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

Meigh, L.; Greenhalgh, S.A.; Rodgers, T.L.; Cann, M.J.; Roper, D.I.; Dale, N.

Abstract

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.

Citation

Meigh, L., Greenhalgh, S., Rodgers, T., Cann, M., Roper, D., & Dale, N. (2013). CO2 directly modulates connexin 26 by formation of carbamate bridges between subunits. eLife, 2, https://doi.org/10.7554/elife.01213

• Journal Article Type: Article
• Publication Date: Nov 12, 2013
• Deposit Date: Nov 28, 2013
• Publicly Available Date: Dec 1, 2014
• Journal: eLife
• Electronic ISSN: 2050-084X
• Publisher: eLife Sciences Publications
• Peer Reviewed: Peer Reviewed
• Volume: 2
• DOI: https://doi.org/10.7554/elife.01213
• Public URL: https://durham-repository.worktribe.com/output/1443960