The Ca(2) (+) signals evoked by inositol 1,4,5-trisphosphate (IP(3)) are built from elementary Ca(2) (+) release events involving progressive recruitment of IP(3) receptors (IP(3)R), intracellular Ca(2) (+) channels that are expressed in almost all animal cells. The smallest events ('blips') result from opening of single IP(3)R. Larger events ('puffs') reflect the near-synchronous opening of a small cluster of IP(3)R. These puffs become more frequent as the stimulus intensity increases and they eventually trigger regenerative Ca(2) (+) waves that propagate across the cell. This hierarchical recruitment of IP(3)R is important in allowing Ca(2) (+) signals to be delivered locally to specific target proteins or more globally to the entire cell. Co-regulation of IP(3)R by Ca(2) (+) and IP(3), the ability of a single IP(3)R rapidly to mediate a large efflux of Ca(2) (+) from the endoplasmic reticulum, and the assembly of IP(3)R into clusters are key features that allow IP(3)R to propagate Ca(2) (+) signals regeneratively. We review these properties of IP(3)R and the structural basis of IP(3)R behavior.
