Pituitary adenylate cyclase activating polypeptide (PACAP) is a hormone that was originally isolated from sheep
hypothalamus on the basis of its ability to stimulate adenylate cyclase in rat anterior pituitary cell cultures Arimura, 1992.
PACAP is present not only in the central nervous system but also in peripheral tissues, including gastrointestinal tract, adrenal
gland, and testis. Its actions include the stimulation of secretion of growth hormone, ACTH, catecholamines, and insulin, as
well as other hormones. In addition, it appears to function as a neuromodulator/neurotransmitter in the central and peripheral
nervous systems. The diverse biologic actions of PACAP are mediated by receptors that are positively coupled to adenylate
cyclase by G(s-alpha). Three different receptors for PACAP have been identified, each of which contains 7 transmembrane
segments and shares significant homology with members of the glucagon/secretin receptor family. The type 1 receptor, which
is found in the hypothalamus, brain stem, pituitary, adrenal gland, pancreas, and testes, has a high affinity only for PACAP Ogi et al., 1993. The type 2 receptor is found in the brain. The adrenal gland has a high affinity for both PACAP and for
vasoactive intestinal peptide.
General function
Receptor, Anti-apoptotic
Comment
Characterization, expression, and functional activity of pituitary adenylate cyclase-activating polypeptide and its receptors in human granulosa-luteal cells. Morelli MB et al. Context: Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) are found in the ovary of mammalian species, though nothing is known about the possible role of PACAP and VIP in the human ovary. Objective: We investigated the expression of PACAP and PACAP/VIP receptors in human granulosa-luteal (GL) cells, obtained from consenting IVF patients attending a private fertility clinic, and assessed a possible antiapoptotic effect of these molecules. Main outcome measures: Expression of PACAP and PACAP/VIP receptor mRNAs in GL cells in response to FSH or LH. Effects of PACAP and VIP on apoptosis, levels of procaspase-3 in GL cells cultured in the absence of serum. Results: After 7 days in culture, GL cells displayed increased responsiveness to FSH and LH (100 ng/ml). FSH and LH promoted PACAP expression, LH in a time-dependent fashion. VIP receptor (VPAC1- and VPAC2-R) mRNAs were also induced by gonadotropin stimulation. Although PACAP receptor (PAC1-R) mRNA was barely detectable, western blot analysis revealed its presence. The apoptotic effect of serum withdrawal from the culture environment was reverted by both PACAP and VIP. Both peptides showed the ability to reverse a decrease in procaspase-3 levels induced by culture in the absence of serum. Conclusions: PACAP and VIP appear to play a role in maintenance of follicle viability as a consequence of the antiapoptotic effect. Further studies are warranted to evaluate the respective roles of PACAP and VIP in ovarian physiology and to identify their mechanism of action.
Expression and functional activity of PACAP and its receptors on cumulus cells: effects on oocyte maturation. Barberi M et al. Pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptor PAC1-R (PACAP type 1 receptor) are transiently expressed in granulosa cells (GCs) of mouse preovulatory follicles and affect several parameters associated with the ovulatory process. We investigated the expression of PACAP and its receptors in cumulus cells (CCs) after the LH surge and their role on cumulus expansion/apoptosis and oocyte maturation. PACAP and PAC1-R expression increased in CCs isolated at different times after treatment with human chorionic gonadotropin (hCG). Moreover, PACAP was able to reverse the inhibition of oocyte meiotic maturation caused by hypoxantine in cumulus cell-oocyte complexes (COCs) and efficiently promoted male pronuclear formation after fertilisation. PACAP was also able to induce cumulus expansion and prevent CC apoptosis. Our results demonstrated the induction of PACAP and its receptors in CCs by LH and EGF, suggesting that PACAP may play a significant role in the complex interactions of gonadotropin and growth factors during ovulation and fertilisation.
Park, et al reported that Northern blot analysis of ovaries obtained from prepubertal rats revealed the increased expression of
PACAPR during prepubertal development. The major cell types expressing PACAPR messenger RNA were granulosa cells of large
preantral follicles. Treatment of immature rats with PMSG caused a decrease in ovarian PACAPR expression. In contrast, treatment
with human (h) CG at 2 days after PMSG treatment stimulated ovarian PACAPR messenger RNA within 3-6 h in granulosa cells of
preovulatory follicles. RNase protection assay revealed that
the short variant of ovarian PACAPR was the predominant form stimulated during prepubertal development and by gonadotropins.
