A ubiquitous family of putative gap junction molecules

Panchina, Yuri; Kelmanson, Ilya V.; Matz, Mikhail V.; Lukyanov, Konstantin A.; Usman, Natalia; Lukyanov, Sergey

doi:10.1016/s0960-9822(00)00576-5

Cited by 504 publications

(419 citation statements)

References 13 publications

(27 reference statements)

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“…Pannexin 1, although originally discovered as a "gap junction protein," rather than forming cell-to-cell channels exerts its physiological role as a freestanding, unapposed membrane channel allowing the flux of molecules between the cytoplasm and the extracellular space (2,8,9,12,16,28,39,42). The channel can be opened at the resting membrane potential by mechanical stress, by an increase in cytoplasmic Ca 2ϩ concentration, or by ATP through P2Y or P2X 7 receptors (2, 33, 34).…”

Section: Resultsmentioning

confidence: 99%

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Probenecid, a gout remedy, inhibits pannexin 1 channels

Silverman¹,

Locovei

Dahl

2008

American Journal of Physiology-Cell Physiology

372

376

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Probenecid is a well-established drug for the treatment of gout and is thought to act on an organic anion transporter, thereby affecting uric acid excretion in the kidney by blocking urate reuptake. Probenecid also has been shown to affect ATP release, leading to the suggestion that ATP release involves an organic anion transporter. Other pharmacological evidence and the observation of dye uptake, however, suggest that the nonvesicular release of ATP is mediated by large membrane channels, with pannexin 1 being a prominent candidate. In the present study we show 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.connexin; transport; erythrocyte; ATP release PROBENECID HAS BEEN USED for decades for the treatment of gout. The mechanism of action of the drug is inhibition of a renal tubular transporter, thereby facilitating the excretion of the disease causative uric acid by blocking reuptake (5, 26, 37). Probenecid-sensitive transporters are widespread and are even found in plants (30,31,44,52,56). The inhibition of the transporter by probenecid is also exploited clinically to increase the effective concentrations of antibiotics, chemotherapeutics, and other medications.The inhibitory effect of probenecid on organic anion transporters is well established, and the effect is thought to be so specific that the drug is often used as a diagnostic tool, i.e., its effect is typically interpreted as an involvement of an anion transporter in the tested parameter. Accordingly, block of cAMP or cGMP release from erythrocytes (18, 25), ATP release from glia cells (1, 17), and block of dye loss in various cell types (20,21,23) by probenecid have been presented as evidence for a role of transporters in these phenomena. However, alternative pathways for the transit of these molecules across the plasma membrane have to be considered. Besides the well-documented vesicular release of ATP, a parallel release through membrane channels must exist, because the release is attenuated by drugs that do not interfere with vesicular release but affect gap junction proteins and because ATP release in several cell types is associated with uptake of dye from the extracellular medium (13).Special attention has to be given to pannexin 1 as an ATP release channel because of the specific properties of pannexin 1 channels and because of the expression pattern of pannexin 1 (2, 16, 28, 32-34, 55, 59). Pannexin 1 channels are highly permeable to ATP and to dyes typically used for dye flux measurements through gap junction channels. These dyes are in the same size range as the Ca 2ϩ indicator dyes whose loss is attenuated by probenecid. Pannexin 1 channels also are mechanosensitive, consistent with a role in Ca 2ϩ wave initiation. Expression of pannexin 1 is found in cells exhibiting ATP release, including er...

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Section: Resultsmentioning

confidence: 99%

“…Pannexins were discovered as a second family of vertebrate "gap junction proteins" based on the limited sequence homology to the innexins found in invertebrates (39). However, presently there is no evidence that pannexins actually form gap junction channels in vivo (8,16,28,32,42).…”

Section: Discussionmentioning

confidence: 99%

Probenecid, a gout remedy, inhibits pannexin 1 channels

Silverman¹,

Locovei

Dahl

2008

American Journal of Physiology-Cell Physiology

372

376

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“…Sequences were collected from four kinds of taxa: Vertebrata, Ecdysozoa, Platyhelminthes, and higher Lophotrochozoa. Sequences contained both innexin and pannexin sequences because these sequences are regarded as orthologous (Panchin et al, 2000;Yen and Saier, 2007). Sequences were aligned by ClustalX (Thompson et al, 1997) and then adjusted by eye.…”

Section: Phylogenetic Analysismentioning

confidence: 99%

The Expression of Tubulin and Tektin Genes in Dicyemid Mesozoans (Phylum: Dicyemida)

Ogino

Tsuneki

Furuya

2007

Journal of Parasitology

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“…1 Although originally thought to constitute a brand new family of gap junction proteins because of their sequence homology to the invertebrate gap junction family (innexins), pannexins have been shown mainly to form functional single membrane channels. 2,3 Out of over 100 published papers, less than half a dozen support a gap junction role for pannexins, and these studies are restricted to pannexin overexpression in in vitro systems.…”

Section: Introductionmentioning

confidence: 99%

The cellular life of pannexins

Peñuela

Laird

2012

WIREs Membr Transp Signal

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The mammalian pannexin family of channel-forming proteins consisting of Panx1, Panx2, and Panx3 has received considerable attention in the last 10 years given their newly discovered physiological roles in development and disease. Pannexins exhibit diverse subcellular profiles indicating that they may serve distinct roles in cells and tissues of different origin. This complexity in cellular residencies may be rooted in the fact that pannexin genes consist of multiple exons that have led to the identification of several splice variants. Additionally, post-translational modifications, especially N-glycosylation, appear to be important in regulating trafficking and intermixing of pannexin family members increasing the diversity of assembled channels. These long-lived membrane proteins are typically trafficked through the classical secretory pathway before reaching the plasma membrane although Panx2 tends to often be retained in intracellular compartments. Trafficking, stability, and function of pannexins likely enlist the services of an interactome that continues to expand. The research field has been amazed by the fact that Panx1 null mice are generally healthy with distinct phenotypes only being revealed when mutant mice encounter additional stress or have comorbidities. The emerging field of pannexin biology has also begun to explore the relationships and potential cross-talk between pannexin channels and connexin hemichannels. It is imperative to dissect the different constituents of the channels and the molecules that pass through these distinct channel types. Finally, as witnessed in connexin biology throughout the 90s, the field awaits to see if germline mutations in the genes that encode pannexins also cause disease.

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A ubiquitous family of putative gap junction molecules

Cited by 504 publications

References 13 publications

Probenecid, a gout remedy, inhibits pannexin 1 channels

Probenecid, a gout remedy, inhibits pannexin 1 channels

The Expression of Tubulin and Tektin Genes in Dicyemid Mesozoans (Phylum: Dicyemida)

The cellular life of pannexins

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