Neural Circuits, Neural Communication and Behaviour

Dale Lab, Neuroscience Research at the University of Warwick

CO2 modulation of Cx26: CO2-dependent dye loading (top) and changes in whole cell conductance (bottom) of Cx26-expressing HeLa cells during increases and decreases of PCO2 indicated by bars.

CO2 chemosensory transduction and physiological processes

Supported by the MRC and BBSRC

Breathing is a vital physiological function that is continually adapted to metabolic activity. Peripheral and central chemosensors, which monitor the levels of O2 and CO2 in arterial blood and brain respectively, are essential components of the homeostatic controls that adjust respiratory activity to keep these blood gasses at their physiological levels.

If PCO2 in arterial blood increases (hypercapnia), ventilatory frequency rapidly increases. This reflex is mainly mediated by central chemoreceptors located at the highly vascularised ventral surface of the medulla oblongata. These chemosensors respond to changes in brain CO2/pH. The importance of the central chemoreceptors can be demonstrated by the persistence of the ventilatory response to hypercapnia after deafferentation of the peripheral chemoreceptors. Although this has been known for a long time, as has indeed the general location of CO2 chemosensors within the medulla, the mechanisms of CO2 chemoreception remain one of the mysteries of the respiratory field. It is often assumed in the field that CO2 is detected via a change in pH. We have now provided a molecular mechanism by which CO2 acts directly on Connexin26 (Cx26) to effect physiological changes in breathing.

Our work on Cx26 extends from high resolution structures, via mutational analysis, to testing of function in vivo via novel genetic constructs that can selectively interfere with the CO2 sensitivity of Cx26 while retaining its other functions.

Banner illustration: montage of CO2-dependent dye loading (FITC) and GFAP staining at the ventral surface of the medulla oblongata. This demonstrates the importance for the response to CO2 of large conductance channels in glial cells at the surface of the medulla.