In the body, extracellular stimuli produce inositol 1,4,5-trisphosphate (IP), an intracellular chemical signal that binds to the IP receptor (IPR) to release calcium ions (Ca2+) from the endoplasmic reticulum. In the past 40 years, the wide-ranging functions mediated by IPR and its genetic defects causing a variety of disorders have been unveiled. Recent cryo-electron microscopy and X-ray crystallography have resolved IPR structures and begun to integrate with concurrent functional studies, which can explicate IP-dependent opening of Ca2+-conducting gates placed ∼90 Å away from IP-binding sites and its regulation by Ca2+. This review highlights recent research progress on the IPR structure and function. We also propose how protein plasticity within IPR, which involves allosteric gating and assembly transformations accompanied by rapid and chronic structural changes, would enable it to regulate diverse functions at cellular microdomains in pathophysiological states.


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