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, Connexin26. 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. Cx26 therefore acts as both the detector of CO2 and conduit (by opening) for subsequent ATP release.

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.

Our latest research exploits understanding of how CO2 binds to Cx26 to develop a dominant negative Cx26 subunit (Cx26DN) which can coassemble with wild type Cx26 and remove CO2 sensitivity from the heteromeric assembly. This has allowed us to link the binding of CO2 to Cx26 to the adaptive control of breathing.