CICR occurs after uncaging calcium at apical (red) but not basal (blue) locations.

Most models of intracellular Ca2+ signaling invoke calcium-induced calcium release (CICR), a positive feedback mechanism that amplifies small elevations in cytoplasmic Ca2+ to produce complex signals. But what determines the pattern of signaling, and how does a cell avoid triggering Ca2+ release in the wrong place? Ashby et al., reporting on page 283, addressed these questions with a powerful new technique and arrived at some surprising conclusions.

Using spatially restricted uncaging of caged Ca2+, the authors were able to boost cytosolic Ca2+ concentrations in specific regions within pancreatic acinar cells. These cells ordinarily produce polarized Ca2+ waves after stimulation with an agonist. When caged Ca2+ uncaged in the apical region of the cells, a CICR wave spreads from the apical region toward the basal membrane. In contrast, uncaging Ca2+ in the basal region does not produce a CICR wave at all.

CICR is usually associated with ryanodine receptors, which are found in both the apical and basal regions of these cells. However, Ashby et al. found that inhibitors of either ryanodine receptors or IP3 receptors block the induced waves, indicating that CICR requires cooperation between both types of Ca2+ release channels. As IP3 receptors are restricted to the apical region, a CICR wave can only be induced there. Ca2+ uncaging did not stimulate IP3 production, so participation of the IP3 receptors in CICR wave generation does not require elevation of the IP3 concentration.

Although CICR waves could not be initiated in the basal region, waves that originate in the apical region can travel through the basal region. One possibility is that Ca2+ channels may be closely spaced along “gunpowder trails” in the basal region, allowing a signal that originated elsewhere to propagate along a route with a high density of Ca2+-sensitive and Ca2+- releasing sites. Such a system would help determine the pattern of Ca2+ signaling while preventing Ca2+ release in the wrong part of the cell.▪