Activin and inhibin
|Locus||Chr. 2 q33-qter|
|inhibin, beta A|
The Activin dimer, from 2ARV.pdb
|Alt. symbols||activin A|
|Locus||Chr. 7 p15-p13|
|inhibin, beta B|
|Alt. symbols||activin B|
|Locus||Chr. 2 cen-q13|
|inhibin, beta C|
|Alt. symbols||activin C|
|Locus||Chr. 12 q13|
|inhibin, beta E|
|Alt. symbols||activin E|
|Locus||Chr. 12 q13.2|
Activin and inhibin are two closely related protein complexes that have almost directly opposite biological effects. Identified in 1990, activin enhances FSH biosynthesis and secretion, and participates in the regulation of the menstrual cycle. Many other functions have been found to be exerted by activin, including roles in cell proliferation, differentiation, apoptosis, metabolism, homeostasis, immune response, wound repair, and endocrine function. Conversely inhibin downregulates FSH synthesis and inhibits FSH secretion.
Activin is a dimer composed of two identical or very similar beta subunits. Inhibin is also a dimer wherein the first component is a beta subunit similar or identical to the beta subunit in activin. However, in contrast to activin, the second component of the inhibin dimer is a more distantly-related alpha subunit. Activin, inhibin and a number of other structurally related proteins such as anti-Müllerian hormone, bone morphogenetic protein, and growth differentiation factor belong to the TGF-β protein superfamily.
The activin and inhibin protein complexes are both dimeric in structure, and, in each complex, the two monomers are linked to one another by a single disulfide bond. In addition, both complexes are derived from the same family of related genes and proteins but differ in their subunit composition. Below is a list of the most common inhibin and activin complexes and their subunit composition:
In mammals, four beta subunits have been described, called activin βA, activin βB, activin βC and activin βE. Activin βA and βB are identical to the two beta subunits of inhibin. A fifth subunit, activin βD, has been described in Xenopus laevis. Two activin βA subunits give rise to activin A, one βA, and one βB subunit gives rise to activin AB, and so on. Various, but not all theoretically possible, heterodimers have been described. The subunits are linked by a single covalent disulfide bond.
- In the ovarian follicle, activin increases FSH binding and FSH-induced aromatization. It participates in androgen synthesis enhancing LH action in the ovary and testis. In the male, activin enhances spermatogenesis.
- Activin is strongly expressed in wounded skin, and overexpression of activin in epidermis of transgenic mice improves wound healing and enhances scar formation. Its action in wound repair and skin morphogenesis is through stimulation of keratinocytes and stromal cells in a dose-dependent manner.
- Activin also regulates the morphogenesis of branching organs such as the prostate, lung, and especially kidney. Activin A increased the expression level of type-I collagen suggesting that activin A acts as a potent activator of fibroblasts.
- Lack of activin during development results in neural developmental defects.
In both females and males, inhibin inhibits FSH production. Inhibin does not inhibit the secretion of GnRH from the hypothalamus (First Aid for the USMLE Step1, 2012 (McGraw Hill), page 534) However, the overall mechanism differs between the sexes:
- Inhibin A reaches its peak in the mid-luteal phase.
It is secreted from the Sertoli cells, located in the seminiferous tubules inside the testes. Androgens stimulate inhibin production; this protein may also help to locally regulate spermatogenesis.
Mechanism of action
As with other members of the superfamily, activins interact with two types of cell surface transmembrane receptors (Types I and II) which have intrinsic serine/threonine kinase activities in their cytoplasmic domains:
Activin binds to the Type II receptor and initiates a cascade reaction that leads to the recruitment, phosphorylation, and activation of Type I activin receptor. This then interacts with and then phosphorylates SMAD2 and SMAD3, two of the cytoplasmic SMAD proteins.
Smad3 then translocates to the nucleus and interacts with SMAD4 through multimerization, resulting in their modulation as transcription factor complexes responsible for the expression of a large variety of genes.
In contrast to activin, much less is known about the mechanism of action of inhibin, but may involve competing with activin for binding to activin receptors and/or binding to inhibin-specific receptors.
Quantification of inhibin A is part of the prenatal quad screen that can be administered during pregnancy at a gestational age of 16–18 weeks. An elevated inhibin A (along with an increased beta-hCG, decreased AFP, and a decreased estriol) is suggestive of the presence of a fetus with Down syndrome. As a screening test, abnormal quad screen test results need to be followed up with more definitive tests.
Inhibin B may be used as a marker of spermatogenesis function and male infertility. The mean serum inhibin B level is significantly higher among fertile men (approximately 140 pg/mL) than in infertile men (approximately 80 pg/mL). In men with azoospermia, a positive test for inhibin B slightly raises the chances for successfully achieving pregnancy through testicular sperm extraction (TESE), although the association is not very substantial, having a sensitivity of 0.65 (95% confidence interval [CI]: 0.56–0.74) and a specificity of 0.83 (CI: 0.64–0.93) for prediction the presence of sperm in the testes in non-obstructive azoospermia.
- Asashima M, Nakano, H, Shimada KK, Kei I, Shibai H, Ueno N (March 1990). "Mesodermal induction in early amphibian embryos by activin A (erythroid differentiation factor)". Roux's Archives of Developmental Biology 198 (6): 330–335. doi:10.1007/BF00383771.
- Chen YG, Wang Q, Lin SL, Chang CD, Chuang J, Chung J, Ying SY (May 2006). "Activin signaling and its role in regulation of cell proliferation, apoptosis, and carcinogenesis". Exp. Biol. Med. (Maywood) 231 (5): 534–44. PMID 16636301.
