Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) 38 and PACAP27 Activate Common and Distinct Intracellular Signaling Pathways to Stimulate Growth Hormone Secretion from Porcine Somatotropes¹

Abstract

We have recently shown that the two bioactive forms of pituitary adenylate cyclase-activating polypeptide, PACAP38 and PACAP27, stimulate GH release and GH messenger RNA (mRNA) accumulation in cultured porcine pituitary cells. However, dose- and time-related differences in the response to both peptides suggested that the signaling mechanisms activated by PACAP38 and PACAP27 in this cell type could differ. To test this hypothesis, we have evaluated hormone release and GH mRNA content after PACAP treatment in combination with selective activators and inhibitors of the adenylate cyclase/cAMP/protein kinase A and the phospholipase C/inositol phosphate (IP)/protein kinase C pathways, and with blockers of intra- and extracellular Ca2+. Our results show that activation of the adenylate cyclase/cAMP/protein kinase A system, and extracellular Ca2+ entry through L-type Ca2+-channels are prevailing and requisite signals for the transduction of the stimulatory effects of both PACAP38 and PACAP27 on GH release and transcription in porcine somatotropes. However, phospholipase C and intracellular Ca2+ also contribute, although partially, to PACAP38-induced, but not to PACAP27-induced increase in porcine GH secretion and mRNA levels. These findings demonstrate that in normal somatotropes, PACAP38 can activate multiple transduction pathways that differ from those employed by PACAP27. Moreover, these differences could account for the previously described divergences in the actions of either peptide in porcine somatotropes.

Modulation of L-type Calcium Channels in Drosophila via a Pituitary Adenylyl Cyclase-activating Polypeptide (PACAP)-mediated Pathway

“…This PACAP-mediated increase in intracellular Ca 2ϩ concentration occurs by influx of Ca 2ϩ through voltage-dependent Ca 2ϩ channels, including L-type Ca 2ϩ channels and/or by release of Ca 2ϩ from intracellular stores via a phospholipase C-␤ (PLC)-mediated pathway (42,49,(52)(53)(54). The data presented here delineate steps in the pathway involved in modulation of L-type Ca 2ϩ channels by PACAP and subsequent increase in Ca 2ϩ influx through these channels.…”

“…PACAP mediates a number of physiological functions (19,38), such as somatodendritic vasopressin release (39), catecholamine secretion (40,41), growth hormone secretion (42), secretin release (43), gene expression (44,45), neuronal protection from apoptosis (46), effects on muscle excitability (47, 48), circadian rhythms (44,49), and behavioral and psychomotor phenomena (50,51). Many of these processes are mediated via Components examined in the present study, as well as those studied in two previous reports from this laboratory (16,26), are shown boxed.…”

“…Modulation of L-type Ca 2ϩ channels via cAMP-and PLC-mediated pathways raises some interesting questions, e.g. whether there is any cross-talk between the two modulatory pathways or whether the two pathways even converge at some point subsequent to the involvement of PKA and protein kinase C. Depending on the particular splice variant subtype of the PAC1 receptor involved, PACAP-38 can induce the activation of both AC and PLC (42,52). It will be interesting to see whether PACAP modulates L-type channels in Drosophila not only via a cAMPmediated pathway but also through the pathway involving PLC.…”

Differential peptide-dependent regulation of growth hormone (GH): A comparative analysis in pituitary cultures of reptiles, birds, and mammals

“…On the other hand, it has been shown that several other hypothalamic hypophysiotropic neuropeptides are involved in GH regulation in vertebrates [ 21 ], including the pituitary adenylate cyclase-activating polypeptide (PACAP) [ 32 ], thyrotropin releasing hormone (TRH) [ 33 ]; and gonadotropin releasing hormone (GnRH) [ 34 ]. Thus, PACAP has been described as a stimulator of GH secretion in fish [ 35 ], amphibians [ 36 ], and birds [ 37 ], while in mammals it has shown differential responses, being stimulatory in rats [ 38 ] and pigs [ 39 ] but without effect or even inhibitory in sheep [ 40 ]. Likewise, TRH modulates the release of GH in fish [ 41 ], amphibia [ 42 ], reptiles [ 27 ], birds [ 43 ], and mammals [ 44 ].…”