CO(2) directly modulates connexin 26 by formation of carbamate bridges between subunits

Homeostatic regulation of the partial pressure of CO(2) (PCO(2)) is vital for life. Sensing of pH has been proposed as a sufficient proxy for determination of PCO(2) and direct CO(2)-sensing largely discounted. Here we show that connexin 26 (Cx26) hemichannels, causally linked to respiratory chemosensitivity, are directly modulated by CO(2). A ‘carbamylation motif’, present in CO(2)-sensitive connexins (Cx26, Cx30, Cx32) but absent from a CO(2)-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 PCO(2). Mutation of the carbamylation motif in Cx26 and mCx31 destroyed CO(2) 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 CO(2). DOI: http://dx.doi.org/10.7554/eLife.01213.001