The complex regulatory function of the ligand-binding domain of the inositol 1,4,5-trisphosphate receptor

The inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) can be divided in three functionally distinct regions: a ligand-binding domain, a modulatory domain and a channel domain. Numerous regulatory mechanisms including inter- and intra-molecular protein-protein interactions and phosphorylation events act via these domains to regulate the function of the IP3R. Regulation at the level of the ligand-binding domain primarily affects the affinity for IP3. The extent of IP3-induced Ca2+ release (IICR) is, however, not only determined by the affinity for IP3 but also by the effectiveness of the coupling between ligand binding and channel opening. As a result, regulation as well as malfunction of IICR may be affected by both steps in the activation mechanism. The 3D structures of the two subdomains of the ligand-binding domain have recently been determined by X-ray diffraction analysis. This allows a more detailed molecular explanation of the regulatory events situated at the ligand-binding domain of the IP3R. In this review, we will focus on recent structural and functional data on the ligand-binding domain that have extended and clarified the view on the molecular mechanisms of IP3R regulation.