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

Inositol 1,4,5-trisphosphate receptors (IPRs) are ubiquitously expressed large-conductance Ca-permeable channels predominantly localized to the endoplasmic reticulum (ER) membranes of virtually all eukaryotic cell types. IPRs work as Ca signaling hubs through which diverse extracellular stimuli and intracellular inputs are processed and then integrated to result in delivery of Ca from the ER lumen to generate cytosolic Ca signals with precise temporal and spatial properties. IPR-mediated Ca 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. IPRs open and release Ca when they bind both IP and Ca, the primary channel agonists. Despite overwhelming evidence supporting functional interplay between IP and Ca in activation and inhibition of IPRs, the mechanistic understanding of how IPR 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 IPR 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 IPRs.

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