Pannexin

Pannexin

Gap junction protein family is composed of connexins, innexins and recently discovered pannexins. A pannexin is a member of both vertebrate and invertebrate family of proteins used to build gap junctions between neurons or glial cells. So far three pannexins were described in human and rodent genomes: PANX1, PANX2 and PANX3. Hypothetical roles of pannexins include participating in sensory processing, hippocampal plasticity, synchronization between neurons, and propagation of the calcium waves supported by glial cells. Pannexins also may participate in pathological reactions in the central nervous system.

Gap junction proteins

Connexins had been considered to be the only class of the vertebrate proteins composing gap junctions, while non-homologous innexins were involved in gap junction formation in invertebrates. However, at the very beginning of our century, genes, homologues to innexins, were discovered in different taxonomic groups, including vertebrates [1-5]. This new protein family was proposed to call pannexins from the Greek “pan” – “all, throughout” and the Latin “nexus” - “connection, bond”.

Distribution

So far three pannexin encoding genes had been found in rodent and human genomes: PANX1, PANX2 and PANX3.

PANX1 is expressed in numerous organs in mouse, rat and human, including brain, lung, spleen, kidney, testis, thymus, prostate and others. PANX1 gene are expressed both in developing and mature nervous system [6].

PANX2 gene was found in many organs in rodents, but so far was found to be brain- specific in humans. PANX3 expression is confirmed only in rat’s skin [6].

Structure

Pannexin-encoding genes are highly conserved in worms, mollusks, insects, and mammals. In humans, PANX1 and PANX3 genes are located on chromosome 11, at 30 Mb distance from each other, while PANX2 is located on chromosome 22 [2]. All PANX1, PANX2 and PANX3 genes have been cloned [2]. They have been predicted to have four transmembrane regions, two extracellular loops, one intracellular loop and intracellular C and N termini.

So far, PANX1 gene was found to form functional channel both alone and in combination with PANX 2, whereas PANX 2 alone was not able to form a channel [3]. Homomeric and heteromeric hemichannels can differ in their gating properties.

Possible functions of the pannexins

Two possible functions have been suggested for pannexins. According to the first scenario, pannexin proteins form gap junctions and are involved in electrical signaling. Thus, they are believed to synchronize neuronal firing and generate oscillatory behaviour.

The other hypothesis proposes their role in extracellular signaling, particularly in propagation of calcium waves. Pannexin channels have been shown to be involved in ATP-induced ATP release, which is typical for calcium wave’s propagation. PANX1 can form functional hemichannels at physiologic calcium concentrations and is expressed in many organs and tissues capable of calcium wave’s propagations [3]. Calcium waves are supported by glial cells, which can maintain and modulate neuronal metabolism.

In addition to the cytoplasm and extracellular signaling, pannexins may have more specific roles. They can participate in a neuronal death after ischemia, may be involved in tumorigenesis. The abundant expression of both pannexins in the retinal neurons suggests their involvement in visual signal processing and/or the development of the retinal neuronal system.

References

1. Panchin Y, Kelmanson I, Matz M, Lukyanov K, Usman N, Lukyanov S. (2000). A ubiquitous family of putative gap junction molecules. Curr Biol., 10: R473–474.

2. Baranova A, Ivanov D, Petrash N, Pestova A, Skoblov M, Kelmanson I, Shagin D, Nazarenko S, Geraymovych E, Litvin O, Tiunova A, Born TL, Usman N, Staroverov D, Lukyanov S, Panchin Y. (2004). The mammalian pannexin family is homologous to the invertebrate innexin gap junction proteins. Genomics, 83(4):706-716.

3. Bruzzone R, Hormuzdi SG, Barbe MT, Herb A, Monyer H. (2003). Pannexins, a family of gap junction proteins expressed in brain. Proc Natl Acad Sci USA.; 100:13644–13649.

4. Kelmanson IV, Shagin DA, Usman N, Matz MV, Lukyanov SA, Panchin YV. (2002). Altering electrical connections in the nervous system of the pteropod mollusk Clione limacina by neuronal injections of gap junction mRNA. Eur J Neurosci.; 16: 2475–2476.

5. Dykes IM, Macagno ER., (2006). Molecular characterization and embryonic expression of innexins in the leech Hirudo medicinalis. Dev Genes Evol.; 216: 185–197.

6. Litvin O, Tiunova A, Connell-Alberts Y, Panchin Y, Baranova A.J. (2006). What is hidden in the pannexin treasure trove: the sneak peek and the guesswork. Cell Mol Med., 10(3):613-634. PMID 16989724.