Author response: CO2 directly modulates connexin 26 by formation of carbamate bridges between subunits

Abstract

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 .