Gap-junction-mediated propagation and amplification of cell injury.
Gap junctions are conductive channels that connect the interiors of coupled cells. We determined whether gap junctions propagate transcellular signals during metabolic stress and whether such signaling exacerbates cell injury. Although overexpression of the human proto-oncogene bcl2 in C6 glioma cells normally increased their resistance to injury, the relative resistance of bcl2+ cells to calcium overload, oxidative stress and metabolic inhibition was compromised when they formed gap junctions with more vulnerable cells. The likelihood of death was in direct proportion to the number and density of gap junctions with their less resistant neighbors. Thus, dying glia killed neighboring cells that would otherwise have escaped injury. This process of glial 'fratricide' may provide a basis for the secondary propagation of brain injury in cerebral ischemia.
Lin
J H
JH
Department of Pathology, New York Medical College, Valhalla, New York 10595, USA. JanevLin@nymc.edu
Weigel
H
H
Cotrina
M L
ML
Liu
S
S
Bueno
E
E
Hansen
A J
AJ
Hansen
T W
TW
Goldman
S
S
Nedergaard
M
M
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001253:Astrocytes / Q000502:physiology; D001921:Brain / Q000166:cytology / Q000196:embryology; D002545:Brain Ischemia / Q000503:physiopathology; D018031:Connexin 43 / Q000378:metabolism; D017629:Gap Junctions / Q000502:physiology*; D006801:Humans; D009474:Neurons / Q000378:metabolism / Q000473:pathology* / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology*; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats / Q000196:embryology; D011930:Reaction Time / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured
D018031:Connexin 43; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2