NERVE GROWTH-FACTOR INDUCES SENSITIVITY TO BOTULINUM NEUROTOXIN TYPE-A IN NOREPINEPHRINE-SECRETING PC12 CELLS

Inhibition of Ca2+-activated norepinephrine secretion by the botulinum neurotoxin (NT) serotypes A and E was examined in permeabilized PC12 cells. The dichain type E NT reduced with dithiothreitol (DTT) completely inhibited secretion whereas the dichain type A NT reduced with DTT exhibited incomplete inhibitory activity. In contrast, Ca2+-activated secretion in PC12 cells treated with nerve growth factor (NGF) was completely inhibited by reduced type A NT. The NGF-treated PC12 cells retained a sensitivity to the type E NT similar to that of untreated PC12 cells. These results indicate that the intracellular mechanisms of inhibition of the types E and A NTs are distinct. NGF appears to either induce the expression of a component selectively required for type A NT sensitivity, or otherwise modifies the secretory apparatus to acquire type A NT sensitivity.