Neuronal turning depends on the source, not the absolute level, of released calcium.

Cell adhesion proteins determine the direction of turning during axon guidance by altering downstream signaling, report Ooashi et al. on page 1159.

Axon guidance cues, such as netrin-1, stimulate growth cone turning by altering intracellular calcium levels. However, no simple correlation exists between the location of calcium increase within the growth cone and the direction of movement. Previous data suggested that the type of cell adhesion matrix influences the direction of movement.

Ooashi et al. tested the effects of calcium release in dorsal root ganglia neurons by uncaging NP-EGTA in a small region of the growth cone. Axons grown on N-cadherin or on L1 immunoglobulin superfamily protein turned toward the side of calcium release and exhibited an increase in cAMP. Blocking cAMP caused the cell to turn away from the stimulus. Meanwhile, cells on laminin turned away from the site of calcium release and did not show an increase in cAMP.

cAMP stimulates protein kinase A activity, which phosphorylates ryanodine receptors (RyRs) and triggers calcium-induced calcium release. When the team blocked RyR activation, axons on N-cadherin or L1, which would normally turn toward the stimulus, turned away, suggesting that both the initial calcium release and a subsequent downstream influx was required for attractive turning. Blocking RyR had no effect on repulsive turning seen in cells on laminin.

The authors conclude that the system enables cells to modify their responses to soluble cues based on their local environment, including the type of cell adhesion molecules present.