Ryanodine Receptors: Structure, Expression, Molecular Details, and Function in Calcium Release

Abstract

Ryanodine receptors (RyRs) are located in the sarcoplasmic/endoplasmic reticulum membrane and are responsible for the release of Ca 2þ from intracellular stores during excitation-contraction coupling in both cardiac and skeletal muscle. RyRs are the largest known ion channels (.2MDa) and exist as three mammalian isoforms (RyR 1 -3), all of which are homotetrameric proteins that interact with and are regulated by phosphorylation, redox modifications, and a variety of small proteins and ions. Most RyR channel modulators interact with the large cytoplasmic domain whereas the carboxy-terminal portion of the protein forms the ion-conducting pore. Mutations in RyR2 are associated with human disorders such as catecholaminergic polymorphic ventricular tachycardia whereas mutations in RyR1 underlie diseases such as central core disease and malignant hyperthermia. This chapter examines the current concepts of the structure, function and regulation of RyRs and assesses the current state of understanding of their roles in associated disorders.

N-terminal and Central Segments of the Type 1 Ryanodine Receptor Mediate Its Interaction with FK506-binding Proteins

“…8B), the same positions that either result in high FRET efficiencies to D-FKBP or disruption of D-FKBP binding to the RyR. Finally, the first discovered MH mutation lies in the N-terminal domain at position 615 (29), whereas there are Ͼ45 mutations sites in the area between amino acids 2157 and 2502 in the central domain (39,40). Thus, these two MH zones may contact each other in the vicinity of the FKBP binding site, and MH mutations could disrupt this interaction.…”

Calcineurin upregulates local Ca2+signaling through ryanodine receptor-1 in airway smooth muscle cells

“…RyR is steadily regulated by phosphorylation, redox modifications from reactive oxygen/nitrogen species, and a variety of small proteins and ions, with the majority of its posttranslational modifications occurring on the large cytoplasmic domain; moreover, RyR1 activity in skeletal myocytes is also regulated by disease-causing mutations and the proteins such as calsequestrin, triadin, and junctin located within the SR (2,21). All of these unique characteristics make RyRs a hub for integrating a known and unknown number of signaling pathways that use Ca 2ϩ as an intracellular second messenger.…”

nNOS regulation of skeletal muscle fatigue and exercise performance

“…The RyR1 plays a pivotal role in Ca 2+ release from the SR during excitation-contraction coupling and is an important target of nNOS-derived NO in skeletal muscle (Lanner et al 2010, Figure 1). RyR1 co-immunoprecipitates and colocalizes with cytoplasmic nNOSμ in human skeletal muscle (Salanova et al 2008).…”