We have previously shown connexin mediated CO2-dependent ATP release from the surface of the medulla oblongata. Given the localization of connexin 26 (Cx26) to the chemosensing areas of the medulla, we have tested in a heterologous expression system (HeLa cells) whether Cx26 may be sensitive to changes in . Cx26 responded to an increase in at constant extracellular pH by opening and to a decrease in by closing. Furthermore, Cx26 was partially activated at a physiological of around 40 mmHg. Cx26 in isolated patches responded to changes in , suggesting direct CO2 sensitivity of the hemichannel to CO2. Heterologous expression of Cx26 in HeLa cells was sufficient to endow them with the capacity to release ATP in a CO2-sensitive manner. We have examined other heterologously expressed connexins for their ability to respond to changes in . The closely related β connexins Cx30 and Cx32 also displayed sensitivity to changes in , but with slightly different characteristics from Cx26. The more distant Cx43 exhibited CO2-dependent closing (possibly mediated through intracellular acidification), while Cx36 displayed no CO2 sensitivity. These surprising findings suggest that connexins may play a hitherto unappreciated variety of signalling roles, and that Cx26 and related β connexins may impart direct sensitivity to CO2 throughout the brain.