Gap junction proteins with no sequence homology to connexins were initially identified in fruit flies. It was suggested that these proteins are specific invertebrate gap junctions, and they were thus named "innexins" (invertebrate analog of connexins). They were later identified in diverse invertebrates. Invertebrate genomes may contain more than a dozen innexin genes. Once the human genome was sequenced, innexin homologues were identified in humans and then in other vertebrates, indicating their ubiquitous distribution in the animal kingdom. These homologues were called "pannexins" (from the Greek pan - all, throughout, and Latin nexus - connection, bond). However, increasing evidence suggests that pannexins do not form gap junctions unless overexpressed in tissue and thus, differ functionally from innexins.
Innexins have four transmembrane segments (TMSs) and, like the vertebrate connexin gap junction protein, six innexin subunits together form a channel (an "innexon") in the plasma membrane of the cell. Two innexons in apposed plasma membranes can form a gap junction. Structurally, pannexins are similar to connexins. Both types of protein consist of a cytoplasmic N-terminal domain, followed by four (TMSs) that delimit one cytoplasmic and two extracellular loops; the C- terminal domain is cytoplasmic. In addition, pannexin1 and pannexin2 channels show quaternary similarities to connexons, but different oligomerization numbers.
Vinnexins, viral homologues of innexins, were identified in polydnaviruses that occur in obligate symbiotic associations with parasitoid wasps. It was suggested that vinnexins may function to alter gap junction proteins in infected host cells, possibly modifying cell-cell communication during encapsulation responses in parasitized insects.
Pannexins can form nonjunctional transmembrane “hemichannels” for transport of molecules of less than 1000 Da, or intercellular gap junctions. These hemichannels can be present in plasma, ER and Golgi membranes. They transport Ca2+, ATP, inositol triphosphate and other small molecules and can form hemichannels with greater ease than connexin subunits. Pannexin 1 constitutes the large conductance cation channel of cardiac myocytes. Pannexin 1 and pannexin 2 underlie channel function in neurons and contribute to ischemic brain damage.
In addition to making gap junctions, innexins also form non-junctional membrane channels with properties similar to those of pannexons. N-terminal- elongated innexins can act as a plug to manipulate hemichannel closure and provide a mechanism connecting the effect of hemichannel closure directly to apoptoticsignal transduction from the intracellular to the extracellular compartment.
The transport reactions catalyzed by innexin gap junctions is:
Small molecules (cell 1 cytoplasm) ⇌ small molecules (cell 2 cytoplasm)
Or for hemichannels:
Small molecules (cell cytoplasm) ⇌ small molecules (out)
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