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To Be or Not to Be an Ion Channel: Cryo-EM Structures Have a Say

Ion channels are the second largest class of drug targets after G protein-coupled receptors. In addition to well-recognized ones like voltage-gated Na/K/Ca channels in the heart and neurons, novel ion channels are continuously discovered in both excitable and non-excitable cells and demonstrated to...

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Autores principales: Chen, Gui-Lan, Li, Jian, Zhang, Jin, Zeng, Bo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10378246/
https://www.ncbi.nlm.nih.gov/pubmed/37508534
http://dx.doi.org/10.3390/cells12141870
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author Chen, Gui-Lan
Li, Jian
Zhang, Jin
Zeng, Bo
author_facet Chen, Gui-Lan
Li, Jian
Zhang, Jin
Zeng, Bo
author_sort Chen, Gui-Lan
collection PubMed
description Ion channels are the second largest class of drug targets after G protein-coupled receptors. In addition to well-recognized ones like voltage-gated Na/K/Ca channels in the heart and neurons, novel ion channels are continuously discovered in both excitable and non-excitable cells and demonstrated to play important roles in many physiological processes and diseases such as developmental disorders, neurodegenerative diseases, and cancer. However, in the field of ion channel discovery, there are an unignorable number of published studies that are unsolid and misleading. Despite being the gold standard of a functional assay for ion channels, electrophysiological recordings are often accompanied by electrical noise, leak conductance, and background currents of the membrane system. These unwanted signals, if not treated properly, lead to the mischaracterization of proteins with seemingly unusual ion-conducting properties. In the recent ten years, the technical revolution of cryo-electron microscopy (cryo-EM) has greatly advanced our understanding of the structures and gating mechanisms of various ion channels and also raised concerns about the pore-forming ability of some previously identified channel proteins. In this review, we summarize cryo-EM findings on ion channels with molecular identities recognized or disputed in recent ten years and discuss current knowledge of proposed channel proteins awaiting cryo-EM analyses. We also present a classification of ion channels according to their architectures and evolutionary relationships and discuss the possibility and strategy of identifying more ion channels by analyzing structures of transmembrane proteins of unknown function. We propose that cross-validation by electrophysiological and structural analyses should be essentially required for determining molecular identities of novel ion channels.
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spelling pubmed-103782462023-07-29 To Be or Not to Be an Ion Channel: Cryo-EM Structures Have a Say Chen, Gui-Lan Li, Jian Zhang, Jin Zeng, Bo Cells Review Ion channels are the second largest class of drug targets after G protein-coupled receptors. In addition to well-recognized ones like voltage-gated Na/K/Ca channels in the heart and neurons, novel ion channels are continuously discovered in both excitable and non-excitable cells and demonstrated to play important roles in many physiological processes and diseases such as developmental disorders, neurodegenerative diseases, and cancer. However, in the field of ion channel discovery, there are an unignorable number of published studies that are unsolid and misleading. Despite being the gold standard of a functional assay for ion channels, electrophysiological recordings are often accompanied by electrical noise, leak conductance, and background currents of the membrane system. These unwanted signals, if not treated properly, lead to the mischaracterization of proteins with seemingly unusual ion-conducting properties. In the recent ten years, the technical revolution of cryo-electron microscopy (cryo-EM) has greatly advanced our understanding of the structures and gating mechanisms of various ion channels and also raised concerns about the pore-forming ability of some previously identified channel proteins. In this review, we summarize cryo-EM findings on ion channels with molecular identities recognized or disputed in recent ten years and discuss current knowledge of proposed channel proteins awaiting cryo-EM analyses. We also present a classification of ion channels according to their architectures and evolutionary relationships and discuss the possibility and strategy of identifying more ion channels by analyzing structures of transmembrane proteins of unknown function. We propose that cross-validation by electrophysiological and structural analyses should be essentially required for determining molecular identities of novel ion channels. MDPI 2023-07-17 /pmc/articles/PMC10378246/ /pubmed/37508534 http://dx.doi.org/10.3390/cells12141870 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Chen, Gui-Lan
Li, Jian
Zhang, Jin
Zeng, Bo
To Be or Not to Be an Ion Channel: Cryo-EM Structures Have a Say
title To Be or Not to Be an Ion Channel: Cryo-EM Structures Have a Say
title_full To Be or Not to Be an Ion Channel: Cryo-EM Structures Have a Say
title_fullStr To Be or Not to Be an Ion Channel: Cryo-EM Structures Have a Say
title_full_unstemmed To Be or Not to Be an Ion Channel: Cryo-EM Structures Have a Say
title_short To Be or Not to Be an Ion Channel: Cryo-EM Structures Have a Say
title_sort to be or not to be an ion channel: cryo-em structures have a say
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10378246/
https://www.ncbi.nlm.nih.gov/pubmed/37508534
http://dx.doi.org/10.3390/cells12141870
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