Abstract
A subclade of connexins comprising Cx26, Cx30, and Cx32 are directly sensitive to CO2. CO2 binds to a carbamylation motif present in these connexins and causes their hemichannels to open. Cx26 may contribute to CO2-dependent regulation of breathing in mammals. Here, we show that the carbamylation motif occurs in a wide range of non-mammalian vertebrates and was likely present in the ancestor of all gnathostomes. While the carbamylation motif is essential for connexin CO2-sensitivity, it is not sufficient. In Cx26 of amphibia and lungfish, an extended C-terminal tail prevents CO2-evoked hemichannel opening despite the presence of the motif. Although Cx32 has a long C-terminal tail, Cx32 hemichannels open to CO2 because the tail is conformationally restricted by the presence of proline residues. The loss of the C-terminal tail of Cx26 in amniotes was an evolutionary innovation that created a connexin hemichannel with CO2-sensing properties suitable for the regulation of breathing.
Highlights
A subclade of connexins comprising Cx26, Cx30, and Cx32 are directly sensitive to CO2
We have discovered that the β connexins, Cx26, Cx30 and Cx32 are modulated by CO26
This approach has given us new insight into the structural determinants of the CO2 sensitivity of both gap junctions and hemichannels and has shown that the carbamylation motif was present in the ancestor of all gnathostomes
Summary
A subclade of connexins comprising Cx26, Cx30, and Cx32 are directly sensitive to CO2. In this paper we use our insights about the nature of the carbamylation motif to further refine our understanding of the phylogenetic occurrence of this motif, and CO2-sensitivity, in the β connexin family This approach has given us new insight into the structural determinants of the CO2 sensitivity of both gap junctions and hemichannels and has shown that the carbamylation motif was present in the ancestor of all gnathostomes. It is a common feature of the amniote species tested that their Cx26 hemichannels lack an extended C-terminal tail and are sensitive to CO2. This suggests that the common ancestor of all extant amniotes had already evolved CO2-sensitive Cx26 hemichannels
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