How the brain senses CO2

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Metabolism requires O2 and produces CO2 as a by-product. The amount of dissolved CO2 controls the acidity (pH) of our body fluids including blood. Many physiological processes are sensitive to pH, thus efficient control of the amount of dissolved CO2 in blood is a critical homoeostatic function. Special mechanisms exist to measure the amount of dissolved CO2 in blood ?if there is too much we breathe faster to drive off the excess, if there is too little we breathe less frequently. While there is evidence that CO2 is detected indirectly as pH, we have discovered a new molecular mechanism for the direct detection of CO2 ?CO2 binds to a type of channel called connexin 26 (Cx26), and in doing so causes it to open and release a chemical called ATP that activates neurons. Cx26 is sensitive to CO2 in exactly the physiological range required ?our normal levels of dissolved CO2 are at the mid-point of channel activation. Cx26 can thus respond to both increases and decreases in dissolved CO2. Cx26 is present in the correct areas of the brain to help control breathing. Our programme seeks to develop the genetic tools to analyze with great rigour the contributions of Cx26 to the measurement of CO2 and the control of breathing. Use of these tools will not only enable us to establish the causal link between Cx26 and behaviour, but also to determine the tissues, regions and cell types that are important for the detection of CO2. We also wish to understand the mechanism by which CO2 binds to the channel to change its conformation and cause it to open. We shall mix and match portions of CO2-sensitive and non-CO2-sensitive connexins to endow a previously non-sensitive connexin with CO2 sensitivity. This will tell us which part of the protein is important. We shall then identify the precise amino acid involved by mutating single amino acids in the critical region of the molecule. In parallel with this we shall use an analytical technique called NMR spectroscopy to directly and definitively test one possible way that CO2 could bind to the protein. Our proposal has the potential to transform understanding of how the brain senses CO2. This is likely to be important in understanding how CO2-sensing may be altered during pathologies such as congestive heart failure and chronic obstructive pulmonary disease.