Generating FSH antagonists and agonists through immunization against FSH receptor N-terminal decapeptides.
Follicle-stimulating hormone (FSH) via interaction with G-protein coupled specific receptors plays a central role in the control of gametogenesis in mammals of both sexes. In females, FSH is crucial for follicle growth, follicle maturation and ovulation. FSH receptors, together with luteinizing hormone-chorionic gonadotropin and thyrotropin receptors belong to a subfamily of structurally related receptors within the seven transmembrane receptor family. Among several other regions, the N-terminus of these receptors is believed to be responsible for important specific hormone-receptor contact sites. Recombinant filamentous phages displaying at their surface three overlapping N-terminal decapeptides of the FSH receptor, peptides A18-27, B25-34 and C29-38 were constructed. Ewes and female mice were immunized against the three FSH receptor (FSHR) recombinant phages. Immunoglobulins purified from immunized animals were analyzed for their biochemical properties on a Chinese hamster ovary cell line expressing the porcine FSH receptor. AntiA and antiB immunoglobulins (IgGs) behave as antagonists for 125I-FSH binding and for FSH-dependent cAMP production, while antiC IgGs did not compete for hormone binding. By contrast, antibodies against the C29-38 peptide displayed FSH agonist activity and stimulated the FSH receptor, whereas antiA and antiB IgGs did not. Furthermore, when the FSHR phages were used as peptidic vaccines, they induced a reversible inhibition of ovulation rate in ewes, and impaired fertility in female mice.
Abdennebi
L
L
Unité Récepteurs et Communications Cellulaires, INRA-Biotechnologies, 78352 Jouy-en-Josas, France.
Couture
L
L
Grebert
D
D
Pajot
E
E
Salesse
R
R
Remy
J J
JJ
D000595:Amino Acid Sequence; D000818:Animals; D001435:Bacteriophages / Q000235:genetics; D016466:CHO Cells; D006224:Cricetinae; D000242:Cyclic AMP / Q000096:biosynthesis; D005260:Female; D005298:Fertility; D005640:Follicle Stimulating Hormone / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007114:Immunization; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010060:Ovulation; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D011247:Pregnancy; D011962:Receptors, FSH / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D012756:Sheep; D013552:Swine
D010446:Peptide Fragments; D011962:Receptors, FSH; D005640:Follicle Stimulating Hormone; D000242:Cyclic AMP