Multifunctional role of protein kinase C in regulating the formation and maturation of specific synapses.

Target-dependent increases in axon growth and varicosities accompany the formation of functional synapses between Aplysia sensory neurons and specific postsynaptic neurons (L7 and not L11). The enhanced growth is regulated in part by a target-dependent increase in the secretion of sensorin, the sensory neuron neuropeptide. We report here that protein kinase C (PKC) activity is required for synapse formation by sensory neurons with L7 and for the target-dependent increases in sensorin synthesis and secretion. Blocking PKC activity reversibly blocked synapse formation and axon growth of sensory neurons contacting L7, but did not affect axon growth of sensory neurons contacting L11 or axon growth of the postsynaptic targets. Blocking PKC activity also blocked the target-induced increase in sensorin synthesis and secretion. Sensorin then activates additional signaling pathways required for synapse maturation and synapse-associated growth. Exogenous anti-sensorin antibody blocked target-induced activation and translocation into sensory neuron nuclei of p42/44 mitogen-activated protein kinase (MAPK), attenuated synapse maturation, and curtailed growth of sensory neurons contacting L7, but not the growth of sensory neurons contacting L11. Inhibitors of MAPK or phosphoinositide 3-kinase also attenuated synapse maturation and curtailed growth and varicosity formation of sensory neurons contacting L7, but not growth of sensory neurons contacting L11. These results suggest that PKC activity regulated by specific cell-cell interactions initiates the formation of specific synapses and the subsequent synthesis and release of a neuropeptide to activate additional signaling pathways required for synapse maturation.