Calcium Mediates Bidirectional Growth Cone Turning Induced by Myelin-Associated Glycoprotein

Abstract Cytoplasmic second messengers, Ca 2+ and cAMP, regulate nerve growth cone turning responses induced by many guidance cues, but the causal relationship between these signaling pathways has been unclear. We here report that, for growth cone turning induced by a gradient of myelin-associated glycoprotein (MAG), cAMP acts by modulating MAG-induced Ca 2+ signaling. Growth cone repulsion induced by MAG was accompanied by localized Ca 2+ signals on the side of the growth cone facing the MAG source, due to Ca 2+ release from intracellular stores. Elevating cAMP signaling activity or membrane depolarization enhanced MAG-induced Ca 2+ signals and converted growth cone repulsion to attraction. Directly imposing high- or low-amplitude Ca 2+ signals with an extracellular gradient of Ca 2+ ionophore was sufficient to trigger either attractive or repulsive turning, respectively. Thus, distinct Ca 2+ signaling, which can be modulated by cAMP, mediates the bidirectional turning responses induced by MAG.