Pannexins in ischemia-induced neurodegeneration

Abstract

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

Analysis of a pannexin 2-pannexin 1 chimeric protein supports divergent roles for pannexin C-termini in cellular localization

“…Recently linked to neuronal differentiation (Swayne et al, 2010) and neurodegeneration (Bargiotas et al, 2011), Panx2 has been proven to be challenging to study from a cell biology perspective, but this new insight into its cellular localization will hopefully provide further clues to its specifi c cellular function. In summary, this work makes important contributions to the understanding of the molecular determinants underlying the cellular roles of Panx proteins.…”

Do not let death do us part: ‘find-me’ signals in communication between dying cells and the phagocytes

“…Under homeostatic conditions, Panx1-deficient mice have no overt phenotype, 61 however, there may be compensation from other pannexin family members (Panx2/Panx3), 62 or other nucleotide release channels. Alternatively, Panx1-deficient mice may need to be stressed to increase apoptotic load, as these mediators may be more readily compensated at basal levels of apoptosis.…”

The cellular life of pannexins

“…This hypothesis seemed to be confirmed at least in the case of cerebral ischemia where it was reported recently that only the double knockout of Panx1 and Panx2 had a significant effect in the function of cortical neurons. 20 In this study, the ablation of either Panx1 or Panx2 had little effect, but double knockout mice had smaller infarcts than the control mice during ischemic stroke. 20 It is likely that there will be a need to create mouse models that lack combinations of two pannexins or all three pannexins to fully reveal the variety of roles that pannexins may play.…”

“…20 In this study, the ablation of either Panx1 or Panx2 had little effect, but double knockout mice had smaller infarcts than the control mice during ischemic stroke. 20 It is likely that there will be a need to create mouse models that lack combinations of two pannexins or all three pannexins to fully reveal the variety of roles that pannexins may play.…”

“…Although the protein-protein interactions with members of the inflammasome have not been disproven, two studies using Panx1 knockout mice showed that Panx1 is not required for inflammasome activation in bone marrow-derived macrophages 35 or peritoneal macrophages. 20 …”