Calcium signalling: Ringing changes to the ‘bell-shaped curve’

The stimulation of cells with agonists that activate phospholipase C, and hence increase the cytoplasmic concentration of inositol 1,4,5-trisphosphate (IP3), often produces complex intracellular Ca2+ signals, such as Ca2+ waves [1]. The key to understanding how Ca2+ waves propagate was the observation that the Ca2+ wave velocity and concentration gradient was maintained as the Ca2+ waves swept across cells. This implies that Ca2+ waves propagate, not passively by diffusion, but rather actively through sequential activation of Ca2+ release units that regenerate the Ca2+ wave as it travels. The mechanism underlying the regenerative Ca2+ release process was the subject of much debate until several groups showed that IP3 receptors are under dual regulation by both IP3 and cytosolic Ca2+ (for review see [2]). IP3 receptors were found to be activated synergistically by IP3 and low (< 1 μM) cytosolic Ca2+ concentrations, but inhibited by high (> 1–10 μM) Ca2+ concentrations.