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. DOI: http://dx.doi.org/10.7554/eLife.01213.001.
Highlights
CO2 is the unavoidable by-product of cellular metabolism
We have previously demonstrated that connexin 26 (Cx26), and two related β connexins, Cx30 and Cx32, open when exposed to modest increases in pressure of CO2 (PCO2) at constant pH (Huckstepp et al, 2010a)
As the connexins were tagged with mCherry, we could verify the presence of fluorescent puncta in both the Cx26 and Cx31 expressing HeLa cells (Figure 1—figure supplement 2)
Summary
CO2 is the unavoidable by-product of cellular metabolism. Humans produce approximately 20 moles of CO2 per day (Marshall and Bangert, 2008). Regulation of PCO2 is a vital homeostatic function that is linked to acid-base balance. Chemosensory reflexes regulate the frequency and depth of breathing to ensure homeostatic control of blood gases. There are several areas of the medulla oblongata which contain neurons that respond to changes in pH/CO2, especially near the highly vascularised ventral surface. For example a population of neurons highly sensitive to pH/CO2 have been described in the retrotrapezoid nucleus (RTN) (Mulkey et al, 2004, 2006; Guyenet et al, 2008) and the medullary raphé nucleus (Richerson, 2004; Ray et al, 2011). If pH is carefully controlled at the medullary surface, an increase in PCO2 at constant pH will still enhance breathing by as much as a pH change at constant PCO2 (Shams, 1985).
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