- Sulyok S, Wankell M, Alzheimer C, Werner S (October 2004). "Activin: an important regulator of wound repair, fibrosis, and neuroprotection". Mol. Cell. Endocrinol. 225 (1–2): 127–32. doi:10.1016/j.mce.2004.07.011. PMID 15451577.
- van Zonneveld P, Scheffer G, Broekmans F, Blankenstein M, de Jong F, Looman C, Habbema J, te Velde E (2003). "Do cycle disturbances explain the age-related decline of female fertility? Cycle characteristics of women aged over 40 years compared with a reference population of young women". Hum Reprod 18 (3): 495–501. doi:10.1093/humrep/deg138. PMID 12615813.
- Burger HG, Igarashi M (April 1988). "Inhibin: definition and nomenclature, including related substances". The Journal of Clinical Endocrinology and Metabolism 66 (4): 885–6. PMID 3346366.
- Robertson DM, Burger HG, Fuller PJ (March 2004). "Inhibin/activin and ovarian cancer". Endocrine-related Cancer 11 (1): 35–49. doi:10.1677/erc.0.0110035. PMID 15027884.
- Kingsley DM (January 1994). "The TGF-beta superfamily: new members, new receptors, and new genetic tests of function in different organisms". Genes & Development 8 (2): 133–46. doi:10.1101/gad.8.2.133. PMID 8299934.
- Ying SY (December 1987). "Inhibins and activins: chemical properties and biological activity". Proc. Soc. Exp. Biol. Med. 186 (3): 253–64. PMID 3122219.
- Xu P, Hall AK (November 2006). "The role of activin in neuropeptide induction and pain sensation". Dev. Biol. 299 (2): 303–9. doi:10.1016/j.ydbio.2006.08.026. PMID 16973148.
- Deli A, Kreidl E, Santifaller S, Trotter B, Seir K, Berger W, Schulte-Hermann R, Rodgarkia-Dara C, Grusch M (March 2008). "Activins and activin antagonists in hepatocellular carcinoma". World J. Gastroenterol. 14 (11): 1699–709. doi:10.3748/wjg.14.1699. PMC 2695910. PMID 18350601.
- Mellor SL, Cranfield M, Ries R, Pedersen J, Cancilla B, de Kretser D, Groome NP, Mason AJ, Risbridger GP (December 2000). "Localization of activin beta(A)-, beta(B)-, and beta(C)-subunits in humanprostate and evidence for formation of new activin heterodimers of beta(C)-subunit". The Journal of Clinical Endocrinology and Metabolism 85 (12): 4851–8. doi:10.1210/jc.85.12.4851. PMID 11134153.
- Bamberger C, Schärer A, Antsiferova M, Tychsen B, Pankow S, Müller M, Rülicke T, Paus R, Werner S (September 2005). "Activin Controls Skin Morphogenesis and Wound Repair Predominantly via Stromal Cells and in a Concentration-Dependent Manner via Keratinocytes". Am. J. Pathol. 167 (3): 733–47. doi:10.1016/S0002-9440(10)62047-0. PMC 1698729. PMID 16127153.
- Skinner M, McLachlan R, Bremner W (1989). "Stimulation of Sertoli cell inhibin secretion by the testicular paracrine factor PModS". Mol Cell Endocrinol 66 (2): 239–49. doi:10.1016/0303-7207(89)90036-1. PMID 2515083.
- citation needed
- Aitken D, Wallace E, Crossley J, Swanston I, van Pareren Y, van Maarle M, Groome N, Macri J, Connor J (1996). "Dimeric inhibin A as a marker for Down syndrome in early pregnancy". N Engl J Med 334 (19): 1231–6. doi:10.1056/NEJM199605093341904. PMID 8606718.
- Robertson D, Pruysers E, Jobling T (2007). "Inhibin as a diagnostic marker for ovarian cancer". Cancer Lett 249 (1): 14–7. doi:10.1016/j.canlet.2006.12.017. PMID 17320281.
- Robertson D, Pruysers E, Burger H, Jobling T, McNeilage J, Healy D (2004). "Inhibins and ovarian cancer". Mol Cell Endocrinol 225 (1–2): 65–71. doi:10.1016/j.mce.2004.02.014. PMID 15451569.
- Myers GM, Lambert-Messerlian GM, Sigman M (November 2008). "Inhibin B reference data for fertile and infertile men in Northeast America". Fertil. Steril. 92 (6): 1920–3. doi:10.1016/j.fertnstert.2008.09.033. PMID 19006797.
- Toulis KA, Iliadou PK, Venetis CA, Tsametis C, Tarlatzis BC, Papadimas I, Goulis DG (2010). "Inhibin B and anti-Mullerian hormone as markers of persistent spermatogenesis in men with non-obstructive azoospermia: a meta-analysis of diagnostic accuracy studies". Hum. Reprod. Update 16 (6): 713–24. doi:10.1093/humupd/dmq024. PMID 20601364.
- Activin at eMedicine Dictionary
- Activin at the US National Library of Medicine Medical Subject Headings (MeSH)
- Inhibin at the US National Library of Medicine Medical Subject Headings (MeSH)
- Grusch M, Kreidl E (2008-08-01). "Activin and follistatin in liver biology and hepatocellular carcinoma". SciTopics. Elsevier. Archived from the original on 9 December 2008. Retrieved 2008-12-24.