CO₂ speaks for itself

eLife 2, e01213 (2013)

CO₂ is a common byproduct of basic metabolism and affects cellular pH via its interconversion with bicarbonate. Thus, changes in pH are generally assumed to serve as a cellular proxy for CO₂ concentration. However, recent research on the gap junction proteins connexin 26, 30 and 32 revealed changes in connexon channel opening in response to varying CO₂ concentrations at constant pH. In their efforts to explain this behavior, Meigh et al. found that, unlike the previous connexins, connexin 31 was CO₂ insensitive. The authors suspected this could be due to protein carbamylation—modification of an amino acid by CO₂—at a lysine present in the sensitive proteins but not connexin 31. Bioinformatic analysis pointed to Lys125 within a KVREI motif as a possible carbamylation site that could create a salt bridge with a neighboring arginine. The authors confirmed that insertion of this motif into connexin 31 made the resulting mutant protein sensitive to CO₂. Mutation of either Lys125 or the neighboring arginine eliminated CO₂ sensitivity, whereas mutation of either residue to glutamate created a constitutively open channel. A coarse-grained elastic network model further suggested that the salt bridge decreased the population of the closed state substantially. Although the authors did not directly observe the carbamylated species, these results provide exciting evidence for the second case of mammalian carbamylation and the first in which CO₂ regulates cellular signaling.