We have previously shown connexin mediated CO(2)-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 PCO2. Cx26 responded to an increase in PCO2 at constant extracellular pH by opening and to a decrease in PCO2 by closing. Furthermore, Cx26 was partially activated at a physiological PCO2 of around 40 mmHg. Cx26 in isolated patches responded to changes in PCO2, suggesting direct CO(2) sensitivity of the hemichannel to CO(2). Heterologous expression of Cx26 in HeLa cells was sufficient to endow them with the capacity to release ATP in a CO(2)-sensitive manner. We have examined other heterologously expressed connexins for their ability to respond to changes in PCO2. The closely related β connexins Cx30 and Cx32 also displayed sensitivity to changes in PCO2, but with slightly different characteristics from Cx26. The more distant Cx43 exhibited CO(2)-dependent closing (possibly mediated through intracellular acidification), while Cx36 displayed no CO(2) 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 CO(2) throughout the brain.