Pannexins are a family of vertebrate proteins identified by their homology to the invertebrate innexins. While innexins are responsible for forming gap junctions in invertebrates, the pannexins have been shown to predominantly exist as large transmembrane channels connecting the intracellular and extracellular space, allowing the passage of ions and small molecules between these compartments. Three pannexins have been described in Chordates: Panx1, Panx2 and Panx3.
Function
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. Pannexin 1 has been shown to be involved in early stages of innate immunity through an interaction with the P2X7purinergic receptor. Activation of the pannexin channel through binding of ATP to P2X7 receptor leads to the release of interleukin-1β. Hypothetical roles of pannexins in the nervous system include participating in sensory processing, synchronization between hippocampus and cortex, hippocampal plasticity, and propagation of calcium waves. Calcium waves are supported by glial cells, which help maintain and modulate neuronal metabolism. According to one of the hypotheses, pannexins also may participate in pathological reactions, including the neural damage after ischemia and subsequent cell death. Pannexin 1 channels are pathways for release of ATP from cells.
Relationship to connexins
Intercellular gap junctions in vertebrates, including humans, are formed by the connexin family of proteins. Structurally, pannexins and connexins are very similar, consisting of 4 transmembrane domains, 2 extracellular and 1 intracellular loop, along with intracellular N- and C-terminal tails. Despite this shared topology, the protein families do not share enough sequence similarity to confidently infer common ancestry. The N-terminal portion of VRAC-forming LRRC8 proteins like LRRC8A may also be related to pannexins. The structure of a Xenopus tropicalis pannexin has been solved. It forms a heptameric disc. The human version is similar.
Clinical significance
Truncating mutations in pannexin 1 have been shown to promote breast and colon cancer metastasis to the lungs by allowing cancer cells to survive mechanical stretch in the microcirculation through the release of ATP. Pannexins may be involved in the process of tumor development. Particularly, PANX2 expression levels predict post diagnosis survival for patients with glial tumors. Probenecid, a well-established drug for the treatment of gout, allows for discrimination between channels formed by connexins and pannexins. Probenecid did not affect channels formed by connexins, but it inhibits pannexin-1 channels.
