interactions, GluR2 C-terminal decoys inhibited both BDNF-triggered GluR1 and GluR2/3 increases, whereas GluR1 C-terminal decoys blocked only the BDNF-triggered GluR1 increase. In agreement, coexpression of SAP97 and GluR1 in nonneuronal HEK293 cells increased both proteins compared with their single transfection, implying mutual stabilization. This work reveals a novel function of BDNF in postsynaptic development by regulating the PDZ protein expression.
Department of Molecular Neurobiology, Brain Research Institute, Niigata University, Niigata, 951-8585, Japan.
Hussam
H
Jourdi
Yuriko
Y
Iwakura
Mako
M
Narisawa-Saito
Kyoko
K
Ibaraki
Huabao
H
Xiong
Masahiko
M
Watanabe
Yasunori
Y
Hayashi
Nobuyuki
N
Takei
Hiroyuki
H
Nawa
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology*; D002454:Cell Differentiation; D002540:Cerebral Cortex / Q000196:embryology*; D000074288:Discs Large Homolog 1 Protein; D051528:Guanylate Kinases; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000502:physiology*; D051958:Nuclear Receptor Coactivator 2; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000737:chemistry / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D019208:Brain-Derived Neurotrophic Factor; D000074288:Discs Large Homolog 1 Protein; D051528:Guanylate Kinases; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D051958:Nuclear Receptor Coactivator 2; D018091:Receptors, AMPA; D014157:Transcription Factors; C000614189:Dlg1 protein, mouse; C501119:Dlg1 protein, rat; C498002:Ncoa2 protein, mouse; C498003:Ncoa2 protein, rat; C104723:glutamate receptor ionotropic, AMPA 3; C104722:glutamate receptor ionotropic, AMPA 2