Connexins, pannexins, innexins: novel roles of "hemi-channels"

Abstract

The advent of multicellular organisms, some 800 million years ago, necessitated the development of mechanisms for cell-to-cell synchronization and for the spread of signals across increasingly large cell populations [168, 185]. Many structures and mechanisms have evolved to achieve such functions [4, 15]. Among these mechanisms, one which is prominent in both the invertebrate and the vertebrate world, across the entire phylogenetic scale, involves the transmembrane flux of large cytosolic and extracellular molecules [, , , , –71, 121, 128, 129, 147, 154, 163]. These fluxes, in turn, are dependent on the formation of specific channels that in all animal classes are made by tetra-span integral membrane proteins [, , –71, 121, 128, 129, 147, 154, 163] (Fig. 1).

Fig. 1

Innexins, pannexins, and connexins form different types of gap junctional and “hemi-channels.” Invertebrates express many different innexins (purple; 25 isoforms in C. elegans) that may form either gap junction channels for cell-to-cell coupling (open arrows) or innexon “hemi-channels” for the permeability of the nonjunctional membrane (solid arrows). Vertebrates express three different isoforms of pannexins (red) that form pannexon “hemi-channels” and 20 different connexin isoforms (green) that essentially form gap junction channels. A few connexin isoforms may also form connexon “hemi-channels”

Fig. 2

Membrane topography of the proteins forming gap junctions and “hemi-channels.” All invertebrate innexins, vertebrate ortholog pannexins, and nonhomologous vertebrate connexins feature four transmembrane domains connected by two extracellular loops and one cytoplasmic loop, and have both N and C termini in the cytosol. Connexins possess 3 Cys residues (solid circles) in each of their extracellular loops. Pannexins and innexins feature only two such Cys residues per loop. Contrasting with both connexins and innexins, pannexin proteins are glycosylated (tree-like structure) on one of their extracellular loop. The gray areas schematize the two lipid layers

Fig. 3

Conditions leading to the detection of functional “hemi-channels.” Functional connexon “hemi-channels” are revealed in the absence of extracellular [Ca²⁺] or [Mg²⁺], and upon supraphysiological depolarizations. Pannexon “hemi-channels” are activated in the presence of normal extracellular [Ca²⁺] and physiologically relevant membrane depolarizations. Many “hemi-channels” of different protein composition are activated by mechanical stress and membrane depolarization

Fig. 4

Cx43 and Pnx1 control the expression of a similar set of genes. Log–log plots of Pearson’s coefficients for Gja1 (X axis), Panx1, KIf16, and Nfx1 (Y axis) with all other genes. The red plot indicates that almost all genes are similarly coordinated with that of the two junctional proteins (overlap of the coordination profiles—OVL=93.2). By contrast, the blue plot shows that almost all genes exhibit opposite coordination for Gja1 and KIf16 (Kruppel-like factor 16; OVL=−94.7). Moreover, the green plot indicates that for other genes there is no association of coordinated expression between Gja1 and the other gene (here, Nfx1, nuclear transcription factor X-box binding 1; OVL=−0.4)