Role for nitric oxide in permeability of hippocampal neuronal hemichannels during oxygen glucose deprivation

Zhang, Le; Deng, Tongle; Sun, Yiguo; Liu, Kezhou; Yang, Yi; Zheng, Xiaoxiang

doi:10.1002/jnr.21675

Cited by 86 publications

(73 citation statements)

References 36 publications

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“…This increase in extracellular K + concentration may be sufficient to activate neuronal Px1 channels (12). Additionally, reactive oxygen species and NO, which are abundant in ischemic brain tissue and have been shown to open pannexons in neurons, may be involved (29). The redox sensitivity of Px1 may stem from an interaction with the K + channel subunit Kvβ3 (30).…”

Section: Discussionmentioning

confidence: 99%

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Pannexins in ischemia-induced neurodegeneration

Bargiotas

Krenz²,

Hormuzdi

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

202

214

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Pannexin 1 (Px1, Panx1) and pannexin 2 (Px2, Panx2) form largepore nonselective channels in the plasma membrane of cells and were suggested to play a role in the pathophysiology of cerebral ischemia. To directly test a potential contribution of pannexins in ischemia-related mechanisms, we performed experiments in Px1 −/− , Px2 −/− , and Px1 −/− Px2 −/− knockout mice. IL-1β release, channel function in astrocytes, and cortical spreading depolarization were not altered in Px1 −/− Px2 −/− mice, indicating that, in contrast to previous concepts, these processes occur normally in the absence of pannexin channels. However, ischemia-induced dye release from cortical neurons was lower, indicating that channel function in Px1 −/− Px2 −/− neurons was impaired. Furthermore, Px1 −/− Px2 −/− mice had a better functional outcome and smaller infarcts than wild-type mice when subjected to ischemic stroke. In conclusion, our data demonstrate that Px1 and Px2 underlie channel function in neurons and contribute to ischemic brain damage.ATP release | gap junctions | macrophage | middle cerebral artery occlusion | metabolic inhibition

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Section: Discussionmentioning

confidence: 99%

“…It is questionable whether this mechanism is involved in the rapid opening of pannexons observed in vitro, but it may be important in vivo as caspase 3 is activated in cerebral ischemia (31). In addition to the opening of pannexin channels, cerebral ischemia may also aggravate the outcome owing to increased expression of Px1 and Px2 (29).…”

Section: Discussionmentioning

confidence: 99%

Pannexins in ischemia-induced neurodegeneration

Bargiotas

Krenz²,

Hormuzdi

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

202

214

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“…How Px1 hemichannels are regulated during physiological and pathological conditions is not yet known, though intracellular Ca 2+ or nitric oxide may be involved. 64,71 It is of great importance to understand how this channel is regulated and what its roles in neuronal (and possibly astrocytic) physiology are.…”

Section: Pannexin Hemichannelsmentioning

confidence: 99%

Connexin and pannexin hemichannels of neurons and astrocytes

Thompson

MacVicar²

2008

Channels

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Hemichannels are large pore ion channels that in the traditional view are formed when half a gap connexin junction opens to the extracellular space. It is now evident that other ion channel families, including the newly discovered pannexin family can form channels with all the nascent properties of hemichannels. This suggests that hemichannels should now be defined to include members of non-connexin families. Several connexin, and two pannexins are expressed in neurons and astrocytes where they may function in release of ATP and glutamate. Additionally, pannexin-1 appears to play a role in neuronal death. Hemichannels form a novel and unique class of ion channels that likely have diverse physiological and pathophysiological roles in the nervous system.

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“…Apparently, Panx1 primarily forms hemichannels (9,11,12). Among others, a role of Panx1 hemichannels was suggested in the initiation and propagation of calcium waves (13), the release of interleukin-1␤ due to interaction with the P2X7 receptor (14 -16), neuronal cell death after ischemia (17,18), and in activation of inflammasomes (19). Panx1 hemichannels open in response to a rise in intracellular Ca 2ϩ , to depolarization to membrane potentials above Ϫ20 mV, and to mechanical stretch (10,11,20).…”

mentioning

confidence: 99%

Intracellular Cysteine 346 Is Essentially Involved in Regulating Panx1 Channel Activity

Bunse

Schmidt

Prochnow

et al. 2010

Journal of Biological Chemistry

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Pannexins constitute a family of proteins exhibiting predominantly hemichannel activity. Pannexin channels have been suggested to participate in a wide spectrum of biological functions such as propagation of calcium waves, release of IL-1␤, and responses to ischemic conditions. At present, the molecular mechanisms regulating pannexin hemichannel activity are essentially unknown. Because cysteines have been shown to constitute key elements in regulating hemichannel properties of the connexin-type we performed site-directed mutagenesis of intracellular cysteine residues of Panx1. Cysteine to serine exchange (Cys 3 Ser) at the C-terminal position amino acid 346 led to a constitutively leaky hemichannel and subsequently to cell death. Increased channel activity was demonstrated by dye uptake and electrophysiological profiling in injected Xenopus laevis oocytes and transfected N2A cells. Mutations of the remaining intracellular cysteines did not result in major changes of Panx1 channel properties. From these data we conclude that the Cys-346 residue is important for proper functioning of the Panx1 channel.In addition to connexins, a second family of proteins, termed pannexins (Panx) 3 (1), is suggested to form hemichannels. The pannexin channel family consists of three members: Panx1, which is abundantly expressed in different organs of the vertebrate organism, Panx2, which is found mainly in the central nervous system, and Panx3, which is primarily expressed in skin and cartilage (2-8). Panx1 is capable of forming gap junctions and hemichannels in the Xenopus laevis oocytes expression system (9, 10), but it is still a matter of debate whether pannexinformed gap junctions do exist under in vivo conditions. Apparently, Panx1 primarily forms hemichannels (9,11,12). Among others, a role of Panx1 hemichannels was suggested in the initiation and propagation of calcium waves (13), the release of interleukin-1␤ due to interaction with the P2X7 receptor (14 -16), neuronal cell death after ischemia (17, 18), and in activation of inflammasomes (19). Panx1 hemichannels open in response to a rise in intracellular Ca 2ϩ , to depolarization to membrane potentials above Ϫ20 mV, and to mechanical stretch (10,11,20).Even though there is no direct sequence homology between pannexins and connexins, both protein types possess the same topology with four transmembrane domains and intracellularly located N and C termini (for review, see Ref. 21). Significant differences between the two protein families are the number of extracellular cysteines and the fact that Panx1 is glycosylated at the second extracellular loop (9, 22). Deglycosylation with N-glycosidase F enhanced gap junctional coupling, indicating that glycosylation might be a regulatory key element to distinguish between gap junctional coupling and hemichannel activity (23).Besides the importance of extracellular cysteines in gap junction channel formation of connexins (24), intracellular cysteine residues have been suggested to be responsible for sensitivity of Cx43 and Cx46 hemi...

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Role for nitric oxide in permeability of hippocampal neuronal hemichannels during oxygen glucose deprivation

Cited by 86 publications

References 36 publications

Pannexins in ischemia-induced neurodegeneration

Pannexins in ischemia-induced neurodegeneration

Connexin and pannexin hemichannels of neurons and astrocytes

Intracellular Cysteine 346 Is Essentially Involved in Regulating Panx1 Channel Activity

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