Modulation of Inositol 1,4,5-Trisphosphate Receptors by Their Primary Physiological Ligands, IP₃, Ca²⁺, and ATP

Inositol 1,4,5-trisphosphate (IP₃) receptors (IP₃Rs) are ubiquitously expressed intracellular calcium (Ca²⁺) release channels predominantly localized to the endoplasmic reticulum. There are three IP₃R subtypes, which assemble as homo-/heterotetramers. The opening of IP₃Rs requires binding of one IP₃ per monomer and Ca²⁺ Recent high-resolution cryogenic electron microscopy (cryo-EM) structures of IP₃Rs in combination with functional assays have greatly increased our understanding of the structural basis for IP₃R channel opening and closing. IP₃R channel activation is facilitated by IP₃ and Ca²⁺ binding to the activation site. Channel inactivation occurs in the presence of IP₃ and high Ca²⁺ when Ca²⁺ is bound to the low-affinity Ca²⁺-binding motif. Specifically, in the near atomic resolution structures of IP₃Rs, densities corresponding to the primary agonists-IP₃ and Ca²⁺-and the allosteric modulator adenosine triphosphate (ATP) were identified. In this article, we aim to provide a comprehensive overview of the current understanding of structure-function relationships for IP₃Rs mediated by IP₃, Ca²⁺, and ATP.