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A tryptophan residue in the caffeine-binding site of the ryanodine receptor regulates Ca(2+) sensitivity

Ryanodine receptors (RyRs) are Ca(2+) release channels in the sarcoplasmic reticulum of skeletal and cardiac muscles and are essential for muscle contraction. Mutations in genes encoding RyRs cause various muscle and arrhythmogenic heart diseases. Although RyR channels are activated by Ca(2+), the a...

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Autores principales: Murayama, Takashi, Ogawa, Haruo, Kurebayashi, Nagomi, Ohno, Seiko, Horie, Minoru, Sakurai, Takashi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123685/
https://www.ncbi.nlm.nih.gov/pubmed/30271978
http://dx.doi.org/10.1038/s42003-018-0103-x
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author Murayama, Takashi
Ogawa, Haruo
Kurebayashi, Nagomi
Ohno, Seiko
Horie, Minoru
Sakurai, Takashi
author_facet Murayama, Takashi
Ogawa, Haruo
Kurebayashi, Nagomi
Ohno, Seiko
Horie, Minoru
Sakurai, Takashi
author_sort Murayama, Takashi
collection PubMed
description Ryanodine receptors (RyRs) are Ca(2+) release channels in the sarcoplasmic reticulum of skeletal and cardiac muscles and are essential for muscle contraction. Mutations in genes encoding RyRs cause various muscle and arrhythmogenic heart diseases. Although RyR channels are activated by Ca(2+), the actual mechanism of Ca(2+) binding remains largely unknown. Here, we report the molecular basis of Ca(2+) binding to RyRs for channel activation and discuss its implications in disease states. RyR1 and RyR2 carrying mutations in putative Ca(2+) and caffeine-binding sites were functionally analysed. The results were interpreted with respect to recent near-atomic resolution RyR1 structures in various ligand states. We demonstrate that a tryptophan residue in the caffeine-binding site controls the structure of the Ca(2+)-binding site to regulate the Ca(2+) sensitivity. Our results reveal the initial step of RyR channel activation by Ca(2+) and explain the molecular mechanism of Ca(2+) sensitization by caffeine and disease-causing mutations.
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spelling pubmed-61236852018-09-28 A tryptophan residue in the caffeine-binding site of the ryanodine receptor regulates Ca(2+) sensitivity Murayama, Takashi Ogawa, Haruo Kurebayashi, Nagomi Ohno, Seiko Horie, Minoru Sakurai, Takashi Commun Biol Article Ryanodine receptors (RyRs) are Ca(2+) release channels in the sarcoplasmic reticulum of skeletal and cardiac muscles and are essential for muscle contraction. Mutations in genes encoding RyRs cause various muscle and arrhythmogenic heart diseases. Although RyR channels are activated by Ca(2+), the actual mechanism of Ca(2+) binding remains largely unknown. Here, we report the molecular basis of Ca(2+) binding to RyRs for channel activation and discuss its implications in disease states. RyR1 and RyR2 carrying mutations in putative Ca(2+) and caffeine-binding sites were functionally analysed. The results were interpreted with respect to recent near-atomic resolution RyR1 structures in various ligand states. We demonstrate that a tryptophan residue in the caffeine-binding site controls the structure of the Ca(2+)-binding site to regulate the Ca(2+) sensitivity. Our results reveal the initial step of RyR channel activation by Ca(2+) and explain the molecular mechanism of Ca(2+) sensitization by caffeine and disease-causing mutations. Nature Publishing Group UK 2018-07-23 /pmc/articles/PMC6123685/ /pubmed/30271978 http://dx.doi.org/10.1038/s42003-018-0103-x Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Murayama, Takashi
Ogawa, Haruo
Kurebayashi, Nagomi
Ohno, Seiko
Horie, Minoru
Sakurai, Takashi
A tryptophan residue in the caffeine-binding site of the ryanodine receptor regulates Ca(2+) sensitivity
title A tryptophan residue in the caffeine-binding site of the ryanodine receptor regulates Ca(2+) sensitivity
title_full A tryptophan residue in the caffeine-binding site of the ryanodine receptor regulates Ca(2+) sensitivity
title_fullStr A tryptophan residue in the caffeine-binding site of the ryanodine receptor regulates Ca(2+) sensitivity
title_full_unstemmed A tryptophan residue in the caffeine-binding site of the ryanodine receptor regulates Ca(2+) sensitivity
title_short A tryptophan residue in the caffeine-binding site of the ryanodine receptor regulates Ca(2+) sensitivity
title_sort tryptophan residue in the caffeine-binding site of the ryanodine receptor regulates ca(2+) sensitivity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123685/
https://www.ncbi.nlm.nih.gov/pubmed/30271978
http://dx.doi.org/10.1038/s42003-018-0103-x
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