IP₃ Receptor Plasticity Underlying Diverse Functions

In the body, extracellular stimuli produce inositol 1,4,5-trisphosphate (IP₃), an intracellular chemical signal that binds to the IP₃ receptor (IP₃R) to release calcium ions (Ca²⁺) from the endoplasmic reticulum. In the past 40 years, the wide-ranging functions mediated by IP₃R and its genetic defects causing a variety of disorders have been unveiled. Recent cryo-electron microscopy and X-ray crystallography have resolved IP₃R structures and begun to integrate with concurrent functional studies, which can explicate IP₃-dependent opening of Ca²⁺-conducting gates placed ∼90 Å away from IP₃-binding sites and its regulation by Ca²⁺. This review highlights recent research progress on the IP₃R structure and function. We also propose how protein plasticity within IP₃R, 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.