Molecular pathways of pannexin1-mediated neurotoxicity

Pannexin1 (Panx1) forms non-selective membrane channels, structurally similar to gap junction hemichannels, and are permeable to ions, nucleotides, and other small molecules below 900 Da. Panx1 activity has been implicated in paracrine signaling and inflammasome regulation. Recent studies in differe...

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Main Authors:	Shestopalov, Valery I., Slepak, Vladlen Z.
Format:	Online
Language:	English
Published:	Frontiers Media S.A. 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3920106/

id	pubmed-3920106
recordtype	oai_dc
spelling	pubmed-39201062014-02-26 Molecular pathways of pannexin1-mediated neurotoxicity Shestopalov, Valery I. Slepak, Vladlen Z. Physiology Pannexin1 (Panx1) forms non-selective membrane channels, structurally similar to gap junction hemichannels, and are permeable to ions, nucleotides, and other small molecules below 900 Da. Panx1 activity has been implicated in paracrine signaling and inflammasome regulation. Recent studies in different animal models showed that overactivation of Panx1 correlates with a selective demise of several types of neurons, including retinal ganglion cells, brain pyramidal, and enteric neurons. The list of Panx1 activators includes extracellular ATP, glutamate, high K+, Zn2+, fibroblast growth factors (FGFs),pro-inflammatory cytokines, and elevation of intracellular Ca2+. Most of these molecules are released following mechanical, ischemic, or inflammatory injury of the CNS, and rapidly activate the Panx1 channel. Prolonged opening of Panx1 channel induced by these “danger signals” triggers a cascade of neurotoxic events capable of killing cells. The most vulnerable cell type are neurons that express high levels of Panx1. Experimental evidence suggests that Panx1 channels mediate at least two distinct neurotoxic processes: increased permeability of the plasma membrane and activation of the inflammasome in neurons and glia. Importantly, both pharmacological and genetic inactivation of Panx1 suppresses both these processes, providing a marked protection in several disease and injury models. These findings indicate that external danger signals generated after diverse types of injuries converge to activate Panx1. In this review we discuss molecular mechanisms associated with Panx1 toxicity and the crosstalk between different pathways. Frontiers Media S.A. 2014-02-11 /pmc/articles/PMC3920106/ /pubmed/24575045 http://dx.doi.org/10.3389/fphys.2014.00023 Text en Copyright © 2014 Shestopalov and Slepak. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Shestopalov, Valery I. Slepak, Vladlen Z.
spellingShingle	Shestopalov, Valery I. Slepak, Vladlen Z. Molecular pathways of pannexin1-mediated neurotoxicity
author_facet	Shestopalov, Valery I. Slepak, Vladlen Z.
author_sort	Shestopalov, Valery I.
title	Molecular pathways of pannexin1-mediated neurotoxicity
title_short	Molecular pathways of pannexin1-mediated neurotoxicity
title_full	Molecular pathways of pannexin1-mediated neurotoxicity
title_fullStr	Molecular pathways of pannexin1-mediated neurotoxicity
title_full_unstemmed	Molecular pathways of pannexin1-mediated neurotoxicity
title_sort	molecular pathways of pannexin1-mediated neurotoxicity
description	Pannexin1 (Panx1) forms non-selective membrane channels, structurally similar to gap junction hemichannels, and are permeable to ions, nucleotides, and other small molecules below 900 Da. Panx1 activity has been implicated in paracrine signaling and inflammasome regulation. Recent studies in different animal models showed that overactivation of Panx1 correlates with a selective demise of several types of neurons, including retinal ganglion cells, brain pyramidal, and enteric neurons. The list of Panx1 activators includes extracellular ATP, glutamate, high K+, Zn2+, fibroblast growth factors (FGFs),pro-inflammatory cytokines, and elevation of intracellular Ca2+. Most of these molecules are released following mechanical, ischemic, or inflammatory injury of the CNS, and rapidly activate the Panx1 channel. Prolonged opening of Panx1 channel induced by these “danger signals” triggers a cascade of neurotoxic events capable of killing cells. The most vulnerable cell type are neurons that express high levels of Panx1. Experimental evidence suggests that Panx1 channels mediate at least two distinct neurotoxic processes: increased permeability of the plasma membrane and activation of the inflammasome in neurons and glia. Importantly, both pharmacological and genetic inactivation of Panx1 suppresses both these processes, providing a marked protection in several disease and injury models. These findings indicate that external danger signals generated after diverse types of injuries converge to activate Panx1. In this review we discuss molecular mechanisms associated with Panx1 toxicity and the crosstalk between different pathways.
publisher	Frontiers Media S.A.
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3920106/
_version_	1612056985514016768

Molecular pathways of pannexin1-mediated neurotoxicity

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