Activity-dependent shedding of heparin-binding EGF-like growth factor in brain neurons.
Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is initially produced as a membrane-anchored precursor (pro-HB-EGF) and subsequently liberated from the cell membrane through ectodomain shedding. Here, we characterized the molecular regulation of pro-HB-EGF shedding in the central nervous system. Cultured neocortical or hippocampal neurons were transfected with the alkaline-phosphatase-tagged pro-HB-EGF gene and stimulated with various neurotransmitters. Both kainate and N-methyl-D-aspartate, but not agonists for metabotropic glutamate receptors, promoted pro-HB-EGF shedding and HB-EGF release, which were attenuated by an exocytosis blocker and metalloproteinase inhibitors. In the brain of transgenic mice over-expressing human pro-HB-EGF, kainate-induced seizure activity decreased content of pro-HB-EGF-like immunoreactivity and conversely increased levels of soluble HB-EGF. There was concomitant phosphorylation of EGF receptors (ErbB1) following seizures, suggesting that seizure activities liberated HB-EGF and activated neighboring ErbB1 receptors. Therefore, we propose that glutamatergic neurotransmission in the central nervous system plays a crucial role in regulating ectodomain shedding of pro-HB-EGF.
Shishido
Yuji
Y
Division of Molecular Neurobiology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.
Tanaka
Takayuki
T
Piao
Ying-shan
YS
Araki
Kazuaki
K
Takei
Nobuyuki
N
Higashiyama
Shigeki
S
Nawa
Hiroyuki
H
D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism*; D006493:Heparin / Q000378:metabolism*; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology*
C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; C587885:Hbegf protein, rat; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D017470:Receptors, Glutamate; D004815:Epidermal Growth Factor; D006493:Heparin