Stress-evoked tyrosine phosphorylation of signal regulatory protein α regulates behavioral immobility in the forced swim test.
Severe stress induces changes in neuronal function that are implicated in stress-related disorders such as depression. The molecular mechanisms underlying the response of the brain to stress remain primarily unknown, however. Signal regulatory protein alpha (SIRPalpha) is an Ig-superfamily protein that undergoes tyrosine phosphorylation and binds the protein tyrosine phosphatase Shp2. Here we show that mice expressing a form of SIRPalpha that lacks most of the cytoplasmic region manifest prolonged immobility (depression-like behavior) in the forced swim (FS) test. FS stress induced marked tyrosine phosphorylation of SIRPalpha in the brain of wild-type mice through activation of Src family kinases. The SIRPalpha ligand CD47 was important for such SIRPalpha phosphorylation, and CD47-deficient mice also manifested prolonged immobility in the FS test. Moreover, FS stress-induced tyrosine phosphorylation of both the NR2B subunit of the NMDA subtype of glutamate receptor and the K+-channel subunit Kvbeta2 was regulated by SIRPalpha. Thus, tyrosine phosphorylation of SIRPalpha is important for regulation of depression-like behavior in the response of the brain to stress.
Ohnishi
Hiroshi
H
Laboratory of Biosignal Sciences, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma 371-8512, Japan. ohnishih@showa.gunma-u.ac.jp
Murata
Takaaki
T
Kusakari
Shinya
S
Hayashi
Yuriko
Y
Takao
Keizo
K
Maruyama
Toshi
T
Ago
Yukio
Y
Koda
Ken
K
Jin
Feng-Jie
FJ
Okawa
Katsuya
K
Oldenborg
Per-Arne
PA
Okazawa
Hideki
H
Murata
Yoji
Y
Furuya
Nobuhiko
N
Matsuda
Toshio
T
Miyakawa
Tsuyoshi
T
Matozaki
Takashi
T
D000818:Animals; D030801:Animals, Genetically Modified; D015153:Blotting, Western; D002460:Cell Line; D002540:Cerebral Cortex / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D046353:Immobility Response, Tonic / Q000502:physiology*; D051379:Mice; D017551:Microdialysis; D010766:Phosphorylation; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological / Q000502:physiology*; D013315:Stress, Psychological / Q000378:metabolism / Q000503:physiopathology*; D013550:Swimming
C501922:Sirpa protein, mouse; D011971:Receptors, Immunologic