Evolutionary analyses of gap junction protein families

Gap junctions are intercellular channels that link the cytoplasm of neighboring cells in animals, enabling straight passage of ions and small molecules. Two different protein families, pannexins and connexins, form these channels. Pannexins are present in all eumetazoans but echinoderms (and are termed innexins in non-chordates) whereas connexins are exclusive of chordates. Despite little sequence similarity, both types of proteins assemble into a common secondary structure with four hydrophobic transmembrane domains linked by one cytoplasmic and two extracellular loops. Although all pannexins and connexins are packed into hexamers forming single channels, only non-chordate pannexins (innexins) and connexins form gap junctions. Here, we revisit and review evolutionary features of pannexin and connexin protein families. For that, we retrieved members of both families from several complete genome projects, and searched for conserved positions in the independent alignments of pannexin and connexin protein families. In addition, the degree of evolutionary conservation was mapped onto the 3D structure of a connexon (i.e. the assembly of six connexins). Finally, we reconstructed independent phylogenies of pannexins and connexins using probabilistic methods of inference. Non-chordate (Drosophila and Caenorhabditis) pannexins (i.e. innexins) were recovered as sister group of chordate pannexins, which included Ciona paralogs and vertebrate pannexins (pannexin-1 and pannexin-3 were recovered as sister groups to the exclusion of pannexin-2). In the reconstructed phylogeny of connexins, subfamilies α and β were recovered as sister groups to the exclusion of subfamily γ, whereas δ and (the newly identified) ζ subfamilies were recovered at the base of the tree. A sixth highly divergent subfamily (ε) was not included in the phylogenetic analyses. Several groups of paralogy were identified within each subfamily. This article is part of a Special Issue entitled: The Communicating junctions, roles and dysfunctions.