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 IP₃Rs and thereby potentiates the Ca²⁺ signals evoked by receptors that stimulate IP₃ formation. We speculate that both IP₃ and cAMP are delivered to IP₃Rs within signalling junctions, wherein the associated IP₃Rs 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. IP₃Rs within ‘IP₃ junctions’ respond directly to receptors that stimulate phospholipase C, whereas extra-junctional IP₃Rs 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 IP₃Rs. The spatial organization of IP₃Rs also allows them to direct Ca²⁺ to specific intracellular targets that include other IP₃Rs, mitochondria and Ca²⁺-regulated channels and enzymes. IP₃Rs also interact functionally with lysosomes because Ca²⁺ released by IP₃Rs, 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 IP₃ and it may regulate lysosomal behaviour.