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

• Published in: Cell calcium (Edinburgh) 2023-09, Vol.114, p.102770-102770, Article 102770
• Main Authors: Baker, Mariah R., Fan, Guizhen, Arige, Vikas, Yule, David I., Serysheva, Irina I.
• Format: Article
• Language: English
• Subjects: Calcium binding sites; Calcium signaling; conformational dynamics; Inositol 1,4,5- trisphosphate receptors; Single particle cryo-EM
• ISSN: 0143-4160; 1532-1991; 1532-1991
• DOI: 10.1016/j.ceca.2023.102770

•The intrinsically flexible 3D architecture of IP3R provides the premise for the allosteric regulation of its activity.•Ligand binding alters the entropic neighborhood of conformations naturally explored by IP3R channels.•IP3 binding to IP3R relies on conformational dynamics of the ARM2 domain.•Binding of IP3 primes IP3R to endow it with a capacity to respond to Ca2+ which then evokes channel opening.•Binding of Ca2+ alters the conformational landscape of IP3R protein to exert its biphasic functional effect. 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. [Display omitted]