Structure of IP₃R channel: high-resolution insights from cryo-EM

Inositol 1,4,5-trisphosphate receptors (IP₃Rs) are ubiquitously expressed intracellular Ca²⁺ channels and the major mediators of cellular Ca²⁺ signals generated by the release of Ca²⁺ ions from intracellular stores in response to a variety of extracellular stimuli. Despite established physiological significance and proven involvements of IP₃R channels in many human diseases, detailed structural basis for signal detection by these ion channels and their gating remain obscure. Recently, single particle electron cryomicroscopy (cryo-EM) has yielded a long-awaited near-atomic resolution structure of the entire full-length type 1 IP₃R. This structure provided exciting mechanistic insights into the molecular assembly of IP₃R, revealing the pronounced structural conservation of Ca²⁺ release channels and raising many fundamental and controversial questions on their activation and gating. Here we summarize the major technological advances that propelled our cryo-EM analysis of IP₃R to near-atomic resolution and discuss what the future holds for structural biology of Ca²⁺ release channels.