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Oxidation Driven Reversal of PIP(2)-dependent Gating in GIRK2 Channels
Physiological activity of G protein gated inward rectifier K(+) (GIRK, Kir3) channel, dynamically regulated by three key ligands, phosphoinositol-4,5-bisphosphate (PIP(2)), Gβγ, and Na(+), underlies cellular electrical response to multiple hormones and neurotransmitters in myocytes and neurons. In a...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10165546/ https://www.ncbi.nlm.nih.gov/pubmed/37168492 http://dx.doi.org/10.1093/function/zqad016 |
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author | Lee, Sun-Joo Maeda, Shoji Gao, Jian Nichols, Colin G |
author_facet | Lee, Sun-Joo Maeda, Shoji Gao, Jian Nichols, Colin G |
author_sort | Lee, Sun-Joo |
collection | PubMed |
description | Physiological activity of G protein gated inward rectifier K(+) (GIRK, Kir3) channel, dynamically regulated by three key ligands, phosphoinositol-4,5-bisphosphate (PIP(2)), Gβγ, and Na(+), underlies cellular electrical response to multiple hormones and neurotransmitters in myocytes and neurons. In a reducing environment, matching that inside cells, purified GIRK2 (Kir3.2) channels demonstrate low basal activity, and expected sensitivity to the above ligands. However, under oxidizing conditions, anomalous behavior emerges, including rapid loss of PIP(2) and Na(+)-dependent activation and a high basal activity in the absence of any agonists, that is now paradoxically inhibited by PIP(2). Mutagenesis identifies two cysteine residues (C65 and C190) as being responsible for the loss of PIP(2) and Na(+)-dependent activity and the elevated basal activity, respectively. The results explain anomalous findings from earlier studies and illustrate the potential pathophysiologic consequences of oxidation on GIRK channel function, as well as providing insight to reversed ligand-dependence of Kir and KirBac channels. |
format | Online Article Text |
id | pubmed-10165546 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-101655462023-05-09 Oxidation Driven Reversal of PIP(2)-dependent Gating in GIRK2 Channels Lee, Sun-Joo Maeda, Shoji Gao, Jian Nichols, Colin G Function (Oxf) Research Article Physiological activity of G protein gated inward rectifier K(+) (GIRK, Kir3) channel, dynamically regulated by three key ligands, phosphoinositol-4,5-bisphosphate (PIP(2)), Gβγ, and Na(+), underlies cellular electrical response to multiple hormones and neurotransmitters in myocytes and neurons. In a reducing environment, matching that inside cells, purified GIRK2 (Kir3.2) channels demonstrate low basal activity, and expected sensitivity to the above ligands. However, under oxidizing conditions, anomalous behavior emerges, including rapid loss of PIP(2) and Na(+)-dependent activation and a high basal activity in the absence of any agonists, that is now paradoxically inhibited by PIP(2). Mutagenesis identifies two cysteine residues (C65 and C190) as being responsible for the loss of PIP(2) and Na(+)-dependent activity and the elevated basal activity, respectively. The results explain anomalous findings from earlier studies and illustrate the potential pathophysiologic consequences of oxidation on GIRK channel function, as well as providing insight to reversed ligand-dependence of Kir and KirBac channels. Oxford University Press 2023-04-10 /pmc/articles/PMC10165546/ /pubmed/37168492 http://dx.doi.org/10.1093/function/zqad016 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of American Physiological Society. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Research Article Lee, Sun-Joo Maeda, Shoji Gao, Jian Nichols, Colin G Oxidation Driven Reversal of PIP(2)-dependent Gating in GIRK2 Channels |
title | Oxidation Driven Reversal of PIP(2)-dependent Gating in GIRK2 Channels |
title_full | Oxidation Driven Reversal of PIP(2)-dependent Gating in GIRK2 Channels |
title_fullStr | Oxidation Driven Reversal of PIP(2)-dependent Gating in GIRK2 Channels |
title_full_unstemmed | Oxidation Driven Reversal of PIP(2)-dependent Gating in GIRK2 Channels |
title_short | Oxidation Driven Reversal of PIP(2)-dependent Gating in GIRK2 Channels |
title_sort | oxidation driven reversal of pip(2)-dependent gating in girk2 channels |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10165546/ https://www.ncbi.nlm.nih.gov/pubmed/37168492 http://dx.doi.org/10.1093/function/zqad016 |
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