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Ion permeation pathway within the internal pore of P2X receptor channels

P2X receptor channels are trimeric ATP-activated ion channels expressed in neuronal and non-neuronal cells that are attractive therapeutic targets for human disorders. Seven subtypes of P2X receptor channels have been identified in mammals that can form both homomeric and heteromeric channels. P2X1–...

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Autores principales: Tam, Stephanie W, Huffer, Kate, Li, Mufeng, Swartz, Kenton J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10027316/
https://www.ncbi.nlm.nih.gov/pubmed/36940138
http://dx.doi.org/10.7554/eLife.84796
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author Tam, Stephanie W
Huffer, Kate
Li, Mufeng
Swartz, Kenton J
author_facet Tam, Stephanie W
Huffer, Kate
Li, Mufeng
Swartz, Kenton J
author_sort Tam, Stephanie W
collection PubMed
description P2X receptor channels are trimeric ATP-activated ion channels expressed in neuronal and non-neuronal cells that are attractive therapeutic targets for human disorders. Seven subtypes of P2X receptor channels have been identified in mammals that can form both homomeric and heteromeric channels. P2X1–4 and P2X7 receptor channels are cation-selective, whereas P2X5 has been reported to have both cation and anion permeability. P2X receptor channel structures reveal that each subunit is comprised of two transmembrane helices, with both N-and C-termini on the intracellular side of the membrane and a large extracellular domain that contains the ATP binding sites at subunit interfaces. Recent structures of ATP-bound P2X receptors with the activation gate open reveal the unanticipated presence of a cytoplasmic cap over the central ion permeation pathway, leaving lateral fenestrations that may be largely buried within the membrane as potential pathways for ions to permeate the intracellular end of the pore. In the present study, we identify a critical residue within the intracellular lateral fenestrations that is readily accessible to thiol-reactive compounds from both sides of the membrane and where substitutions influence the relative permeability of the channel to cations and anions. Taken together, our results demonstrate that ions can enter or exit the internal pore through lateral fenestrations that play a critical role in determining the ion selectivity of P2X receptor channels.
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spelling pubmed-100273162023-03-21 Ion permeation pathway within the internal pore of P2X receptor channels Tam, Stephanie W Huffer, Kate Li, Mufeng Swartz, Kenton J eLife Structural Biology and Molecular Biophysics P2X receptor channels are trimeric ATP-activated ion channels expressed in neuronal and non-neuronal cells that are attractive therapeutic targets for human disorders. Seven subtypes of P2X receptor channels have been identified in mammals that can form both homomeric and heteromeric channels. P2X1–4 and P2X7 receptor channels are cation-selective, whereas P2X5 has been reported to have both cation and anion permeability. P2X receptor channel structures reveal that each subunit is comprised of two transmembrane helices, with both N-and C-termini on the intracellular side of the membrane and a large extracellular domain that contains the ATP binding sites at subunit interfaces. Recent structures of ATP-bound P2X receptors with the activation gate open reveal the unanticipated presence of a cytoplasmic cap over the central ion permeation pathway, leaving lateral fenestrations that may be largely buried within the membrane as potential pathways for ions to permeate the intracellular end of the pore. In the present study, we identify a critical residue within the intracellular lateral fenestrations that is readily accessible to thiol-reactive compounds from both sides of the membrane and where substitutions influence the relative permeability of the channel to cations and anions. Taken together, our results demonstrate that ions can enter or exit the internal pore through lateral fenestrations that play a critical role in determining the ion selectivity of P2X receptor channels. eLife Sciences Publications, Ltd 2023-03-20 /pmc/articles/PMC10027316/ /pubmed/36940138 http://dx.doi.org/10.7554/eLife.84796 Text en https://creativecommons.org/publicdomain/zero/1.0/This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication (https://creativecommons.org/publicdomain/zero/1.0/) .
spellingShingle Structural Biology and Molecular Biophysics
Tam, Stephanie W
Huffer, Kate
Li, Mufeng
Swartz, Kenton J
Ion permeation pathway within the internal pore of P2X receptor channels
title Ion permeation pathway within the internal pore of P2X receptor channels
title_full Ion permeation pathway within the internal pore of P2X receptor channels
title_fullStr Ion permeation pathway within the internal pore of P2X receptor channels
title_full_unstemmed Ion permeation pathway within the internal pore of P2X receptor channels
title_short Ion permeation pathway within the internal pore of P2X receptor channels
title_sort ion permeation pathway within the internal pore of p2x receptor channels
topic Structural Biology and Molecular Biophysics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10027316/
https://www.ncbi.nlm.nih.gov/pubmed/36940138
http://dx.doi.org/10.7554/eLife.84796
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