These results demonstrate the expression of PACAPR messenger RNA in granulosa cells of growing follicles and of preovulatory
follicles stimulated by gonadotropins, and suggest that PACAP may play a role in the growth of developing follicles and in ovulation as
an autocrine/paracrine factor.
Cecconi S,et al 2004 reported the Effect of Pituitary Adenylate Cyclase-Activating Polypeptide and Vasoactive Intestinal Polypeptide on Mouse Preantral Follicle Development in Vitro.
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a bioactive peptide isolated from ovine hypothalamus. It is transiently expressed in preovulatory follicles and positively affects several parameters correlated with the ovulatory process. It has also been shown to be expressed in the interstitial tissue around primordial and preantral follicles. The aim of the present study was to investigate whether PACAP influences preantral follicle growth and differentiation. Mouse preantral follicles were cultured for 5 d in the presence of FSH and increasing concentrations of PACAP or vasoactive intestinal polypeptide (VIP) (10(-12) to 10(-7) m). In the presence of FSH, follicles increased in diameter and formed an antrum. At the concentrations tested, neither PACAP alone nor VIP alone had any effect on follicle development, but the addition of either peptide to FSH-stimulated follicles caused a dose-dependent inhibition of follicle growth, antrum formation, granulosa cell proliferation, and estradiol production. The effect of PACAP on follicle growth and antrum formation was directly correlated with the length of stimulation and was reversible. Although exposure of follicles to 10(-7) m PACAP and VIP did not affect oocyte growth, it severely impaired completion of meiotic maturation in oocytes isolated from the follicles and cultured for 17 h in medium alone. The cyclic production of PACAP by preovulatory follicles during the estrous cycle in adult rats and its induction by LH in the rat and mouse ovary suggest that this peptide may play a role in the local regulation of preantral follicle growth.
Expression regulated by
FSH, LH
Comment
Ovarian localization
Oocyte, Cumulus, Granulosa, Luteal cells
Comment
Gras S et al reported that Pituitary adenylate cyclase-activating polypeptide is an auto/paracrine stimulator of acute progesterone accumulation and subsequent
luteinization in cultured periovulatory granulosa/lutein cells.
Kotani E et al used reverse
transcription and polymerase chain reaction to study PACAP type I receptor mRNA encoding PACAP type IA receptor in rat granulosa cells. Increasing concentrations of PACAP-38 significantly stimulated the production of progestins (progesterone and 20
alpha-OH-P) and cAMP accumulation in cultured granulosa cells.
Characterization and expression of different pituitary adenylate cyclase-activating polypeptide/vasoactive intestinal polypeptide receptors in rat ovarian follicles. Vaccari S et al. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a bioactive peptide transiently expressed in preovulatory follicles. PACAP acts by interacting with three types of PACAP receptors. PACAP type I receptor (PAC(1)-R), which binds specifically to both PACAPs and vasoactive intestinal polypeptide (VIP), although with lower affinity, and two VIP receptors, VPAC(1)-R and VPAC(2)-R, which bind to PACAP and VIP with equal affinity. In the present study, we showed the expression of all three receptors in whole ovaries obtained from juvenile and gonadotropin-treated immature rats. A more detailed analysis on cells from preovulatory follicles showed that PAC(1)-R and VPAC(2)-R were expressed in granulosa cells, whereas only VIP receptors were expressed in theca/interstitial (TI) cells and fully grown oocytes presented only PAC(1)-R. The distribution of the VIP receptors was confirmed by immunofluorescence. HCG treatment induced stimulation of PAC(1)-R in granulosa cells and VPAC(2)-R in TI cells. The presence of functional PACAP/VIP receptors was also supported by metabolic studies. We further evaluated the presence of PACAP and VIP receptors by testing the effect of these peptides on apoptosis in granulosa cells cultured, isolated or in whole follicles. Treatment of follicles with PACAP and VIP dose-dependently inhibited apoptosis, while only PACAP significantly inhibited isolated granulosa cells. These results demonstrate a different expression of PACAP/VIP receptors in the various follicle compartments and suggest a possible role for PACAP and VIP on granulosa and TI cells, both during follicle development and ovulation.
Follicle stages
Antral, Corpus luteum
Comment
Kotani E et al reported that rat corpus luteum expresses both PACAP and PACAP type IA receptor mRNAs.