Connexin-related signaling in cell death: to live or let die?

Evidence is accumulating that some forms of cell death, like apoptosis, are not only governed by the complex interplay between extracellular and intracellular signals but are also strongly influenced by intercellular communicative networks. The latter is provided by arrays of channels consisting of connexin proteins, with gap junctions directly connecting the cytoplasm of neighboring cells and hemichannels positioned as pores that link the cytoplasm to the extracellular environment. The role of gap junctions in cell death communication has received considerable interest and recently hemichannels have joined in as potentially toxic pores adding their part to the cell death process. However, despite a large body of existing evidence, especially for gap junctions, the exact contribution of the connexin channel family still remains controversial, as both gap junctions and hemichannels may furnish cell death as well as cell survival signals. An additional layer of complexity is formed by the fact that connexin proteins as such, beyond their channel function, may influence the cell death process. We here review the current knowledge on connexins and their channels in cell death and specifically address the molecular mechanisms that underlie connexin-related signaling. We also briefly focus on pannexins, a novel set of connexin-like proteins that have been implicated in cellular responses to pathological insults.