Neural Circuits, Neural Communication and Behaviour

Dale Lab, Neuroscience Research at the University of Warwick

Our research

Collaborating with Alex Gourine (UCL), we have found compelling causal evidence suggesting an important role for ATP as a mediator of CO2 chemosensory transduction. ATP is released in the correct location (the surface of the ventral medulla) and the correct time to play this role. Furthermore application of ATP to the surface of the ventral medulla will enhance breathing; whereas application of ATP receptor antagonists, will greatly reduce the CO2 induced enhancement of breathing.

Left: ATP release during hypercapnia, recorded from the ventral surface of the medulla oblongata. PNG -phrenic nerve activity. Right: Localization of ATP release to defined areas at the surface of the medulla.

Our results show that CO2 can be detected directly as molecular CO2 by a specific receptor molecule, Connexin 26. This is a very surprising and hitherto unknown role for this connexin. We have found that related connexins are also CO2-sensitive. When CO2 binds to Cx26, it causes it to open and allow the efflux of ATP. Blocking Cx26, prevents this release of ATP and reduces the adaptive ventilatory response to hypercapnia. Connexin 26 therefore acts as both the detector of CO2 and conduit (by opening) for subsequent ATP release. Our results give major new insight into the chemosensory control of respiration and other physiological processes.

Left: Cx26 is sufficient to recapitulate CO2-dependent ATP release in HeLa cells. Right: Blockers of Cx26 reduce hypercapnic ATP release in vivo and the adaptive ventilatory response.

Collaborating with Prof Georgy Koentges, we are now altering the expression of Cx26 selectively in different cell types to understand how this molecule contributes to the control of respiration. We have made great progress in understanding the molecular mechanism by which how CO2 interacts with Cx26, and how this leads to channel opening.