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Precursors of a-Inhibin Modulate Follicle-Stimulating Hormone Receptor Binding and Biological Activity^*

Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital Boston, Massachusetts 02114
the Department of Urology, University of Rochester Medical Center (P.M.S.) Rochester, New York 14642
the Laboratory of Molecular Neuroendocrinobgy, Center for Molecular Biology (R.S.) University of Heidelberg, Germany

Address requests for reprints to: Dr. Alan L. Schneyer, Reproductive Endocrinology Unit, Massachusetts General Hospital, BHX-5, Harvard University School of Medicine, Boston, Massachusetts 02114.

Abstract

Although several forms of monomeric -inhibin have been isolated from follicular fluid, no biological function has yet been ascribed to these posttranslationally processed forms of the -subunit precursor protein. Moreover, previous studies of a FSH receptor binding competitor (FRBC) isolated and characterized from porcine follicular fluid (pFF) suggested certain biochemical similarities between this protein and ainhibin precursors. We, therefore, investigated the hypothesis that -inhibin and/or its precursors might represent autocrine and/or paracrine modulators of FSH action in the ovary, accounting for some of this FRBC activity and thereby exerting some degree of regulation over follicular maturation,

Three separate sources of -inhibin proteins were investigated for FRBC activity, including pFF, human FF (hFF), and a 293 cell line into which the full-length human -inhibin cDNA had been stably transfected. Conditioned medium from these transfected cells contained several forms of -inhibtn precursors as well as mature -inhibin, but no β-subunit or intact inhibin. -Inhibin proteins from all three sources, purified by a variety of methods, including immunoaffinity chromatography on an anti--inhibin column, inhibited FSH binding to both natural tissue FSH receptors as well as recombinant rat FSH receptors expressed in 293 cells. Furthermore, dimeric inhibin and activin, medium from untransfected 293 cells, and non--inhibin-containing purification fractions were inactive in either assay. In addition, purified recombinant -inhibin proteins were partial in vitro FSH antagonists in a bioassay in which cAMP generation from 293 cells expressing the recombinant FSH receptor is used as an index of FSH biological activity. These same fractions of hFF containing FRBC activity did not bind to LH receptors, thereby demonstrating receptor specificity for this activity. Using sodium dodecyl sul fate -poly aery lam ide gel electrophoresis and Western blotting with -inhibin or FRBC antisera, a 57,000 mol wt protein was identified in FRBC-active fractions from all three sources, suggesting that the active moiety was the fulllength -inhibin precursor protein or a large mol wt fragment, but not mature -inhibin. Lastly, all FRBC activity from all three sources was extracted by an -inhibin immunoaffinity column and was recoverable upon elution.

These results demonstrate that proteins derived from the ainhibin precursor modulate FSH binding to its receptor as well as its biological activity. Since -inhibin precursors have been reported in FF at concentrations exceeding 2.5 µg/ml, the potency of the FSH antagonism determined for -inhibin is consistent with a potential physiological role for -inhibin as an autocrine or paracrine FSH modulator.(Endocrinology 129: 1987–1999, 1991)

Footnotes

^* This work was supported in part by NIH Grants HD-25941 (to A.L.S.), HD-19302 (to P.M.S.), and HD-15080 and HD-1578S (to W.F.C.).

Received May 10, 1991.

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