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Atomistic Insights of Calmodulin Gating of Complete Ion Channels
Intracellular calcium is essential for many physiological processes, from neuronal signaling and exocytosis to muscle contraction and bone formation. Ca(2+) signaling from the extracellular medium depends both on membrane potential, especially controlled by ion channels selective to K(+), and direct...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072864/ https://www.ncbi.nlm.nih.gov/pubmed/32075037 http://dx.doi.org/10.3390/ijms21041285 |
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author | Núñez, Eider Muguruza-Montero, Arantza Villarroel, Alvaro |
author_facet | Núñez, Eider Muguruza-Montero, Arantza Villarroel, Alvaro |
author_sort | Núñez, Eider |
collection | PubMed |
description | Intracellular calcium is essential for many physiological processes, from neuronal signaling and exocytosis to muscle contraction and bone formation. Ca(2+) signaling from the extracellular medium depends both on membrane potential, especially controlled by ion channels selective to K(+), and direct permeation of this cation through specialized channels. Calmodulin (CaM), through direct binding to these proteins, participates in setting the membrane potential and the overall permeability to Ca(2+). Over the past years many structures of complete channels in complex with CaM at near atomic resolution have been resolved. In combination with mutagenesis-function, structural information of individual domains and functional studies, different mechanisms employed by CaM to control channel gating are starting to be understood at atomic detail. Here, new insights regarding four types of tetrameric channels with six transmembrane (6TM) architecture, Eag1, SK2/SK4, TRPV5/TRPV6 and KCNQ1–5, and its regulation by CaM are described structurally. Different CaM regions, N-lobe, C-lobe and EF3/EF4-linker play prominent signaling roles in different complexes, emerging the realization of crucial non-canonical interactions between CaM and its target that are only evidenced in the full-channel structure. Different mechanisms to control gating are used, including direct and indirect mechanical actuation over the pore, allosteric control, indirect effect through lipid binding, as well as direct plugging of the pore. Although each CaM lobe engages through apparently similar alpha-helices, they do so using different docking strategies. We discuss how this allows selective action of drugs with great therapeutic potential. |
format | Online Article Text |
id | pubmed-7072864 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-70728642020-03-19 Atomistic Insights of Calmodulin Gating of Complete Ion Channels Núñez, Eider Muguruza-Montero, Arantza Villarroel, Alvaro Int J Mol Sci Review Intracellular calcium is essential for many physiological processes, from neuronal signaling and exocytosis to muscle contraction and bone formation. Ca(2+) signaling from the extracellular medium depends both on membrane potential, especially controlled by ion channels selective to K(+), and direct permeation of this cation through specialized channels. Calmodulin (CaM), through direct binding to these proteins, participates in setting the membrane potential and the overall permeability to Ca(2+). Over the past years many structures of complete channels in complex with CaM at near atomic resolution have been resolved. In combination with mutagenesis-function, structural information of individual domains and functional studies, different mechanisms employed by CaM to control channel gating are starting to be understood at atomic detail. Here, new insights regarding four types of tetrameric channels with six transmembrane (6TM) architecture, Eag1, SK2/SK4, TRPV5/TRPV6 and KCNQ1–5, and its regulation by CaM are described structurally. Different CaM regions, N-lobe, C-lobe and EF3/EF4-linker play prominent signaling roles in different complexes, emerging the realization of crucial non-canonical interactions between CaM and its target that are only evidenced in the full-channel structure. Different mechanisms to control gating are used, including direct and indirect mechanical actuation over the pore, allosteric control, indirect effect through lipid binding, as well as direct plugging of the pore. Although each CaM lobe engages through apparently similar alpha-helices, they do so using different docking strategies. We discuss how this allows selective action of drugs with great therapeutic potential. MDPI 2020-02-14 /pmc/articles/PMC7072864/ /pubmed/32075037 http://dx.doi.org/10.3390/ijms21041285 Text en © 2020 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Review Núñez, Eider Muguruza-Montero, Arantza Villarroel, Alvaro Atomistic Insights of Calmodulin Gating of Complete Ion Channels |
title | Atomistic Insights of Calmodulin Gating of Complete Ion Channels |
title_full | Atomistic Insights of Calmodulin Gating of Complete Ion Channels |
title_fullStr | Atomistic Insights of Calmodulin Gating of Complete Ion Channels |
title_full_unstemmed | Atomistic Insights of Calmodulin Gating of Complete Ion Channels |
title_short | Atomistic Insights of Calmodulin Gating of Complete Ion Channels |
title_sort | atomistic insights of calmodulin gating of complete ion channels |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072864/ https://www.ncbi.nlm.nih.gov/pubmed/32075037 http://dx.doi.org/10.3390/ijms21041285 |
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