Connexin hemichannels and pannexin channels in toxicity: Recent advances and mechanistic insights

Connexin hemichannels and pannexin channels are two types of transmembrane channels that allow autocrine/paracrine signalling through the exchange of ions and molecules between the intra- and extracellular compartments. However, owing to the poor selectivity of permeable ions and metabolites, the massive opening of these plasma membrane channels can lead to an excessive influx of toxic substances and an outflux of essential metabolites, such as adenosine triphosphate, glutathione, glutamate and ions, resulting in unbalanced cell homeostasis and impaired cell function. It is becoming increasingly clear that these channels can be activated in response to external stimuli and are involved in toxicity, yet their concrete mechanistic roles in the toxic effects induced by stress and various environmental changes remain poorly defined. This review provides an updated understanding of connexin hemichannels and pannexin channels in response to multiple extrinsic stressors and how these activated channels and their permeable messengers participate in toxicological pathways and processes, including inflammation, oxidative damage, intracellular calcium imbalance, bystander DNA damage and excitotoxicity.