Understanding IP₃R channels: From structural underpinnings to ligand-dependent conformational landscape

Inositol 1,4,5-trisphosphate receptors (IP₃Rs) are ubiquitously expressed large-conductance Ca²⁺-permeable channels predominantly localized to the endoplasmic reticulum (ER) membranes of virtually all eukaryotic cell types. IP₃Rs work as Ca²⁺ signaling hubs through which diverse extracellular stimuli and intracellular inputs are processed and then integrated to result in delivery of Ca²⁺ from the ER lumen to generate cytosolic Ca²⁺ signals with precise temporal and spatial properties. IP₃R-mediated Ca²⁺ signals control a vast repertoire of cellular functions ranging from gene transcription and secretion to the more enigmatic brain activities such as learning and memory. IP₃Rs open and release Ca²⁺ when they bind both IP₃ and Ca²⁺, the primary channel agonists. Despite overwhelming evidence supporting functional interplay between IP₃ and Ca²⁺ in activation and inhibition of IP₃Rs, the mechanistic understanding of how IP₃R channels convey their gating through the interplay of two primary agonists remains one of the major puzzles in the field. The last decade has seen much progress in the use of cryogenic electron microscopy to elucidate the molecular mechanisms of ligand binding, ion permeation, ion selectivity and gating of the IP₃R channels. The results of these studies, summarized in this review, provide a prospective view of what the future holds in structural and functional research of IP₃Rs.