Pannexin 1 and pannexin 3 are glycoproteins that exhibit many distinct characteristics from the connexin family of gap junction proteins

Peñuela, Silvia; Bhalla, Ruchi; Gong, Xiang-Qun; Cowan, Kyle N.; Celetti, Steven J.; Cowan, Bryce J.; Bai, Donglin; Shao, Qing; Laird, Dale W.

doi:10.1242/jcs.009514

Cited by 376 publications

(661 citation statements)

References 38 publications

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“…Conversely, Cx43 is typically cleared from the cell surface in the presence of BFA in only 3-6 h. 26,37 Additionally, cycloheximide treatment of Panx1-expressing BICR-M1R k cells failed to reduce the detectable levels of Panx1 protein even after 8 h of protein synthesis inhibition again suggesting that this molecule has a longer half-life than what has been reported for Cx43. 26 …”

Section: Pannexin Life Cycle and Traffickingmentioning

confidence: 90%

“…Although pannexin sequence examination suggests that there are several potential phosphorylation sites within the C-terminus, intracellular loop, and N-terminus of all three pannexins, 26,27 there has been no direct evidence so far that pannexins are phosphoproteins. To that end we at least know that the multiple banding pattern of Panx1 and Panx3 observed in Western blots does not change upon dephosphorylation with alkaline phosphatase as often seen and demonstrated for the well-known phosphoprotein, Cx43.…”

Section: Post-translational Modification Of Pannexinsmentioning

confidence: 99%

“…To that end we at least know that the multiple banding pattern of Panx1 and Panx3 observed in Western blots does not change upon dephosphorylation with alkaline phosphatase as often seen and demonstrated for the well-known phosphoprotein, Cx43. 26 It remains to be discovered if phosphorylation plays a regulatory role on trafficking or channel function of pannexins as is the case for connexins. 28 On the other hand, the predicted extracellular loop sequence consensus sites for N-glycosylation ( Figure 1) in Panx1 (N254) and Panx3 (N71) have been confirmed to indeed be sites of glycosylation as demonstrated by site-directed mutagenesis studies 9,26,29 and by sensitivity to N-glycosidase F and endoglycosidase H enzymatic digestion.…”

Section: Post-translational Modification Of Pannexinsmentioning

confidence: 99%

“…26 It remains to be discovered if phosphorylation plays a regulatory role on trafficking or channel function of pannexins as is the case for connexins. 28 On the other hand, the predicted extracellular loop sequence consensus sites for N-glycosylation ( Figure 1) in Panx1 (N254) and Panx3 (N71) have been confirmed to indeed be sites of glycosylation as demonstrated by site-directed mutagenesis studies 9,26,29 and by sensitivity to N-glycosidase F and endoglycosidase H enzymatic digestion. These complementary approaches led to the conclusion that there were two levels of Panx1 and Panx3 glycosylation and three distinct species: the non-glycosylated core species-Gly0, the predominant endoplasmic reticulum (ER) resident high-mannose species-Gly1, and the complex glycosylated species-Gly2 ( Figure 3).…”

Section: Post-translational Modification Of Pannexinsmentioning

confidence: 99%

“…We and others found that they appear to have a longer halflife than Cx43. 26,37 Upon brefeldin A (BFA) blocking of de novo protein secretion in Panx1-and Panx3-expressing BICR-M1R k mammary tumor cells or Madin-Darby canine kidney (MDCK) cells expressing Panx1, the cell surface population of Panx1 remained unchanged from 6 to 21 h of BFA treatment before some clearing of pannexins from the cell surface was evident. Conversely, Cx43 is typically cleared from the cell surface in the presence of BFA in only 3-6 h. 26,37 Additionally, cycloheximide treatment of Panx1-expressing BICR-M1R k cells failed to reduce the detectable levels of Panx1 protein even after 8 h of protein synthesis inhibition again suggesting that this molecule has a longer half-life than what has been reported for Cx43.…”

