Ryanodine Receptor

1.1 Size and Evolution The ryanodine receptor (RyR) is a selective Ca release channel that is localized to the endoplasmic reticulum (ER) in both excitable and non-excitable cells. The RyR owes its name to the plant alkaloid and high affinity ligand ryanodine. The functional RyR exists as a tetramer composed of a single unit of approximately 565kDa. To date, it is the largest known ion channel. In mammals, there are three RyR isoforms that share approximately 70% homology and several biophysical properties (26). RyR1 is the dominant Ca release channel present on sarcoplasmic reticulum (SR) in skeletal muscles (104, 127), RyR2 is predominant in cardiac muscle (73), and in brain there is more general expression of all three isoforms (29, 36, 67, 73, 126). Based on phylogenetic analysis, it is likely that all three RyR isoforms evolved from a single ancestor. In addition, there is evidence to suggest that the RyR as well as another intracellular Ca channel the inositol 1,4,5-trisphosphate receptor (IP3R) evolved from a common ancestral gene (107). Sequence analysis reveals a high degree of similarity in the channel pore region (107), supporting the common ancestor theory. This structural homology is also present between the pore-forming region of RyRs and other ion channels, which include voltage gated ion channels, cyclic nucleotide gated channels, and the transient receptor potential channels (TRP) (41). Phylogenetic studies also reveal that certain RyR domains are highly conserved from worms to humans. For instance, there is 35-40% homology at the amino acid level between C. elegans and vertebrates, and the functional domains including the leucine/isoleucine zipper, the pore region, and the transmembrane domains are highly conserved in all three RyR isoforms. Mutations in these domains alter channel functions such as caffeineinduced Ca release, ryanodine binding, single channel conductance, and cation selectivity (31, 122).