Structural Basis for the Modulation of Ryanodine Receptors

• Published in: Trends in biochemical sciences (Amsterdam. Regular ed.) Vol. 46; no. 6; pp. 489 - 501
• Main Authors: Gong, Deshun, Yan, Nieng, Ledford, Hannah A.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.06.2021
• Subjects: allosteric regulation; Ca2+ channel; caffeine; calcium; calmodulin; cryo-EM; electron microscopy; excitation–contraction coupling; RyR1; RyR2; RyR2; RyR1; allosteric regulation; cryo-EM; excitation–contraction coupling; Ca2+ channel; Ca(2+) channel
• ISSN: 0968-0004; 1362-4326
• DOI: 10.1016/j.tibs.2020.11.009

Historically, ryanodine receptors (RyRs) have presented unique challenges for high-resolution structural determination despite long-standing interest in their role in excitation–contraction coupling. Owing to their large size (nearly 2.2 MDa), high-resolution structures remained elusive until the advent of cryogenic electron microscopy (cryo-EM) techniques. In recent years, structures for both RyR1 and RyR2 have been solved at near-atomic resolution. Furthermore, recent reports have delved into their more complex structural associations with key modulators – proteins such as the dihydropyridine receptor (DHPR), FKBP12/12.6, and calmodulin (CaM), as well as ions and small molecules including Ca2+, ATP, caffeine, and PCB95. This review addresses the modulation of RyR1 and RyR2, in addition to the impact of such discoveries on intracellular Ca2+ dynamics and biophysical properties. Ca2+ release from sarcoplasmic reticulum (SR) intracellular stores to the cytoplasm triggers a cascade of molecular events that leads to muscle contraction.The ryanodine receptors (RyR1 in skeletal muscle and RyR2 in cardiomyocytes), that are responsible for the rapid Ca2+ release from the SR, are activated by the upstream voltage-gated Ca2+ channels in response to membrane depolarization, a process known as excitation–contraction coupling.RyRs are the largest ion channels whose structures have been investigated by the cryogenic electron microscopy (cryo-EM) over the past several decades, and atomic RyR1/2 structures have now been resolved by this technique.RyRs are subject to sophisticated regulation by a large number of modulators, including proteins, ions, and small molecules; recent advances in cryo-EM have made high-resolution structures possible, yielding a wealth of information about direct interactions of these modulators with RyRs.