Interaction Between Adrenergic and Peptide Stimulation in the Rat Pineal: Pituitary Adenylate Cyclase‐Activating Peptide

Abstract

The 27 amino acid peptide, pituitary adenylate cyclase‐activating polypeptide (PACAP‐27), and its 38 amino acid analogue, PACAP‐38, stimulate serotonin‐N‐acetyltransferase (NAT) activity and N‐acetylserotonin (NAS) and melatonin content of pineal glands from adult rats. Maximal stimulation of rat pineal NAT by PACAP‐38 is not increased further significantly by concurrent stimulation with the two related peptides, vasoactive intestinal polypeptide (VIP) and/or peptide N‐terminal histidine C‐terminal isoleucine (PHI). Isoproterenol was a more potent inducer of NAT activity than any of these peptides alone or in combination. PACAP‐38 also stimulates melatonin production by chicken pineal cells in culture as does VIP. Stimulation by both was not greater than after either alone. Prior stimulation of rat pineal NAT activity with VIP, PHI, or PACAP‐38 reduces the magnitude of subsequent stimulation with PACAP‐38 or forskolin. Concurrent stimulation of α‐receptors or treatment with active phorbol ester augments rat pineal response to PACAP‐38 stimulation just as it increases the response to VIP, PHI, and β‐receptor stimulation. Pineals from newborn rats respond to PACAP‐38 with an increase in NAT activity and the increase is augmented by concomitant α1‐adrenergic stimulation. The putative PACAP inhibitor PACAP (6–38) and the putative VIP inhibitor (Ac‐Tyr,d‐Phe)‐GRF 1–29 amide, in 100–1,000‐fold excess, did not affect the stimulatory activity of any of the peptides. Pineal melatonin concentration parallels changes in pineal NAT activity.

Pituitary Adenylate Cyclase-Activating Polypeptide and Its Receptors: 20 Years after the Discovery

“…Exposure of pinealocytes to graded concentrations of PACAP enhances cAMP production (Rekasi and Czompoly, 2002) and causes an increase in the activity of two key enzymes of the melatonin biosynthetic pathway, serotonin-N-acetyltransferase (Yuwiler et al, 1995;Schomerus et al, 2002) and hydroxyindole-O-methyltransferase (Ribelayga et al, 1997). Consistent with these observations, PACAP has been found to stimulate melatonin secretion by perifused rat pineal glands (Simonneaux et al, 1993) and cultured pinealocytes (Chik and Ho, 1995;Simonneaux et al, 1998;Schomerus et al, 2002).…”

Accumulation of rat pineal serotonin N-acetyltransferase mRNA induced by pituitary adenylate cyclase activating polypeptide and vasoactive intestinal peptide in vitro

“…Functional studies have demonstrated that VIP also stimulates adenylate cyclase activity (Kaneko et al 1980a), cAMP production (Kaneko et al 1980b, Chik et al 1988, Rekasi et al 1998, CREB phosphorylation (Schomerus et al 1996), AA-NAT activity (Kaneko et al 1980a, Yuwiler 1983) and MT secretion (Simonneaux et al 1990, Rekasi et al 1994 with, however, much less potency than NE. PACAP also stimulates cAMPinduced AA-NAT activity and MT secretion (Simonneaux et al 1993, Chik & Ho 1995, Yuwiler et al 1995 in rat pineal gland in a similar manner to VIP.…”

“…In addition to the adrenergic regulation of MT secretion, an increasing number of peptidergic neurons have been reported to play a modulating role in pineal function (Simonneaux 1995, Yuwiler et al 1995, Moller et al 1996, Rekasi et al 1998, Pfeffer et al 1999. Among the peptides of the secretin superfamily, VIP and PACAP proved to be the most potent in stimulating MT synthesis and release (Simonneaux et al 1990, 1993, Rekasi et al 1994, Pfeffer et al 1999).…”

“…In addition to the sympathetic innervation (Kappers 1960) an increasing number of peptidergic neurons have been reported to play a modulating role in pineal function (Simonneaux 1995, Yuwiler et al 1995, Moller et al 1996, Rekasi et al 1998. Among these, vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP) seem to play the most important role in mammalian pineal indole metabolism.…”

“…The submaximal activation of the cAMPsignaling pathway by VIP or PACAP allows for an -adrenergic potentiation of cAMP accumulation (Chik et al 1988, Chik & Ho 1995, CREB phosphorylation (Pfeffer et al 1999), AA-NAT enzymatic activity (Yuwiler 1983, Yuwiler et al 1995, MT synthesis (Simonneaux et al 1993, Chik & Ho 1995, Yuwiler et al 1995 and ICER protein levels (Pfeffer et al 1999). However, the -adrenergic potentiation of AA-NAT mRNA has to be elucidated.…”