TY - JOUR TI - CO2 directly modulates connexin 26 by formation of carbamate bridges between subunits AU - Meigh, Louise AU - Greenhalgh, Sophie A AU - Rodgers, Thomas L AU - Cann, Martin J AU - Roper, David I AU - Dale, Nicholas A2 - Aldrich, Richard VL - 2 PY - 2013 DA - 2013/11/12 SP - e01213 C1 - eLife 2013;2:e01213 DO - 10.7554/eLife.01213 UR - https://doi.org/10.7554/eLife.01213 AB - Homeostatic regulation of the partial pressure of CO2 (PCO2) is vital for life. Sensing of pH has been proposed as a sufficient proxy for determination of PCO2 and direct CO2-sensing largely discounted. Here we show that connexin 26 (Cx26) hemichannels, causally linked to respiratory chemosensitivity, are directly modulated by CO2. A ‘carbamylation motif’, present in CO2-sensitive connexins (Cx26, Cx30, Cx32) but absent from a CO2-insensitive connexin (Cx31), comprises Lys125 and four further amino acids that orient Lys125 towards Arg104 of the adjacent subunit of the connexin hexamer. Introducing the carbamylation motif into Cx31 created a mutant hemichannel (mCx31) that was opened by increases in PCO2. Mutation of the carbamylation motif in Cx26 and mCx31 destroyed CO2 sensitivity. Course-grained computational modelling of Cx26 demonstrated that the proposed carbamate bridge between Lys125 and Arg104 biases the hemichannel to the open state. Carbamylation of Cx26 introduces a new transduction principle for physiological sensing of CO2. KW - respiratory chemosensitivity KW - connexin KW - signal transduction KW - membrane channel JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -