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fbtwitterlinkedinvimeoflicker grey 14rssslideshare1
Meigh, Louise
Languages: English
Types: Doctoral thesis
Subjects: QP
The mechanism through which changes in PCO2 in the blood are detected is much disputed. Although many believe the stimulus for CO2 detection to be the associated increase in H+, increasing evidence supports a role for direct CO2 detection. In a recent development, Huckstepp et al demonstrated that connexin 26 hemichannels open in response to elevated CO2 in the absence of a pH change. This model however remained incomplete, with the mechanism of CO2 interaction with the channel being unknown.\ud \ud In this work I have employed site directed mutagenesis and dye loading studies to identify the CO2 binding site of connexin 26. This was found to be lysine 125, with binding through the formation of a carbamate bond. Mutational and modelling studies support an intersubunit salt bridge between the subsequent negative charge and the positive arginine 104 as the mechanisms of channel opening. Using this model for connexin 26 channel opening I was also able to manipulate the channel to respond to novel stimuli. These new mutants act both to support our mechanism for channel opening and to provide tools for further research. The production of connexin 26 channels lacking the key residues of interest also provides the basis of a novel method for producing animal models lacking CO2-sensitvity for further research in vivo.\ud \ud The findings of this work confirm that connexin 26 interacts with CO2 through direct binding. Connexin 26 therefore represents the first established CO2 sensor in the chemosensitive areas of the brain and strongly supports the idea that CO2 itself participates in monitoring PCO2 levels. As this model requires no accessory proteins, this work also offers the intriguing possibility that CO2-sensitvity may be an important function of this protein in other tissues and supports the idea of connexin proteins as novel ligand gated channels.

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