Dale's hypothesis revisited: different neuropeptides derived from a common prohormone are targeted to different processes.

In the bag cells of Aplysia californica, the prohormone of egg-laying hormone is processed by means of endoproteolytic cleavage into two sets of peptides. The amino-terminal region of the prohormone gives rise to the bag cell peptides (alpha, beta, and gamma). These serve an autocrine function; they are autoexcitatory on the bag cells and also act locally to alter the firing patterns of neurons in the abdominal ganglion. The carboxyl-terminal portion of the prohormone gives rise to the egg-laying hormone. This peptide acts as a hormone on nearby neurons and by means of the circulation on peripheral tissues to bring about egg-laying. We have previously reported that the first cleavage of the prohormone, which occurs in the trans-Golgi network, results in two intermediates that are sorted into distinct vesicle classes prior to further processing. Here we show that these distinct vesicles are localized to separate processes, thus spatially segregating autocrine and hormonal release sites. The findings of segregation indicate that neurons need not always release the same set of chemical messengers from all of their endings.