Section: Pannexin Life Cycle and Traffickingmentioning

confidence: 99%

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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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Section: Pannexin Life Cycle and Traffickingmentioning

confidence: 90%

Section: Post-translational Modification Of Pannexinsmentioning

confidence: 99%

Section: Post-translational Modification Of Pannexinsmentioning

confidence: 99%

Section: Post-translational Modification Of Pannexinsmentioning

confidence: 99%

Section: Pannexin Life Cycle and Traffickingmentioning

confidence: 99%

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The cellular life of pannexins

Peñuela

Laird

2012

WIREs Membr Transp Signal

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The Pannexin1 membrane channel: distinct conformations and functions

Dahl

2018

FEBS Letters

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The Pannexin1 (Panx1) membrane channel responds to different stimuli with distinct channel conformations. Most stimuli induce a large cation- and ATP-permeable conformation, hence Panx1 is involved in many physiological processes entailing purinergic signaling. For example, oxygen delivery in the peripheral circulatory system is regulated by ATP released from red blood cells and endothelial cells through Panx1 channels. The same membrane channel, however, when stimulated by positive membrane potential or by cleavage with caspase 3, is highly selective for the passage of chloride ions, excluding cations and ATP. Although biophysical data do not allow a distinction between the chloride-selective channels induced by voltage or by caspase cleavage, there must be other subtle differences in the structure, because overexpression of wtPanx1 is well tolerated by cells, while expression of the truncation mutant Panx1Δ378 results in slow cell death. Thus, in addition to the well-characterized two open conformations, there might be a third, more subtle conformational change involved in cell death.

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Global Deletion of Pannexin 3 Resulting in Accelerated Development of Aging‐Induced Osteoarthritis in Mice

Moon

Shao

Wambiekele

et al. 2021

Arthritis & Rheumatology

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Objective Osteoarthritis (OA) results in pathologic changes in the joint tissue. The mechanisms driving disease progression remain largely unclear, and thus disease‐modifying treatments are lacking. Pannexin 3 (Panx3) was identified as a potential mediator of cartilage degeneration in OA, and our previous study in mice indicated that deletion of the Panx3 gene delayed surgically induced cartilage degeneration. This study was undertaken to examine the role of Panx3 in other OA subtypes, particularly primary OA during aging, in a mouse model of aging‐induced OA. Methods Wild‐type (WT) and Panx3−/− C57BL/6J (Black‐6) mice, ages 18–24 months, were analyzed by micro–computed tomography to investigate bone mineral density and body composition. Joints were harvested from the mice, and histopathologic analysis of the joint tissue for OA development was conducted with a specific focus on changes in articular cartilage, subchondral bone, and synovial tissue. Results Global loss of Panx3 in aging mice was not associated with increased mortality or changes in body composition. Mice lacking Panx3 had shorter appendicular skeletons than WT mice, but overall the body compositions appeared quite similar. Panx3 deletion dramatically accelerated cartilage degeneration and subchondral bone thickening with aging in both 18‐month‐old and 24‐month‐old mice, while promoting synovitis in 18‐month‐old mice. Conclusion These observations in a mouse model of OA suggest that Panx3 has a protective role against the development of primary aging‐associated OA. It appears that Panx3 has opposing context‐specific roles in joint health following traumatic injury versus that associated with aging. These data strongly suggest that there are differences in the molecular pathways driving different subtypes of OA, and therefore a detailed understanding of these pathways could directly improve strategies for OA diagnosis, therapy, and research.

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Pannexin 1 and pannexin 3 are glycoproteins that exhibit many distinct characteristics from the connexin family of gap junction proteins

Cited by 376 publications

References 38 publications

The cellular life of pannexins

The cellular life of pannexins

The Pannexin1 membrane channel: distinct conformations and functions

Global Deletion of Pannexin 3 Resulting in Accelerated Development of Aging‐Induced Osteoarthritis in Mice

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