MITOGENIC AND ANTIMITOGENIC EFFECTS OF PITUITARY ADENYLATE CYCLASE-ACTIVATING POLYPEPTIDE (PACAP) IN ADULT-RAT CHROMAFFIN CELL-CULTURES

The neurotransmitter, pituitary adenylate cyclase-activating polypepti de (PACAP), is present in the rat adrenal medulla and is a potent stim ulus for catecholamine secretion. Previous studies have suggested that neurally derived signals stimulate proliferation of chromaffin cells in adult rats. To determine whether PACAP might be involved in mitogen ic signalling, its effects on bromodeoxyuridine incorporation were stu died in adrenal medullary cell cultures from adult female rats. Both P ACAP 27 and PACAP 38 are able to stimulate proliferation of adult rat chromaffin cells in vitro, either alone or in conjunction with PMA, an activator of protein kinase C. BrdU-labelled nuclei are observed in b oth epinephrine and norepinephrine cells, and proliferation of both ce ll types is stimulated by the same concentrations of PACAP that elicit secretion of catecholamines. The mitogenic effects of PACAP are poten tiated by indolidan, a phosphodiesterase inhibitor known to cause pheo chromocytomas in rats, and are inhibited by H-89, an inhibitor of prot ein kinase A. Mitogenic concentrations of PACAP inhibit mitogenic effe cts of nerve growth factor. These findings support the hypothesis that neurally derived signals regulate chromaffin cell proliferation in ad ult rats. Indolidan and a variety of non-genotoxic agents that cause p heochromocytomas in rats may do so indirectly by increasing neurally m ediated chromaffin cell turnover. The antagonism between PACAP and NGF suggests that neurotransmitters may supersede growth factors in regul ating chromaffin cell proliferation during development by suppressing or co-opting portions of growth factor signaling pathways.