Pituitary Adenylate Cyclase-activating Polypeptide Stimulates Nitric-oxide Synthase Type I Expression and Potentiates the cGMP Response to Gonadotropin-releasing Hormone of Rat Pituitary Gonadotrophs

Abstract

Nitric-oxide synthase type I (NOS I) is expressed primarily in gonadotrophs and in folliculo-stellate cells of the anterior pituitary. In gonadotrophs, the expression and the activity of NOS I are stimulated by gonadotropin-releasing hormone (GnRH) under both experimental and physiological conditions. In the present study, we show that pituitary adenylate cyclase-activating polypeptide (PACAP) is twice as potent as GnRH at increasing NOS I levels in cultured rat anterior pituitary cells. The action of PACAP is detectable after 4–6 h and maximal at 24 h, this effect is mimicked by 8-bromo-cAMP and cholera toxin and suppressed by H89 suggesting a mediation through the cAMP pathway. Surprisingly, NADPH diaphorase staining revealed that these changes occurred in gonadotrophs exclusively although PACAP and cAMP, in contrast to GnRH, have the potential to target several types of pituitary cells including folliculo-stellate cells. There was no measurable alteration in NOS I mRNA levels after cAMP or PACAP induction. PACAP also stimulated cGMP synthesis, which was maximal within 15 min and independent of cAMP, however, only part resulted from NOS I/soluble guanylate cyclase activation implying that in contrast to GnRH, PACAP has a dual mechanism in cGMP production. Interestingly, induction of NOS I by PACAP markedly enhanced the capacity of gonadotrophs to produce cGMP in response to GnRH. The fact that PACAP may act on gonadotrophs to alter NOS I levels, generate cGMP, and potentiate the cGMP response to GnRH, suggests that cGMP could play important cellular functions. Nitric-oxide synthase type I (NOS I) is expressed primarily in gonadotrophs and in folliculo-stellate cells of the anterior pituitary. In gonadotrophs, the expression and the activity of NOS I are stimulated by gonadotropin-releasing hormone (GnRH) under both experimental and physiological conditions. In the present study, we show that pituitary adenylate cyclase-activating polypeptide (PACAP) is twice as potent as GnRH at increasing NOS I levels in cultured rat anterior pituitary cells. The action of PACAP is detectable after 4–6 h and maximal at 24 h, this effect is mimicked by 8-bromo-cAMP and cholera toxin and suppressed by H89 suggesting a mediation through the cAMP pathway. Surprisingly, NADPH diaphorase staining revealed that these changes occurred in gonadotrophs exclusively although PACAP and cAMP, in contrast to GnRH, have the potential to target several types of pituitary cells including folliculo-stellate cells. There was no measurable alteration in NOS I mRNA levels after cAMP or PACAP induction. PACAP also stimulated cGMP synthesis, which was maximal within 15 min and independent of cAMP, however, only part resulted from NOS I/soluble guanylate cyclase activation implying that in contrast to GnRH, PACAP has a dual mechanism in cGMP production. Interestingly, induction of NOS I by PACAP markedly enhanced the capacity of gonadotrophs to produce cGMP in response to GnRH. The fact that PACAP may act on gonadotrophs to alter NOS I levels, generate cGMP, and potentiate the cGMP response to GnRH, suggests that cGMP could play important cellular functions. Anterior pituitary gonadotrophs are endocrine cells that produce and secrete luteinizing hormone (LH) 1The abbreviations used for: LH, luteinizing hormone; CNP, C-type natriuretic peptide; GnRH, gonadotropin-releasing hormone; FSH, follicle-stimulating hormone; MAPK, mitogen-activated protein kinase; NO, nitric oxide; NOS, nitric-oxide synthase; NOS I, NOS type I or neuronal NOS; NOS II, NOS type II or inducible NOS; NOS III, NOS type III or endothelial NOS; l-NMMA, NOS inhibitor; ODQ, soluble guanylate cyclase inhibitor; PACAP, pituitary adenylate cyclase-activating polypeptide; PACAP38, the 38-amino acid form of PACAP; PACAP27, the 27-amino acid form of PACAP; PKA, protein kinase A; PKC, protein kinase C; sGC, soluble guanylate cyclase; TPA, 12-O-tetradecanoylphorbol-13-acetate; 8-Br-cAMP, 8-bromo-cAMP; IBMX, 3-isobutyl-1-methylxanthine; PBS, phosphate-buffered saline; RIA, radioimmunoassay. 1The abbreviations used for: LH, luteinizing hormone; CNP, C-type natriuretic peptide; GnRH, gonadotropin-releasing hormone; FSH, follicle-stimulating hormone; MAPK, mitogen-activated protein kinase; NO, nitric oxide; NOS, nitric-oxide synthase; NOS I, NOS type I or neuronal NOS; NOS II, NOS type II or inducible NOS; NOS III, NOS type III or endothelial NOS; l-NMMA, NOS inhibitor; ODQ, soluble guanylate cyclase inhibitor; PACAP, pituitary adenylate cyclase-activating polypeptide; PACAP38, the 38-amino acid form of PACAP; PACAP27, the 27-amino acid form of PACAP; PKA, protein kinase A; PKC, protein kinase C; sGC, soluble guanylate cyclase; TPA, 12-O-tetradecanoylphorbol-13-acetate; 8-Br-cAMP, 8-bromo-cAMP; IBMX, 3-isobutyl-1-methylxanthine; PBS, phosphate-buffered saline; RIA, radioimmunoassay. and follicle-stimulating hormone (FSH), two gonadotropins that are crucial for the control of the reproductive function. 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Full Text Full Text PDF PubMed Scopus Google Scholar). most of the pituitary endocrine types as well as folliculo-stellate cells have to to PACAP M. Endocr. Rev. Google Scholar). type that to PACAP activation of in to adenylate and M. Endocr. Rev. Google Scholar). In these cells PACAP a potent of cAMP of E. R. PubMed Scopus Google Scholar). to PACAP and suggesting of both GnRH several signaling among which are the activation of in the of and that are for protein kinase activation and GnRH also the activation of the mitogen-activated protein kinase and the of have that the two are the from the activation of R. Trends Endocrinol. Metab. 11: Full Text Full Text PDF PubMed Scopus Google and the from the of in the activation of nitric-oxide synthase type I PubMed Scopus Google Scholar, R. Endocrinol. PubMed Scopus Google Scholar). 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In its effect on NOS I protein that after a PACAP also a of The NOS I PACAP the capacity of pituitary cells to produce cGMP and the cGMP response of gonadotrophs to GnRH. that PACAP and GnRH to the signaling in these cells. PACAP27, PACAP38, 8-Br-cAMP, from and from and by Anterior pituitary from The cells the R. R. PubMed Scopus Google Scholar). in of and in at a cells for the min for the was to and the cells for at in a in as in the and h the of the the was and at for of release and the cells phosphate-buffered protein and as R. PubMed Google Scholar). The pituitary cells in and for min at and protein in the was to PubMed Scopus Google Scholar). in in a NOS I, NOS II, or NOS III specific at of and and the enhanced to The used in this was and R. PubMed Scopus Google Scholar). The of the to of the the pituitary and by J.J. Google Scholar, PubMed Scopus Google Scholar). 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