cAMP-mediated regulation of neurotrophin-induced collapse of nerve growth cones.

Neurotrophins are known to promote the survival, differentiation, and neurite outgrowth of developing neurons. Here we report that acutely applied brain-derived neurotrophic factor (BDNF) induces rapid growth cone collapse and neurite retraction of embryonic Xenopus spinal neurons in culture. The collapsing effect of BDNF depends on the activation of Trk receptor tyrosine kinase, requires an influx of extracellular Ca2+, and is regulated by cAMP-dependent activity. Elevation of intracellular cAMP levels ([cAMP]i) by forskolin or (Sp)-cAMP completely blocked the collapsing effect, whereas inhibition of protein kinase A (PKA) by (Rp)-cAMP potentiated the collapsing action. BDNF-induced growth cone collapse was only observed in 6 hr cultures but not in 24 hr cultures. However, inhibition of PKA by (Rp)-cAMP restored the collapsing response of these "old" neurons in 24 hr cultures, suggesting that embryonic Xenopus spinal neurons may upregulate their endogenous cAMP-dependent activity during development in culture, leading to the blockade of their collapsing response to BDNF. Taken together, our results suggest the presence of cross-talk between Ca2+- and cAMP-signaling pathways involved in the collapsing action of neurotrophins, in which the cAMP-pathway regulates the Ca2+-mediated signal transduction required for BDNF-induced collapse. By modulating the cAMP-dependent activity through the intrinsic programming or interaction with other factors present in the environment, a neuron thus could respond to the same extracellular factors with different morphological and cellular changes at different stages during development.