Abstract
Cardiac arrhythmias are serious, life-threatening diseases associated with the dysregulation of Ca influx into the cytoplasm of cardiomyocytes. This dysregulation often arises from dysfunction of ryanodine receptor 2 (RyR2), the principal Ca release channel. Dysfunction of RyR1, the skeletal muscle isoform, also results in less severe, but also potentially life-threatening syndromes. The RYR2 and RYR1 genes have been found to harbor three main mutation “hot spots”, where mutations change the channel structure, its interdomain interface properties, its interactions with its binding partners, or its dynamics. In all cases, the result is a defective release of Ca ions from the sarcoplasmic reticulum into the myocyte cytoplasm. Here, we provide an overview of the most frequent diseases resulting from mutations to RyR1 and RyR2, briefly review some of the recent experimental structural work on these two molecules, detail some of the computational work describing their dynamics, and summarize the known changes to the structure and function of these receptors with particular emphasis on their N-terminal, central, and channel domains.
Highlights
Ryanodine receptors (RyRs) are the largest ion channels presently known
Mouse knock-out experiments have shown that RyR1 and ryanodine receptor 2 (RyR2) have a critical role in physiology and development [18,19]: mice deficient in RyR1 died perinatally due to respiratory failure while those lacking RyR2 died during the early stages of embryonic development
Over 450 mutations have been identified in the gene of RYR1, which are associated with life-threatening myopathies
Summary
Ryanodine receptors (RyRs) are the largest ion channels presently known. They are very large (2.2 MDa) Ca2+ channels that play a key role in excitation-contraction (EC) coupling [1,2,3,4,5]. RyRs are homotetramers, with each subunit having around 5000 amino acids They are most often found embedded in the sarcoplasmic reticulum (SR) membrane of striated muscle cells at t-tubule triad junctions [27]. Ca2+ to pass from the extracellular space into the myocyte cytoplasm These Ca2+ ions bind to high-affinity sites on the RyR, thereby activating it [37,38,39,40,41,42] and increasing the likelihood that it will open [43]. RyR opening releases the Ca2+ stored in the SR into the cytoplasm These ions go on to bind to the troponin C in myofilaments, thereby initiating muscle contraction [44,45,46]. We will outline the most frequent diseases associated with RyR1 and RyR2 and review the results of recent structural and computational studies with an emphasis on how individual mutations might disrupt either the structure or the regulation of one of the receptors
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