Cysteine residues in a synthetic peptide corresponding to human follicle-stimulating hormone beta-subunit receptor-binding domain 81-95 [hFSH-beta-(81-95)] modulate the in vivo effects of hFSH-beta-(81-95) on the mouse estrous cycle
P. Grasso et al., Cysteine residues in a synthetic peptide corresponding to human follicle-stimulating hormone beta-subunit receptor-binding domain 81-95 [hFSH-beta-(81-95)] modulate the in vivo effects of hFSH-beta-(81-95) on the mouse estrous cycle, REGUL PEPT, 81(1-3), 1999, pp. 67-71
We have previously reported that synthetic peptide amides corresponding to
subdomains of the human FSH beta-subunit, hFSH-beta-(33-53) and hFSH-beta-(
81-95), interact with the external domain of the FSH receptor in two in vit
ro model systems. Consistent with these in vitro observations, we found tha
t intraperitoneal (i.p.) administration of each of these peptides prolonged
vaginal estrus in normally cycling mice in vivo. Both hFSH-beta-(33-53) an
d hFSH-beta-(81-95) contain cysteine (Cys) residues with free sulfhydryl gr
oups of potential significance in receptor interactions. To assess the poss
ible involvement of these groups in the in vivo effects of hFSH-beta-(33-53
) and hFSH-beta-(81-95), synthetic peptide analogs were prepared in which a
ll Cys residues were replaced with serine (Ser). In the present study, we d
emonstrate that the in vivo effect of hFSH-beta-(33-53) on the mouse estrou
s cycle, extension of vaginal estrus, was not changed by substitution of Cy
s-51 with Ser. In contrast, mice receiving the Ser-substituted analog of hF
SH-beta-(81-95) had normal estrus stages, but were arrested in diestrus. hF
SH-beta-(33-53)-(81-95), a linear peptide encompassing both domains, also p
rolonged vaginal estrus. The Ser-substituted analog of this peptide, howeve
r, prolonged vaginal estrus in some of the mice tested and induced cycle ar
rest at diestrus in others. hFSH-beta-(90-95), the active subdomain at the
C-terminus of hFSH-beta-(81-95), extended vaginal estrus, but diestrus stag
es were of normal duration. Its Ser-substituted analog, however, prolonged
the estrus stage of the majority of mice treated, but induced diestrus arre
st in some. The differing responses to these peptides are presumably due to
interactions of the synthetic peptides with different regions of the FSH r
eceptor. This further suggests that one consequence of ligand interaction w
ith multiple receptor binding domains may be variable effects on ovarian fu
nction, and that Cys to Ser analogs may have value in the design of a novel
class of synthetic peptides capable of fertility regulation and control. (
C) 1999 Elsevier Science B.V. All rights reserved.