Mechanism of Action of Pituitary Adenylate Cyclase‐Activating Polypeptide (PACAP) in Human Nonfunctioning Pituitary Tumors

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Abstract
Several evidence suggest that pituitary adenylate cyclase activating polypeptides (PACAP‐38 and ‐27) could function as hypophysiotropic factors. Both peptides interact with either the type I receptor, which preferentially binds the two PACAPs and has a much lower affinity for vasoactive intestinal polypeptide (VIP) or the type II receptor, which binds the two PACAPs and VIP with a nearly equal affinity. In addition to the stimulation of adenylyl cyclase (AC) activity, in different cell types PACAP causes an increase of cytosolic calcium levels ([Ca2+]i), consequent to phospholipase‐C activation. In the present study, we investigated the effect of PACAP on cAMP formation and [Ca2+]i levels in 16 human nonfunctioning pituitary adenomas (NFPA). PACAP‐38 increased cAMP formation in all tumors; the peptide stimulated either AC activity in membrane preparations from 26 ± 10 to 214 ± 179 pmol/mg prot/min (P < 0.01) or cAMP efflux from 12 ± 5.4 to 73.2 ± 32 pmol/well (P < 0.01) in cultured cells. The effect, detectable at concentrations higher than 1‐10 pM, was maximal at 0.1‐10 nM. While PACAP‐38 and PACAP‐27 were nearly equally effective and potent, 100‐fold higher concentrations of VIP were required to obtain similar AC activation. GHRH and CRH were ineffective in any NFPA. The PACAP effect was not antagonized by a VIP antagonist, while PACAP fragment 6–27 amide partially reduced the stimulatory effects of both PACAP‐27 and VIP in 2 out of 3 tumors tested. PACAP‐38 caused a [Ca2+]i rise in cells obtained from 7 NFPA (from 110 ± 34 to 151 ± 40 nM [Ca2+]i, P < 0.05) while in the remaining 7 the peptide was ineffective at any concentrations tested (from 1 nM to 10 μM). In the responsive tumors, PACAP‐38 effect was not consequence of phospholipase‐C activation since removal of extracellular Ca2+ as well as blockade of L‐type Ca2+ channels by dihydropyridine antagonists abolished [Ca2+]i increase triggered by the peptide. These data indicate that PACAP is by far the most potent activator of cAMP formation in NFPA and suggest a possible modulatory action of this peptide on cell growth.

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