Activin and inhibin are two closely related
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
complexes that have almost directly opposite biological effects. Identified in 1986,
activin enhances
FSH biosynthesis
Biosynthesis, i.e., chemical synthesis occurring in biological contexts, is a term most often referring to multi-step, enzyme-Catalysis, catalyzed processes where chemical substances absorbed as nutrients (or previously converted through biosynthe ...
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
Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
,
metabolism
Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...
,
homeostasis
In biology, homeostasis (British English, British also homoeostasis; ) is the state of steady internal physics, physical and chemistry, chemical conditions maintained by organism, living systems. This is the condition of optimal functioning fo ...
,
immune response,
wound repair,
and
endocrine function. Conversely, inhibin downregulates FSH synthesis and inhibits FSH secretion. The existence of inhibin was hypothesized as early as 1916; however, it was not demonstrated to exist until
Neena Schwartz and
Cornelia Channing's work in the mid-1970s, after which both proteins were molecularly characterized ten years later.
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.
Structure
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:

The alpha and beta subunits share approximately 25%
sequence similarity, whereas the similarity between beta subunits is approximately 65%.
In mammals, four beta subunits have been described, called activin β
A, activin β
B, activin β
C and activin β
E. Activin β
A and β
B are identical to the two beta subunits of inhibin. A fifth subunit, activin β
D, has been described in ''
Xenopus laevis''. Two activin β
A subunits give rise to activin A, one β
A, and one β
B 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.
The
βC subunit is able to form activin heterodimers with β
A or β
B subunits but is unable to dimerize with inhibin α.
Function
Activin
Activin is produced in the
gonad
A gonad, sex gland, or reproductive gland is a Heterocrine gland, mixed gland and sex organ that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gon ...
s,
pituitary gland,
placenta, and other organs:
* In the
ovarian follicle, activin increases FSH binding and FSH-induced
aromatization. It participates in
androgen
An androgen (from Greek ''andr-'', the stem of the word meaning ) is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This includes ...
synthesis enhancing
LH action in the
ovary
The ovary () is a gonad in the female reproductive system that produces ova; when released, an ovum travels through the fallopian tube/ oviduct into the uterus. There is an ovary on the left and the right side of the body. The ovaries are end ...
and
testis. In the male, activin enhances
spermatogenesis.
* Activin is strongly expressed in wounded
skin
Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation.
Other animal coverings, such as the arthropod exoskeleton, have different ...
, and overexpression of activin in
epidermis of
transgenic mice improves wound healing and enhances
scar
A scar (or scar tissue) is an area of fibrosis, fibrous tissue that replaces normal skin after an injury. Scars result from the biological process of wound repair in the skin, as well as in other Organ (anatomy), organs, and biological tissue, t ...
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
The lungs are the primary Organ (biology), organs of the respiratory system in many animals, including humans. In mammals and most other tetrapods, two lungs are located near the Vertebral column, backbone on either side of the heart. Their ...
, 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.
*Upregulation of Activin A drives pluripotent
stem cells into a mesoendodermal fate, and thus provides a useful tool for stem cell
differentiation and
organoid formation.
Inhibin
In both females and males, inhibin inhibits
FSH production. Inhibin does not inhibit the secretion of GnRH from the hypothalamus.
However, the overall mechanism differs between the sexes:
In females
Inhibin is produced in the
gonads,
pituitary gland,
placenta,
corpus luteum and other organs.
FSH stimulates the secretion of inhibin from the
granulosa cells of the ovarian follicles in the
ovaries
The ovary () is a gonad in the female reproductive system that produces ova; when released, an ovum travels through the fallopian tube/oviduct into the uterus. There is an ovary on the left and the right side of the body. The ovaries are endocr ...
. In turn, inhibin suppresses FSH.
* ''Inhibin B'' reaches a peak in the early- to mid-
follicular phase, and a second peak at
ovulation.
* ''Inhibin A'' reaches its peak in the mid-
luteal phase.
Inhibin secretion is diminished by
GnRH, and enhanced by
insulin-like growth factor-1 (IGF-1).
In males
It is secreted from the
Sertoli cells, located in the
seminiferous tubules inside the
testes.
Androgens stimulate inhibin production; this
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
may also help to locally regulate
spermatogenesis.
Mechanism of action
Activin
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 type 1 receptors:
ACVR1,
ACVR1B,
ACVR1C
*
Activin type 2 receptors:
ACVR2A,
ACVR2B
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
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...
complexes responsible for the expression of a large variety of genes.
Inhibin
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.
Clinical significance
Activin
Activin A is more plentiful in the
adipose tissue of obese, compared to lean persons.
Activin A promotes the proliferation of
adipocyte progenitor cells, while inhibiting their
differentiation into adipocytes.
Activin A also increases inflammatory
cytokines in
macrophage
Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
s.
A
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...
in the gene for the activin receptor
ACVR1 results in
fibrodysplasia ossificans progressiva, a fatal disease that causes muscle and soft tissue to gradually be replaced by bone tissue.
This condition is characterized by the formation of an extra skeleton that produces immobilization and eventually death by suffocation.
The mutation in ACVR1 causes activin A, which normally acts as an antagonist of the receptor and blocks
osteogenesis (bone growth), to behave as an agonist of the receptor and to induce hyperactive bone growth.
On 2 September 2015,
Regeneron Pharmaceuticals announced that they had developed an
antibody
An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as pathogenic bacteria, bacteria and viruses, includin ...
for
activin A that effectively cures the disease in an
animal model of the condition.
Mutations in the ACVR1 gene have also been linked to cancer, especially
diffuse intrinsic pontine glioma(DIPG).
Elevated Activin B levels with normal Activin A levels provided a possible
biomarker for
myalgic encephalomyelitis/chronic fatigue syndrome.
Activin A is overexpressed in many
cancer
Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
s. It was shown to promote
tumorigenesis by hampering the
adaptive anti-tumor immune response in
melanoma.
Inhibin
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.
It also has been used as a marker for
ovarian cancer.
Inhibin B may be used as a marker of
spermatogenesis function and
male infertility
Male infertility refers to a sexually mature male's inability to impregnate a fertile female. Male infertility can wholly or partially account for 40% of infertility among couples who are trying to have children. "A problem with the male is the s ...
. 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.
References
External links
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*
*
{{DEFAULTSORT:Activin And Inhibin
Mammal reproductive system
Hormones of the ovary
Peptide hormones
TGFβ domain
Human female endocrine system