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Connexin mediates gap junction-independent resistance to cellular injury
Jane H-C Lin1, Jay Yang, Shujun Liu
1Department of Pathology, New York Medical College, Valhalla, New York 10595, USA. jane_lin@nymc.edu
Abstract:
Although gap junctions regulate essential processes during development and differentiation, the role of gap junctions in cell death is poorly understood. We demonstrate here that the forced expression of connexin 43 (Cx43), the main constituent of astrocytic gap junctions, protected against cell injury with a potency that was comparable with that from the expression of the proto-oncogene bcl2. The expression of two other members of the Cx family, Cx32 and Cx40, also increased the resistance to injury from exposures to calcium overload, oxidative stress, metabolic inhibition, tamoxifen, and UV irradiation, but not against staurosporine- and dexamethasone-mediated death. Surprisingly, the anti-death activity of connexin proteins was independent of gap junction channel function, because physical isolation or the pharmacological inhibition of coupling did not significantly increase cell death. Moreover, cells expressing nonfunctional mutant connexins also acquired a high resistance to injury. These observations identify Cx proteins as active players in cell survival.
Insights
Connexin proteins, like connexin 43 (Cx43), protect cells from injury and death. This cell survival benefit is independent of gap junction channel function, highlighting connexins
Area of Science:
- Cell Biology
- Neuroscience
- Biochemistry
Background:
- Gap junctions are crucial for cellular communication, development, and differentiation.
- The specific role of gap junctions in regulating cell death remains largely unclear.
- Connexins (Cx) are the primary protein subunits forming gap junctions.
Purpose of the Study:
- To investigate the role of gap junctions, specifically connexin 43 (Cx43), in cell death.
- To determine if other connexin family members also influence cell survival.
- To elucidate whether the protective effects are dependent on gap junction channel functionality.
Main Methods:
- Forced expression of connexin 43 (Cx43) in cells.
- Expression analysis of other connexin family members (Cx32, Cx40).
- Exposure of cells to various death-inducing agents: calcium overload, oxidative stress, metabolic inhibition, tamoxifen, UV irradiation, staurosporine, and dexamethasone.
- Inhibition of gap junction coupling through physical isolation and pharmacological agents.
- Utilizing nonfunctional mutant connexins.
Main Results:
- Forced expression of Cx43 conferred significant protection against cell injury, comparable to bcl2.
- Expression of Cx32 and Cx40 also enhanced resistance to several injury types, but not all.
- The anti-death activity of connexins was independent of gap junction channel function; inhibition of coupling or use of nonfunctional mutants did not abolish protection.
Conclusions:
- Connexin proteins actively promote cell survival.
- The protective role of connexins in cell death is independent of their function as gap junction channels.
- Connexins represent a novel class of proteins involved in cellular resistance to injury.