Endogenous betaglycan is essential for high-potency inhibin antagonism in gonadotropes.
Inhibins are endocrine hormones that regulate gametogenesis and reproduction through a negative feedback loop with FSH. Inhibin action involves antagonism of signaling by activin or other TGFbeta family ligands. In transfection assays, antagonism by inhibin can be potentiated by betaglycan, a coreceptor for selected TGFbeta family ligands. We tested whether betaglycan is an obligate inhibin coreceptor through disruption of betaglycan function by RNA interference-mediated knockdown and immunoneutralization. Betaglycan knockdown and anti-betaglycan IgG each independently prevented inhibin-A binding to betaglycan and reversed functional effects of transfected betaglycan. Neither betaglycan immunoneutralization nor knockdown affected activin responsiveness in cell lines or in rat anterior pituitary cultures. Betaglycan knockdown decreased the potency of inhibin antagonism of activin-induced FSH secretion in primary gonadotropes. Similarly, anti-betaglycan IgG decreased the potency of inhibin antagonism in primary gonadotropes in a dose-dependent manner, with a reduction in the sensitivity to inhibin-A of greater than 1000-fold. These data establish that betaglycan is an endogenous inhibin coreceptor required for high-sensitivity inhibin antagonism of activin signaling in rat anterior pituitary gonadotropes.
Wiater
Ezra
E
Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Lewis
Kathy A
KA
Donaldson
Cynthia
C
Vaughan
Joan
J
Bilezikjian
Louise
L
Vale
Wylie
W
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004526:Efficiency; D052681:Gonadotrophs / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007265:Inhibins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D011509:Proteoglycans / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D000906:Antibodies; D011509:Proteoglycans; D034741:RNA, Small Interfering; D018125:Receptors, Transforming Growth Factor beta; C422362:inhibin A; C071736:betaglycan; D007265:Inhibins