PACAP: A regulator of mammalian reproductive function

Abstract

Pituitary adenylate cyclase-activating polypeptide (PACAP) is an ancestral molecule that was isolated from sheep hypothalamic extracts based on its action to stimulate cAMP production by pituitary cell cultures. PACAP is one of a number of ligands that coordinate with GnRH to control reproduction. While initially viewed as a hypothalamic releasing factor, PACAP and its receptors are widely distributed, and there is growing evidence that PACAP functions as a paracrine/autocrine regulator in the CNS, pituitary, gonads and placenta, among other tissues. This review will summarize current knowledge concerning the expression and function of PACAP in the hypothalamic-pituitary-gonadal axis with special emphasis on its role in pituitary function in the fetus and newborn.

Keywords: Hypothalamus; Ovary; Pituitary; Pituitary adenylate cyclase-activating polypeptide (PACAP); Sexual maturation; Testis.

Figure 1.

PACAP receptor second messenger signaling in pituitary cells. The schema describes a paracrine/autocrine feed-forward mechanism to maintain a high level of PACAP in the fetal pituitary. PACAP and PAC1-R in gonadotrophs and folliculostellate cells likely contribute to the autocrine/paracrine system. The mouse PACAP promoter is depicted with three AP1 sites (−948, −448, −275) and two CRE sites (−205, −179).

Figure 2.

Pattern of PACAP expression in the hypothalamus (PVN), anterior pituitary, and ovaries during the rat estrus cycle. PACAP expression increases in the PVN just prior to the rise in GnRH in the preoptic area which initiates the surge in serum LH and FSH. PACAP expression in the pituitary rises prior to a decline in FSH secretion. PACAP expression in the ovary rises in response to the proestrus surge in circulating gonadotropins, and soon thereafter serum progesterone increases. Abbreviations: MET Metestrus; DI Diestrus; PRO Proestrus; EST Estrus; E₂ estradiol; P₄ progesterone. a: Schirman-Hildesheim, 2005 (150), b: Moore, 2003 (151) c: Ozawa, 2005 (152), d: Smith, 1975 (153), e: Ko, 1999 (154).

Figure 3.

A model for the mechanism by which PACAP differentially regulates gonadotropin expression. Experiments using primary pituitary cell cultures and/or immortalized gonadotroph cell lines have shown that PACAP directly stimulates transcription of each of the gonadotropin subunits, enhances GnRH-stimulated expression of α-subunit and LHb as well as expression of PACAP and the PAC₁ receptor. PACAP also stimulates expression of GnRH-R and enhances GnRH signaling. On the other hand, PACAP suppresses Fshb and GnRH-R expression indirectly by stimulating follistatin (FST) expression in gonadotrophs and folliculo-stellate cells, which neutralizes stimulation of Fshb and GnRH-R by activin.

Figure 4.

Hypothalamic (PVN) and pituitary PACAP expression in the male rat during early maturation. PACAP expression in the PVN and pituitary decrease significantly between postnatal days 17 and 29. There is parallel decrease in pituitary follistatin (FST) expression and a reciprocal rise for the gonadotropin subunits (LHb and Fshb) and GnRH-R.

Figure 5.

Schematic representation of a model elucidating the possible role of pituitary PACAP expression in the ontogeny of sexual development in the perinatal period. In late fetal life, pituitary PACAP expression is very high and stimulates expression of αGSU and LHb. PACAP stimulation also produces high levels of follistatin that effectively block activin signaling to GnRH-R and fshb. As the hypothalamic dopaminergic system develops, increased dopamine exposure activates type 2 dopamine receptors (Drd2) and thereby Gα_i which suppresses cAMP production and block the PACAP-stimulated cAMP feed-forward mechanism. As PACAP signaling declines, follistatin production is reduced, and activin is freed to stimulate GnRH-R and FSH synthesis, among other genes. The top graphs depict the rep orted changes in brain levels of GnRH (155), PACAP (156) and dopamine (132).