Inositol 1,4,5-trisphosphate-gated calcium channel ITPR3
inositol 1,4,5-trisphosphate-gated calcium channel activity
Structural basis for the regulation of inositol trisphosphate receptors by Ca<sup>2+</sup> and IP<sub>3</sub>.
Inositol trisphosphate receptors (IP<sub>3</sub>Rs) are ubiquitous Ca<sup>2+</sup>-permeable channels that mediate release of Ca<sup>2+</sup> from the endoplasmic reticulum, thereby regulating numerous processes including cell division, cell death, differentiation and fertilization. IP<sub>3</sub>Rs are jointly activated by inositol trisphosphate (IP<sub>3</sub>) and their permeant ion, Ca<sup>2+</sup>. At high concentrations, however, Ca<sup>2+</sup> inhibits activity, ensuring precise spatiotemporal control over intracellular Ca<sup>2+</sup>. Despite extensive characterization of IP<sub>3</sub>R, the mechanisms through which these molecules control channel gating have remained elusive. Here, we present structures of full-length human type 3 IP<sub>3</sub>Rs in ligand-bound and ligand-free states. Multiple IP<sub>3</sub>-bound structures demonstrate that the large cytoplasmic domain provides a platform for propagation of long-range conformational changes to the ion-conduction gate. Structures in the presence of Ca<sup>2+</sup> reveal two Ca<sup>2+</sup>-binding sites that induce the disruption of numerous interactions between subunits, thereby inhibiting IP<sub>3</sub>R. These structures thus provide a mechanistic basis for beginning to understand the regulation of IP<sub>3</sub>R.