Activin andinhibin are two closely relatedproteincomplexes that have almost directly opposite biological effects. Identified in 1986,[1][2] activin enhancesFSHbiosynthesis andsecretion, and participates in the regulation of themenstrual cycle. Many other functions have been found to be exerted by activin, including roles in cell proliferation,differentiation,apoptosis,[3]metabolism,homeostasis,immune response,wound repair,[4] andendocrine function. Conversely, inhibin downregulates FSH synthesis and inhibits FSH secretion.[5] The existence of inhibin was hypothesized as early as 1916; however, it was not demonstrated to exist untilNeena Schwartz andCornelia Channing's work in the mid-1970s, after which both proteins were molecularly characterized ten years later.[6]
Activin is adimer 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.[7][8] Activin, inhibin and a number of other structurally related proteins such asanti-Müllerian hormone,bone morphogenetic protein, andgrowth differentiation factor belong to theTGF-β protein superfamily.[9]
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 singledisulfide bond.[10] In addition, both complexes are derived from the same family of related genes and proteins but differ in their subunit composition.[7] Below is a list of the most common inhibin and activin complexes and their subunit composition:
Schematic diagram of the 1D structures of inhibin and activin. The black line between the monomers represents a disulfide bond.
The alpha and beta subunits share approximately 25%sequence similarity, whereas the similarity between beta subunits is approximately 65%.[9]
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 inXenopus 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.[11][12] The subunits are linked by a single covalent disulfide bond.
TheβC subunit is able to form activin heterodimers with βA or βB subunits but is unable to dimerize with inhibin α.[13]
Activin also regulates themorphogenesis of branching organs such as theprostate,lung, and especiallykidney. Activin A increased the expression level oftype-I collagen suggesting that activin A acts as a potent activator offibroblasts.
Lack of activin during development results in neural developmental defects.
Upregulation of Activin A drives pluripotentstem cells into a mesoendodermal fate, and thus provides a useful tool for stem celldifferentiation andorganoid formation.[15]
In both females and males, inhibin inhibitsFSH production. Inhibin does not inhibit the secretion of GnRH from the hypothalamus.[16][17] However, the overall mechanism differs between the sexes:
As with other members of the superfamily, activins interact with two types of cell surfacetransmembrane receptors (Types I and II) which have intrinsicserine/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 phosphorylatesSMAD2 andSMAD3, two of the cytoplasmicSMAD proteins.
Smad3 then translocates to the nucleus and interacts withSMAD4 through multimerization, resulting in their modulation astranscription 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.[8]
Amutation in the gene for the activin receptorACVR1 results infibrodysplasia ossificans progressiva, a fatal disease that causes muscle and soft tissue to gradually be replaced by bone tissue.[21] This condition is characterized by the formation of an extra skeleton that produces immobilization and eventually death by suffocation.[21] The mutation in ACVR1 causes activin A, which normally acts as an antagonist of the receptor and blocksosteogenesis (bone growth), to behave as an agonist of the receptor and to induce hyperactive bone growth.[21] On 2 September 2015,Regeneron Pharmaceuticals announced that they had developed anantibody foractivin A that effectively cures the disease in ananimal model of the condition.[22]
Quantification of inhibin A is part of the prenatalquad screen that can be administered during pregnancy at a gestational age of 16–18 weeks. An elevated inhibin A (along with an increasedbeta-hCG, decreasedAFP, and a decreasedestriol) is suggestive of the presence of a fetus withDown syndrome.[28] 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 ofspermatogenesis function andmale 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).[31] In men withazoospermia, a positive test for inhibin B slightly raises the chances for successfully achieving pregnancy throughtesticular 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.[32]
^Vale W, Rivier J, Vaughan J, McClintock R, Corrigan A, Woo W, et al. (1986). "Purification and characterization of an FSH releasing protein from porcine ovarian follicular fluid".Nature.321 (6072):776–9.Bibcode:1986Natur.321..776V.doi:10.1038/321776a0.PMID3012369.S2CID4365045.
^Sulyok S, Wankell M, Alzheimer C, Werner S (October 2004). "Activin: an important regulator of wound repair, fibrosis, and neuroprotection".Molecular and Cellular Endocrinology.225 (1–2):127–32.doi:10.1016/j.mce.2004.07.011.PMID15451577.S2CID6943949.
^abBurger HG, Igarashi M (April 1988). "Inhibin: definition and nomenclature, including related substances".The Journal of Clinical Endocrinology and Metabolism.66 (4):885–6.PMID3346366.
^Ying SY (December 1987). "Inhibins and activins: chemical properties and biological activity".Proceedings of the Society for Experimental Biology and Medicine.186 (3):253–64.doi:10.3181/00379727-186-42611a.PMID3122219.S2CID36872324.
^Xu P, Hall AK (November 2006). "The role of activin in neuropeptide induction and pain sensation".Developmental Biology.299 (2):303–9.doi:10.1016/j.ydbio.2006.08.026.PMID16973148.
^Luisi S, Florio P, Reis FM, Petraglia F (2005). "Inhibins in female and male reproductive physiology: role in gametogenesis, conception, implantation and early pregnancy".Human Reproduction Update.11 (2):123–35.doi:10.1093/humupd/dmh057.PMID15618291.
^abcShore EM, Xu M, Feldman GJ, Fenstermacher DA, Cho TJ, Choi IH, et al. (May 2006). "A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva".Nature Genetics.38 (5):525–527.doi:10.1038/ng1783.PMID16642017.S2CID41579747.
^Robertson DM, Pruysers E, Jobling T (April 2007). "Inhibin as a diagnostic marker for ovarian cancer".Cancer Letters.249 (1):14–7.doi:10.1016/j.canlet.2006.12.017.PMID17320281.
^Robertson DM, Pruysers E, Burger HG, Jobling T, McNeilage J, Healy D (October 2004). "Inhibins and ovarian cancer".Molecular and Cellular Endocrinology.225 (1–2):65–71.doi:10.1016/j.mce.2004.02.014.PMID15451569.S2CID33801243.
