What we don't know about the structure of ryanodine receptor calcium release channels.

1. The ryanodine receptor (RyR) is the Ca2+ release channel in the sarcoplamic reticulum of skeletal and cardiac muscle and is essential for respiration and heart beat. The RyR channel releases Ca2+ from intracellular stores in a variety of other cell types, where it normally coexists with the inositiol 1,4,5-trisphosphate receptor (IP3R). The RyR and IP3R, forming a superfamily of homotetrameric ligand-gated intracellular Ca2+ channels, serve discrete functions: they can be located in independent Ca2+ stores with different activation mechanisms and can be coupled to different signalling pathways. 2. Although functional characteristics of the RyR have been investigated intensely, there remain major gaps in our knowledge about the structure of the protein, its ion-conducting pore, its ligand-binding sites and sites supporting the many protein/protein interactions that underlie the in vivo function of the channel. 3. Of particular importance are the transmembrane segments that form the membrane-spanning domain of the protein and the pore, define the conductance and selectivity of the channel and dictate the cytoplasmic and luminal domains and the overall protein structure. Hydropathy profiles predict between four and 12 transmembrane segments. One popular model shows four transmembrane segments in the C-terminal one-tenth of the protein. However, there is substantial evidence for a larger number of membrane-spanning segments located in both the C-terminal and central parts of the protein. 4. A model of the RyR pore based on the Streptomyces lividans KcsA channel structure is presented. Protein/protein interactions between the RyR and other regulatory proteins, as well as within the RyR subunit, are discussed.