HUMAN INHIBIN A

Mr approx. 32,000 (mature inhibin). Additional Mr forms of 55,000–105,000 exist due to the processing of the precursor (Mr 105,000).5 pI 6.9–7.3. Stable in 8M urea. Dissociated to two subunits in 2% (v/v) 2-mercaptoethanol

The inhibin α- and β-subunits are encoded by separate genes. The human inhibin α-subunit gene, INHA, location 2q35, consists of two exons. The α-subunit mRNA has 1098 b that encode a precursor comprised of three domains: the prodomain, the αN domain, and the αC domain. The human βA-subunit gene, INHBA, location 7p14.1, consists of two exons. The human βB-subunit gene, INHBB, location 2q14.2, consists of two exons. The INHBA and INHBB mRNAs have 1278 and 1221 b, respectively. The precursor β-subunits consist of a prodomain at the N terminus and a mature βA or βB domain at the C terminus. The coexpression of inhibin α- and β-subunit genes suggests the production of inhibin molecules. In females, mRNAs for α-, βA-, and βB-subunits are localized in the granulosa cells of mammals, birds, and fish. mRNAs for α- and βA-subunits are localized in the luteal cells of humans and primates and in the placenta of mice and humans. In males, α-, βA-, and βB-subunit mRNAs are localized in Sertoli cells and Leydig cells. These mRNAs are also detected in the adrenal cortex.

FSH, cAMP, and forskolin stimulate the secretion of inhibins from granulosa cells and Sertoli cells in various mammals. Inhibin production from granulosa cells is suppressed by the epidermal growth factor (EGF). Inhibin production in primate and human luteal cells is promoted by the luteinizing hormone (LH) and human chorionic gonadotropin (hCG). Adrenocorticotropic hormone (ACTH) stimulates inhibin secretion from adrenal cortex cells. In the chicken, theca cell-derived bone morphogenetic protein (BMP) stimulates inhibin production from granulosa cells.6 In zebrafish, oocyte-derived BMP stimulates inhibin production from ovarian follicle cells.

A specific receptor for inhibin has not been identified. It is now accepted that inhibin actions result from the antagonism of activin signaling in the presence of betaglycan. Human betaglycan (type III TGF-β receptor) has 851 aa residues that are expressed on the surface of pituitary cells, granulosa cells, theca cells, Sertoli cells, Leydig cells, and adrenal cortex cells. It consists of an extracellular domain, a transmembrane region, and a short intracellular domain but lacks a signaling domain. Inhibins bind to activin type II receptors via their β-subunits, and to betaglycan via the α-subunit to form a stable complex. The complex occupies activin type II receptors and prevents activin from activation of the type I receptors, resulting in a blockade of the Smad 2/3 signaling pathway.

Inhibins suppress the expression of the FSH β-subunit in the pituitary, and thereby regulate gonadal functions and development. In addition, inhibins have paracrine and autocrine effects in various cells. Inhibin α-subunit gene knockout mice develop Sertoli cell tumors in males and granulosa cell tumors in females. When the knockout mice were gonadectomized, the life expectancy increased; however, these mice developed adrenal tumors around 30 weeks of age. Inhibin βA-subunit gene knockout mice die perinatally and have defects in tooth, palate, and retinal formation.

From the findings that inhibin α-subunit knockout mice develop gonadal and adrenal tumors, the α-subunit gene is expected to act as a tumor suppressor gene. However, no consistent gene mutations have been identified in cancer patients. Correlated with tumor growth, inhibin production is enhanced in several types of adrenal and gonadal tumors. Women affected with premature ovarian failure show low serum levels of inhibin A and inhibin B. A decrease in testicular inhibin B production is noted in men with testicular dysfunction. Pregnancies affected with Down’s syndrome accompany high circulating concentrations of inhibin A. Hyperplasia of the adrenal cortex (Cushing’s syndrome) often raises inhibin A secretion from the adrenal gland.

Inhibin is a glycoprotein, a member of the transforming growth factor (TGF)-β superfamily. Inhibin is secreted mainly from the gonads and inhibits follicle-stimulating hormone (FSH) secretion from the anterior pituitary and in turn regulates gonadal function and development. The presence of FSH-inhibiting activity had been reported in the gonads since the 1970s, and the FSHinhibiting factor “inhibin” was first isolated in 1985 from porcine1 and bovine follicular fluid.

Inhibin levels in the circulation are a reliable marker for granulosa cell tumors and serous and mucinous epithelial carcinomas. This may be true for granulosa cell tumors in mares. Evaluation of plasma inhibin A levels until the second trimester of pregnancy is useful for screening for Down’s syndrome. The circulating inhibin B is a good predictor for the conditions of spermatogenesis. High levels of inhibin are noted in humans, rats, and dogs with Leydig cell tumors, whereas a low level clinically suggests a premature ovarian failure.

Inhibins and activins are structurally related glycoprotein hormones. Inhibins are disulfide-linked heterodimers composed of an α-subunit and either a βA-subunit (inhibin A) or a βB-subunit (inhibin B), whereas activins are homodimers or heterodimers made up of βA- and βB-subunits. The monomeric α-subunit, devoid of FSHsuppressing activity, has also been identified in follicular fluid. The α-subunit has N-linked glycosylation sites and their degree of glycosylation modifies biological activity. An approximate 80% identity is seen in the sequences of the human, porcine, bovine, and rat α-subunits . The mature βA-subunit shares the same aa sequence among the above species while the βB-subunit shows an approximate 90% identity. The human βA- and βB-subunits share 64% aa sequence identity.