Fig. 8.

Schematic diagram showing the proposed model involved in the cAMP regulation of BDNF-induced collapse. Activation of TrkB receptors by BDNF induces multiple intracellular signaling cascades including a Ca²⁺ influx through Ca²⁺ channels, and the Ca²⁺pathway mediates the collapsing effect (double lineswith arrows). Although the unknown protein X is involved in the main Ca²⁺-signaling pathway for collapse, its activity can be modulated by phosphorylation and dephosphorylation by cAMP-dependent activity (single lines witharrows). PKA phosphorylates and inactivates (−) X, whereas phosphotase(s) dephosphorylate(s) and activate(s) (+) X. An equilibrium between the active and inactive X is likely reached in the cell. Experimental manipulation of PKA activity by (R_p)-cAMP or (S_p)-cAMP (dashed lines with arrows) can change the equilibrium and thus regulate the collapsing effect of BDNF. Activation of PKA by (S_p)-cAMP causes more X to become inactive, leading to the blockade of the collapsing effect; inhibition of the resting level of PKA activity by (R_p)-cAMP results in more active X, leading to the potentiation of the collapsing effect induced by the low concentrations of BDNF. Alternatively, the cAMP-mediated regulation can be upstream of Ca²⁺. In this case, the protein X mediates BDNF-induced Ca²⁺ influx required for growth cone collapse (dotted double lines witharrows), and its activity can be regulated by cAMP-dependent activity in a similar way.