Ryanodine Receptors: Structure and Function

Abstract

Ryanodine receptors (RyRs) are huge ion channels that are responsible for the release of Ca 2؉ from the sarco/endoplasmic reticulum. RyRs form homotetramers with a mushroom-like shape, consisting of a large cytoplasmic head and transmembrane stalk. Ca 2؉ is a major physiological ligand that triggers opening of RyRs, but a plethora of modulatory proteins and small molecules in the cytoplasm and sarco/endoplasmic reticulum lumen have been recognized. Over 300 mutations in RyRs are associated with severe skeletal muscle disorders or triggered cardiac arrhythmias. With the advent of high-resolution structures of individual domains, many of these can be mapped onto the three-dimensional structure.The South American plant Ryania speciosa has long been recognized for its insecticidal properties (1). Its active compound, an alkaloid known as ryanodine, targets a eukaryotic membrane protein known as the ryanodine receptor (RyR). 2Long before their isolation, RyRs had already been visualized in thin section or negative stain electron microscopy studies of muscle ultrastructure. These images showed the presence of intracellular junctions between the sarcoplasmic reticulum (SR) and transverse tubular invaginations of the plasma membrane. Electron dense protrusions, named "feet," were found to span these junctions (2). Although the identities of the feet structures were initially unknown, later purification and electron microscopy studies confirmed them to be RyRs (3, 4).RyRs form homotetrameric assemblies and constitute the largest ion channels known to date, with molecular masses of ϳ2.2 MDa and each monomer consisting of ϳ5000 amino acid residues (3, 4). They are responsible for the release of Ca 2ϩ from the endoplasmic reticulum (ER) and SR and thus control many Ca 2ϩ -dependent processes within the cell. Ryanodine binds RyRs preferentially in the open state. At nanomolar concentrations, it "locks" the channel in a subconductance state, but at concentrations Ͼ100 M, it inhibits Ca 2ϩ release (5).In mammalian organisms, RyRs are found in a wide variety of cell types, including neurons, exocrine cells, epithelial cells, lymphocytes, and many more (6). They are known mostly for their involvement in excitation-contraction coupling, releasing Ca 2ϩ from the SR and thus driving muscle contraction. Three different isoforms (RyR1-3) have been found to date. RyR1 is widely expressed in skeletal muscle and was the first one to be cloned (7, 8). RyR2 is found primarily in the heart (9, 10), and RyR3 was originally identified in the brain (11), although each isoform is found in many different cell types (6). They share ϳ65% sequence identity, and the largest degree of difference is found in three "divergent regions" throughout the sequence, known as D1 (residues 4254 -4631 in RyR1), D2 (residues 1342-1403), and D3 (residues 1872-1923). Lower organisms express fewer RyR isoforms. Non-mammalian vertebrates express two isoforms, RyR␣ and RyR␤, whereas a single isoform was found to be expressed in lower organisms, including nematodes, f...

Roles of the NH2-terminal Domains of Cardiac Ryanodine Receptor in Ca2+ Release Activation and Termination

“…The intra-and intersubunit interactions between domains A and B are believed to be important for stabilizing the closed state of the channel. Disease mutations located in interfaces between domains A and B would weaken these interactions, thus facilitating channel opening (7)(8)(9)(10)(11)(12)(13)(14). Del-A would be expected to remove both intra-and intersubunit interactions between domains A and B, leading to destabilization of the closed state and channel activation.…”

“…The recently solved crystal structures of the NH 2 -terminal region of RyR have provided novel insights into the structural basis of disease mechanisms associated with the NH 2 -terminal mutations (7)(8)(9)(10)(11)(12)(13)(14). The three-dimensional structure of the NH 2 -terminal region of RyR contains three domains: domain A (residues 1-217), domain B (residues 218 -409), and domain C (residues 410 -543) (9).…”

Enhanced activity of eccentric contraction induces alterations in <i>in vitro</i> sarcoplasmic reticulum Ca²⁺ handling in rat hindlimb muscles

“…Mechanical stress in ECC-induced overstretched muscle fibers elicited damage in the triad junction of the t-tubule system 2) . Because the release of Ca 2+ from the SR is performed by the ryanodine receptor (RyR), which is the largest ion channel located in the intracellular junctions between the SR and t-tubules 32) , we suggest that the RyR abutted to the triad junction would also be impaired by ECC. On the other hand, during repeated muscle activity, each action potential leads to an efflux of K + in the cytoplasm.…”

How to open a Ryanodine Receptor

“…RyRs represent the pinnacle of complexity in ion channels, as they are targeted by tens of auxiliary proteins and small molecules that can affect their gating properties [1]. What are the allosteric transitions that govern opening and closing?…”

“…RyR1 is the primary skeletal muscle isoform and is the target for hundreds of mutations linked to central core disease and malignant hyperthermia. RyR2 predominates in the heart and is linked to stress-induced cardiac arrhythmias [1].…”