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Gap-junction-mediated propagation and amplification of cell injury

A Correction to this article was published on 01 December 1998

Abstract

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.

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Figure 1: Bcl2 expression increases the resistance of C6 cells.
Figure 2: Gap junctions amplify injury to include bcl2-expressing cells.
Figure 3: Bystander killing of bcl2-expressing cells is a function of gap junctional coupling.
Figure 4: Bcl+Cx+ cell death is delayed compared with Cx+ cell death in mixed cultures.
Figure 5: Loss of autonomous calcium regulation in gap-junction-coupled bcl2-expressing cells.
Figure 6: Gap junctions remain functional in the exposed rat parietal cortex for more than one hour after cardiac arrest.

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Acknowledgements

We thank V. A. Fried for discussions and L. He for technical support. Supported by NIH/NINDS (RO130007 and RO135011). M. N. is an Established Investigator sponsored by the American Heart Association.

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Correspondence to Jane H-C Lin.

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Lin, JC., Weigel, H., Cotrina, M. et al. Gap-junction-mediated propagation and amplification of cell injury. Nat Neurosci 1, 494–500 (1998). https://doi.org/10.1038/2210

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