Ryanodine Receptors

The ryanodine receptor (RyR) is the largest known channel, named for specifically binding the alkaloid ryanodine. It is a homotetramer with high conductance for monovalent and divalent cations. Although not very Ca²⁺ selective, RyRs function as a Ca²⁺ release channel from the sarco/endoplasmic reticulum, amplifying the initial Ca²⁺ signaling from the sarcolemmal L-type Ca²⁺ channels for contraction or secretion. There are three RyR subtypes: RyR1 in skeletal muscle, RyR2 mainly in cardiac muscle and brain, and RyR3 that is more ubiquitous. RyR crystallography structure shows a bulky cytosolic N-terminal portion and a transmembrane portion. Its natural activator is the cytosolic Ca²⁺, but it is also sensitive to the luminal Ca²⁺. The RyR interacts with multiple proteins in both sides of the sarco/endoplasmic reticulum, which modify its function. RyRs also suffer posttranslational modifications, which for most of them increase their activity. Alteration of regulatory proteins or in posttranslational status is associated with diseases, such as heart failure. Today, more than 300 RyR mutations have been linked to different genetic diseases, such as myopathies for RyR1, cardiac diseases for RyR2 and Alzheimer’s disease for RyR3. Because RyRs are linked to both genetic and acquired diseases, current research is seeking agents targeting RyRs.