Structural organization of signalling to and from IP3 receptors

In the 30 years since IP3 (inositol 1,4,5-trisphosphate) was first shown to release Ca2+ from intracellular stores, the importance of spatially organized interactions within IP3-regulated signalling pathways has been universally recognized. Recent evidence that addresses three different levels of the structural determinants of IP3-evoked Ca2+ signalling is described in the present review. High-resolution structures of the N-terminal region of the IP3R (IP3 receptor) have established that the two essential phosphate groups of IP3 bind to opposite sides of the IP3-binding site, pulling its two domains together. This conformational change is proposed to disrupt an interaction between adjacent subunits within the tetrameric IP3R that normally holds the channel in a closed state. Similar structural changes are thought to allow gating of ryanodine receptors. cAMP increases the sensitivity of IP(3)Rs and thereby potentiates the Ca2+ signals evoked by receptors that stimulate IP3 formation. We speculate that both IP3 and cAMP are delivered to IP(3)Rs within signalling junctions, wherein the associated IP(3)Rs are exposed to a saturating concentration of either messenger. The concentration-dependent effects of extracellular stimuli come from recruitment of junctions rather than from a graded increase in the activity of individual junctions. IP(3)Rs within 'IP3 junctions' respond directly to receptors that stimulate phospholipase C, whereas extra-junctional IP(3)Rs are exposed to suboptimal concentrations of IP3 and open only when they are sensitized by cAMP. These results highlight the importance of selective delivery of diffusible messengers to IP(3)Rs. The spatial organization of IP(3)Rs also allows them to direct Ca2+ to specific intracellular targets that include other IP(3)Rs, mitochondria and Ca2+ regulated channels and enzymes. IP(3)Rs also interact functionally with lysosomes because Ca2+ released by IP(3)Rs, but not that entering cells via store-operated Ca2+ entry pathways, is selectively accumulated by lysosomes. This Ca2+ uptake shapes the Ca2+ signals evoked by IP(3)z and it may regulate lysosomal behaviour.