Activation of Pannexin-1 Hemichannels Augments Aberrant Bursting in the Hippocampus

Thompson, Roger; Jackson, Michael; Olah, Michelle E.; Rungta, Ravi L.; Hines, Dustin J.; Beazely, Michael A.; MacDonald, John F.; MacVicar, Brian A.

doi:10.1126/science.1165209

Cited by 317 publications

(346 citation statements)

References 19 publications

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“…Previous reports have linked Panx1 channels to the release of ATP in neurons (36) and astrocytes (37) and in cellular response to pathological insults, such as initiation of inflammatory action (10,38), ischemia-induced death of neurons (39), and tumor suppression (13). Our understanding of Panx3 is even more rudimentary.…”

Section: Discussionmentioning

confidence: 98%

Pannexin1 and Pannexin3 Delivery, Cell Surface Dynamics, and Cytoskeletal Interactions

Bhalla-Gehi

Peñuela

Churko

et al. 2010

Journal of Biological Chemistry

101

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Pannexins (Panx) are a class of integral membrane proteins that have been proposed to exhibit characteristics similar to those of connexin family members. In this study, we utilized Cx43-positive BICR-M1R k cells to stably express Panx1, Panx3, or Panx1-green fluorescent protein (GFP) to assess their trafficking, cell surface dynamics, and interplay with the cytoskeletal network. Expression of a Sar1 dominant negative mutant revealed that endoplasmic reticulum to Golgi transport of Panx1 and Panx3 was mediated via COPII-dependent vesicles. Distinct from Cx43-GFP, fluorescence recovery after photobleaching studies revealed that both Panx1-GFP and Panx3-GFP remained highly mobile at the cell surface. Unlike Cx43, Panx1-GFP exhibited no detectable interrelationship with microtubules. Conversely, cytochalasin B-induced disruption of microfilaments caused a severe loss of cell surface Panx1-GFP, a reduction in the recoverable fraction of Panx1-GFP that remained at the cell surface, and a decrease in Panx1-GFP vesicular transport. Furthermore, co-immunoprecipitation and cosedimentation assays revealed actin as a novel binding partner of Panx1. Collectively, we conclude that although Panx1 and Panx3 share a common endoplasmic reticulum to Golgi secretory pathway to Cx43, their ultimate cell surface residency appears to be independent of cell contacts and the need for intact microtubules. Importantly, Panx1 has an interaction with actin microfilaments that regulates its cell surface localization and mobility.The pannexin family is a new class of integral membrane glycoproteins that have been identified to share sequence homology with the invertebrate gap junction proteins, innexins (1). Unlike the connexin family that is composed of 21 members (2), both the human and mouse genomes contain only three pannexin-encoding genes (Panx1, Panx2, and Panx3) (1). Although connexins and pannexins exhibit no sequence homology, pannexins are predicted to share similar topology with connexins, which includes four transmembrane domains, two extracellular loops, a cytoplasmic loop, and intracellular amino and carboxyl termini (3-5). Our previous study has shown that ectopically expressed Panx1 and Panx3 are capable of trafficking to normal rat kidney (NRK) 2 cell surfaces; however, their distribution profile at cell-cell interfaces is not typically clustered or punctate as seen for Cx43 (5). Consistently, electron micrographs of Panx1 overexpressing Madin-Darby canine kidney cells also revealed dispersed Panx1 localization at the plasma membrane with no evidence of gap junction plaques (4).Cx43 has a relatively short half-life of ϳ1-3 h (6). As a result, Cx43 subunits assembled into connexons within the transGolgi network (7) are constantly being transported to and removed from the plasma membrane (8). Recent reports provide evidence that although Panx1 appears to form similar hexameric channel units defined as pannexons (4), they exhibit slower turnover dynamics in comparison with Cx43, as assessed by the use of pharmacological blocke...

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Section: Discussionmentioning

confidence: 98%

Pannexin1 and Pannexin3 Delivery, Cell Surface Dynamics, and Cytoskeletal Interactions

Bhalla-Gehi

Peñuela

Churko

et al. 2010

Journal of Biological Chemistry

101

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“…In hippocampal neurons the glutamate agonist NMDA induced channel activity that showed the pharmacological and electrophysiological characteristics of pannexons (22). These channels were also activated by oxygen glucose deprivation, an in vitro model of cerebral ischemia (23).…”

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confidence: 97%

Pannexins in ischemia-induced neurodegeneration

Bargiotas

Krenz²,

Hormuzdi

et al. 2011

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

198

211

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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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“…12,13 Panx1 is expressed in pyramidal neurons at the postsynaptic density [14][15][16] and is activated after NMDA receptor stimulation, where it can contribute to bursting patterns in the hippocampus. 17 The mechanisms by which P2X7r and Panx1 are involved in the pathology of ischemia are the subject of intense debate. However, it has been previously shown that P2X7r inhibition provides protection against cerebral ischemia 9 and that the participation Panx1 opening and during this injury.…”

Section: Introductionmentioning

confidence: 99%

Blockade of P2X7 Receptors or Pannexin-1 Channels Similarly Attenuates Postischemic Damage

Cisneros-Mejorado

Gottlieb

Cavaliere

et al. 2015

J Cereb Blood Flow Metab

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The role of P2X7 receptors and pannexin-1 channels in ischemic damage remains controversial. Here, we analyzed their contribution to postanoxic depolarization after ischemia in cultured neurons and in brain slices. We observed that pharmacological blockade of P2X7 receptors or pannexin-1 channels delayed the onset of postanoxic currents and reduced their slope, and that simultaneous inhibition did not further enhance the effects of blocking either one. These results were confirmed in acute cortical slices from P2X7 and pannexin-1 knockout mice. Oxygen-glucose deprivation in cortical organotypic cultures caused neuronal death that was reduced with P2X7 and pannexin-1 blockers as well as in organotypic cultures derived from mice lacking P2X7 and pannexin 1. Subsequently, we used transient middle cerebral artery occlusion to monitor the neuroprotective effect of those drugs in vivo. We found that P2X7 and pannexin-1 antagonists, and their ablation in knockout mice, substantially attenuated the motor symptoms and reduced the infarct volume to~50% of that in vehicle-treated or wild-type animals. These results show that P2X7 receptors and pannexin-1 channels are major mediators of postanoxic depolarization in neurons and of brain damage after ischemia, and that they operate in the same deleterious signaling cascade leading to neuronal and tissue demise.

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Activation of Pannexin-1 Hemichannels Augments Aberrant Bursting in the Hippocampus

Cited by 317 publications

References 19 publications

Pannexin1 and Pannexin3 Delivery, Cell Surface Dynamics, and Cytoskeletal Interactions

Pannexin1 and Pannexin3 Delivery, Cell Surface Dynamics, and Cytoskeletal Interactions

Pannexins in ischemia-induced neurodegeneration

Blockade of P2X7 Receptors or Pannexin-1 Channels Similarly Attenuates Postischemic Damage

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