IN SYMPATHETIC BUT NOT SENSORY NEURONS, PHOSPHOINOSITIDE-3 KINASE IS IMPORTANT FOR NGF-DEPENDENT SURVIVAL AND THE RETROGRADE TRANSPORT OF I-125 BETA-NGF

The way in which the same ligands and receptors have different functio nal effects in different cell types must depend on subtle differences in the second messenger cascades. Sensory and sympathetic neurones bot h retrogradely transport nerve growth factor (NGF) and depend on NGF f or their developmental survival. NGF binding to the high affinity tyro sine kinase (TrkA) receptors initiates second messenger signalling cas cades, one of which includes the activation of phosphoinositide-3 kina se (PI3-kinase). We demonstrate that 100-fold higher concentrations of the PI3-kinase inhibitor, Wortmannin, are required to inhibit the sur vival effects and retrograde axonal transport of NGF in sensory neuron es than in sympathetic neurones. Similarly, although less patently tha n Wortmannin, the PI3-kinase inhibitor LY294002 required a 10-fold hig her concentration to inhibit the survival effects of NGF in sensory th an in sympathetic neurones. Inhibitors of other second messengers, inc luding staurosporine, pertussis and cholera toxins, failed to have an effect on the transport of the NGF receptor complex in both cell types . Also, Wortmannin did not affect the structural integrity of the symp athetic nerve terminals. As PI3-kinase is present in both neuronal pop ulations, this suggests that the Wortmannin sensitive isoform of PI3-k inase (p110) is essential in sympathetic neurones both for survival an d for NGF-TrkA receptor complex trafficking. As sensory neurones also depend on NGF for their developmental survival and endocytose and retr ogradely transport the NGF-TrkA receptor complex, this population of n eurones may either recruit a different isoform of PI3-kinase or utiliz e PI3-kinase independent signalling pathways for these cellular functi ons.