Elucidation of ryanodine receptor channel gating mechanism at atomic level
| Project/Area Number |
16K08507
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
General physiology
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| Research Institution | Juntendo University |
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Principal Investigator |
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| Project Period (FY) |
2016-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | リアノジン受容体 / カルシウムイオン / イオンチャネル / 動作原理 / 骨格筋 / 心筋 / カルシウムチャネル / 構造活性相関 / 筋疾患 / カフェイン / 筋小胞体 / カルシウム / 疾患変異 / 作動機構 / 構造モデル / チャネル / 構造解析 |
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| Outline of Final Research Achievements |
To understand the gating mechanism of ryanodine receptor (RyR), a calcium-release channel of sarcoplasmic reticulum, we combined functional analysis of RyR carrying disease-associated mutations with its structural model at near atomic resolution. We have elucidated for the first time the molecular mechanism of action of caffeine, which has long been known as a drug that increases Ca2+ sensitivity. In addition, we identified a series of interaction sites from the cytoplasmic region to the transmembrane region that require channel opening by Ca2+ binding.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究では変異体の機能解析と高分解能構造モデルを組み合わせることで、RyRの動作原理の本質に原子レベルで迫ることができた。特にカフェインによるCa2+感受性増大機構の解明は世界初であり、RyR制御機構における重要な成果である。本研究成果はリガンド作動性チャネルの動作原理として、イオンチャネル研究における大きな一歩である。また、本手法はRyRに特徴的な巨大な細胞質領域にも応用が可能である。細胞質領域には疾患変異が集中しているため、今後の研究により疾患変異の分子機構や薬物開発が大きく加速することが期待される。
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Report
(5 results)
Research Products
(40 results)
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[Journal Article] Co-Phenotype of Left Ventricular Non-Compaction Cardiomyopathy and Atypical Catecholaminergic Polymorphic Ventricular Tachycardia in Association With R169Q, a <i>Ryanodine Receptor Type 2</i> Missense Mutation2020
Author(s)
Nozaki Y, Kato Y, Uike K, Yamamura K, Kikuchi M, Yasuda M, Ohno S, Horie M, Murayama T, Kurebayashi N, Horigome H
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Journal Title
Circulation Journal
Volume: 84
Issue: 2
Pages: 226-234
DOI
NAID
ISSN
1346-9843, 1347-4820
Year and Date
2020-01-24
Related Report
Peer Reviewed / Open Access
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[Journal Article] TRIC-A Channel Maintains Store Calcium Handling by Interacting With Type 2 Ryanodine Receptor in Cardiac Muscle2020
Author(s)
Zhou X, Park KH, Yamazaki D, Lin PH, Nishi M, Ma Z, Qiu L, Murayama T, Zou X, Takeshima H, Zhou J, Ma J.
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Journal Title
Circulation Reserach
Volume: 126
Issue: 4
Pages: 417-435
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Long-term, but not short-term high-fat diet induces fiber composition changes and impaired contractile force in mouse fast-twitch skeletal muscle2017
Author(s)
Eshima H,Tamura Y, Kakehi S, Kurebayashi N, Murayama T, Nakamura K, Kakigi R,Okada T,Sakurai T, Kawamori R, Watada H
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Journal Title
Physiological reports
Volume: 5
Issue: 7
Pages: e13250-e13250
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Journal Article] Genotype-phenotype correlations of malignant hyperthermia and central core disease mutations in the central region of the RYR1 channel.2016
Author(s)
Murayama, T., Kurebayashi, N., Ogawa, H., Yamazawa, T., Oyamada, H., Suzuki, J., Kanemaru, K., Oguchi, K., Iino, M. and Sakurai, T.
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Journal Title
Hum Mutat.
Volume: 37
Issue: 11
Pages: 1231-1241
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Nitric oxide-induced activation of the type 1 ryanodine receptor is critical for epileptic seizure-induced neuronal cell death.2016
Author(s)
Mikami, Y., Kanemaru, K., Okubo, Y., Nakaune, T., Suzuki, J., Shibata, K., Sugiyama, H., Koyama, R., Murayama, T., Ito, A., Yamazawa, T., Ikegaya, Y., Sakurai, T., Saito, N., Kakizawa, S. and Iino, M.
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Journal Title
EBioMedicine.
Volume: 11
Pages: 253-261
DOI
Related Report
Peer Reviewed / Open Access
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[Presentation] Therapeutic effects of a novel RyR1 inhibitor on malignant hyperthermia model mice2020
Author(s)
Murayama T, Yamazawa T, Kobayashi T, Kurebayashi N, Noguchi S, Nishino N, Mori S, Kagechika H, Lopez JR, Allen PD, Sakurai T
Organizer
Biophysical Society 64th Annual Meeting
Related Report
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