Ca2+, cAMP and cGMP Signaling

Our work has shown that extracellular guidance cues can induce an intracellular gradient of the second messenger Ca2+ in the growth cone, and that both cyclic nucleotides and neuronal activity can modulate these Ca2+ signals to convert growth cone repulsion to attraction. We found that it is the magnitude of Ca2+ signal that specifies either attractive or repulsive growth cone turning, presumably depending on the activation of distinct downstream effectors. We also found that migrating growth cones can adapt to their environment, undergoing consecutive phases of desensitization and resensitization in the presence of increasing basal concentrations of guidance factors. Desensitization is accompanied by a reduction of Ca2+ signaling, whereas resensitization requires local protein synthesis and activation of a specific enzyme called mitogen-activated protein kinase. Such adaptive behavior allows the growth cone to readjust its sensitivity over a wide range of concentrations of the guidance factor, an essential feature for long-range directed motility. The mechanism of this adaptive process remains to be fully elucidated. We hope that by better understanding these processes in the normal developing nervous system, we will gain insight into methods that can be used to overcome inhibition to nerve growth in the adult central nervous system. This approach holds great promise, since many repulsive guidance factors also inhibit nerve growth and regeneration. Thus, methods that modulate intracellular signals and convert growth cone repulsion to attraction may also promote regeneration, thereby providing insight into potential therapeutic approaches for enhancing nerve regeneration in the brain and spinal cord following degeneration or injury.