1.A.25 The Gap Junction-forming Innexin (Innexin) Family
Innexins comprise a large family of proteins that form intercellular gap junctional channels in invertebrates, but only a few have been functionally characterized. These junctions allow electrical coupling as well as the free flow of small molecules between cells. The C. elegans INX-3, but not a paralogue, EAT-5, induced electrical coupling between Xenopus oocyte pairs (Landesman et al., 1999). Voltage and pH gating of INX-3 channels is functionally similar to that of vertebrate connexin channels (TC #1.A.24). Many paralogues of the Innexin family are found in both C. elegans and D. melanogaster as well as other invertebrates, and these proteins are subject to differential developmental control in various body tissues. Innexins exhibit a 4 TMS topology. Homologues, called pannexins, have been identified in vertebrates (Hua et al., 2003; Yen and Saier, 2007).
Gap junctions are widespread in immature neuronal circuits. A transient network formed by the innexin gap-junction protein NSY-5 coordinates left-right asymmetry in the developing nervous system of C. elegans. NSY-5 forms hemichannels and intercellular gap-junction channels, consistent with a combination of cell-intrinsic and network functions (Chuang et al., 2007). In addition to making gap junctions, innexins also form non-junctional membrane channels with properties similar to those of pannexons (Bao et al., 2007).
Pannexins in vertebrates have been studied in some detail (Shestopalov and Panchin, 2008; Boyce et al. 2013). They can form nonjunctional transmembrane 'hemichannels' for transport of molecules of less than 1000 Da, or intercellular gap junctions. They transport Ca2+, ATP, inositol triphosphate, and other small molecules. They can be present in plasma, ER and golgi membranes. Pannexin1 can form homooligomeric channels and heterooligomeric channels with Pannexin2. They form hemichannels with greater ease than connexin subunits (Shestopalov and Panchin, 2008). Scemes (2011) summarized the published data on hemichannel formation by junctional proteins.
Silverman et al. 2008 have showed that probenecid inhibited currents mediated by pannexin 1 channels in the same concentration range as observed for inhibition of transport processes. Probenecid did not affect channels formed by connexins. Thus probenecid allows for discrimination between channels formed by connexins and pannexins.
The transport reaction catalyzed by innexin gap junctions is:
Small molecules (cell1 cytoplasm) Small molecules (cell2 cytoplasm)
- or for hemichannels:
Small molecules (all cytoplasm)Small molecules (out)