CALCIUM-RELEASE CHANNELS: STRUCTURE AND FUNCTION OF IP3 RECEPTORS AND RYANODINE RECEPTORS

Ca2+-release channels are giant membrane proteins that control the release of Ca2+ from the endoplasmic and sarcoplasmic reticulum. The two members, ryanodine receptors (RyRs) and inositol-1,4,5-trisphosphate receptors (IP Rs), are evolutionarily related and are both activated by cytosolic Ca2+. They share a common architecture, but RyRs have evolved additional modules in the cytosolic region. Their massive size allows for the regulation 3 by tens of proteins and small molecules, which can affect the opening and closing of the channels. In addition to Ca2+, other major triggers include IP3 for the IP(3)Rs and depolarization of the plasma membrane for a particular RyR subtype expressed in skeletal muscle. Their size has made them popular targets for study via electron microscopic methods, with current structures culminating near 3 angstrom. The available structures have provided many new mechanistic insights into the binding of auxiliary proteins and small molecules, how these can regulate channel opening, and the mechanisms of disease-associated mutations. They also help scrutinize previously proposed binding sites, as some of these are now incompatible with the structures. Many questions remain around the structural effects of posttranslational modifications, additional binding partners, and the higher order complexes these channels can make in situ. This review summarizes our current knowledge about the structures of Ca2+-release channels and how this informs on their function.

Automated summary

Ca2+-release channels are membrane proteins that control the release of Ca2+ from the endoplasmic and sarcoplasmic reticulum. They are activated by cytosolic Ca2+ and have a common architecture, with additional modules in the cytosolic region for ryanodine receptors (RyRs). Their regulation involves the binding of proteins and small molecules, with major triggers including IP3 and membrane depolarization. Electron microscopic studies have provided valuable insights into their structure and mechanisms, including the binding of auxiliary proteins, regulation of channel opening, and disease-associated mutations.