A FERTILIZATION PROMOTING PEPTIDE (FPP)-RELATED TRIPEPTIDE COMPETITIVELY INHIBITS RESPONSES TO FPP - A CAUSE OF MALE SUBFERTILITY

Fertilization promoting peptide (FPP; pGlu-Glu-ProNH(2)), a tripeptide structurally related to thyrotrophin releasing hormone (TRH; pGlu-His -ProNH(2)), is present in the prostate gland and seminal plasma of sev eral mammalian species. FPP has been shown not only to stimulate the c apacitation and fertilizing ability of epididymal mouse and ejaculated human spermatozoa, but also to inhibit spontaneous acrosome loss in m ouse spermatozoa. These results suggest a possible role in vivo for FP P to maximize the fertilizing potential of the few cells that reach th e ampulla. In this study we have investigated the effects of FPP-relat ed peptides on mouse sperm capacitation and the acrosome reaction (usi ng chlortetracycline fluorescence) and in vitro fertilizing ability. D eamidated FPP neither stimulated capacitation when tested at 50-200 nM nor interfered with FPP's stimulation of capacitation. Three neutral peptides (pGlu-Phe-ProNH(2), MeO-FPP, pGlu-Gln-ProNH(2)) were also eva luated. pGlu-Phe-ProNH(2), slightly stimulatory when used alone, had n o additive effect when used in combination with FPP and the methyl der ivative of FPP had no bioactivity itself and did not inhibit responses to FPP. In marked contrast, pGlu-Gln-ProNH(2) (Gln-FPP), which had no bioactivity when added to uncapacitated suspensions at 50-100 nM, sig nificantly inhibited FPP's stimulation of capacitation and fertilizing ability in vitro. Furthermore, when Gln-FPP + FPP were added to capac itated suspensions, Gln-FPP prevented FPP's inhibition of spontaneous acrosome loss. Our recent studies have indicated that FPP and adenosin e can elicit similar responses but appear to act at different sites. T he fact that Gln-FPP inhibited responses to FPP, but not to adenosine, indicates that Gln-FPP is acting at an FPP-specific site. We, therefo re, conclude that the specific structure of the FPP molecule is crucia l for biological activity. Removal of the terminal amide group abolish es bioactivity and changes to the central amino acid can have signific ant functional consequences. Since Gln-FPP is a candidate intermediate peptide in the FPP biosynthetic pathway and has been identified in hu man semen, abnormality in prostate function could lead to release of G ln-FPP along with, or instead of, FPP. Our results suggest that the re lative proportions of FPP and related peptides in seminal plasma could have a significant effect on fertility in vivo. (C) 1997 Wiley-Liss, Inc.