Relaxin

Last updated
Relaxin 1
Relaxin.png
Identifiers
SymbolRLN1
Alt. symbolsH1
NCBI gene 6013
HGNC 10026
OMIM 179730
RefSeq NM_006911
UniProt P04808
Other data
Locus Chr. 9 qter-q12
Search for
Structures Swiss-model
Domains InterPro
Relaxin 2
Identifiers
SymbolRLN2
Alt. symbolsH2, RLXH2, bA12D24.1.1, bA12D24.1.2
NCBI gene 6019
HGNC 10027
OMIM 179740
PDB 6RLX
RefSeq NM_134441
UniProt P04090
Other data
Locus Chr. 9 qter-q12
Search for
Structures Swiss-model
Domains InterPro
Relaxin 3
Identifiers
SymbolRLN3
Alt. symbolsZINS4, RXN3, H3
NCBI gene 117579
HGNC 17135
OMIM 606855
RefSeq NM_080864
UniProt Q8WXF3
Other data
Locus Chr. 19 p13.3
Search for
Structures Swiss-model
Domains InterPro

Relaxin is a protein hormone of about 6000 Da, [1] first described in 1926 by Frederick Hisaw. [2] [3]

Contents

The relaxin family peptide hormones belong to the insulin superfamily and consists of seven peptides of high structural but low sequence similarity; relaxin-1 (RLN1), 2 (RLN2) and 3 (RLN3), and the insulin-like (INSL) peptides, INSL3, INSL4, INSL5 and INSL6. The functions of relaxin-3, INSL4, INSL5, and INSL6 remain uncharacterised. [4] [5]

Synthesis

In the female, relaxin is produced by the corpus luteum of the ovary, the breast and, during pregnancy, also by the placenta, chorion, and decidua. In the male, it is produced in the prostate and is present in human semen. [6]

Structure

Structurally, relaxin is a heterodimer of two peptide chains of 24 and 29 amino acids linked by three [7] disulfide bridges, and it appears related to insulin. [8]

Relaxin is produced from its prohormone, "prorelaxin", by post-translational proteolytic cleavage of its signal peptide and C domain peptide. [9]

Function in humans

Reproduction

In females, relaxin is produced mainly by the corpus luteum, in both pregnant and nonpregnant females. [1] Relaxin levels rise to a peak within approximately 14 days of ovulation, and then decline in the absence of pregnancy, resulting in menstruation. [10] Relaxin may be involved in the vital process of decidualisation, working alongside steroid hormones to allow the endometrium to prepare for implantation. [11] During the first trimester of pregnancy, levels rise and additional relaxin is produced by the decidua. Blood plasma levels of relaxin peak during the first trimester (8-12 weeks) at 1.2 ng/mL and subsequently drop following demise of the corpus luteum. [12] In pregnancy, relaxin mediates the hemodynamic changes that occur such as increased cardiac output and increased renal blood flow. [13] [14]

Relaxin is believed to relax the uterine muscle and to loosen the ligaments holding the pelvic bones together, in order to prepare the birth canal for the birth. It may cause a woman to feel that other ligaments are looser, such as in the shoulders, knees, hips, and ankles. [15]

In males, relaxin enhances motility of sperm in semen. Also, relaxin is found in higher than normal concentrations in the ejaculate of men who were born without their vas deferens and seminal vesicles. [16]

Cardiovascular function

In the cardiovascular system, relaxin is secreted by the heart [17] and functions as a vasodilator mainly through the nitric oxide pathway. Other mechanisms include activation of NFκB leading to vascular endothelial growth factor (VEGF), activation of PI3K/Akt-associated signaling pathways, [18] and matrix metalloproteinases transcription. [19] In ex vivo experiments using subcutaneous resistance arteries, relaxin has shown to be a powerful endothelium-dependent vasodilator. [17]

Via upregulation of VEGF, relaxin also plays a key role in blood vessel formation (angiogenesis) during pregnancy, tumour development or ischaemic wounds. [20]

Function in other animals

Reproduction

In animals, relaxin widens the pubic bone and facilitates labor; it also softens the cervix (cervical ripening), and softens the pubic symphysis in rat and guinea pig models. [13] Thus, for a long time, relaxin was looked at as a pregnancy hormone. However, its significance may reach much further. Relaxin may affect collagen metabolism, inhibiting collagen synthesis and enhancing its breakdown by increasing matrix metalloproteinases. [21] It also enhances angiogenesis and is a potent renal vasodilator.[ citation needed ]

In horses (Equus caballus), relaxin is also an important hormone involved in pregnancy; however, before pregnancy occurs, relaxin is expressed by ovarian structures during the oestrous cycle. [22] Prior to ovulation, relaxin will be produced by ovarian stromal cells, which will promote secretion of gelatinases and tissue inhibitors of metalloproteinases. These enzymes will then aid the process of ovulation, which will lead to the release of a developed follicle into the fallopian tube. [22] Furthermore, granular and theca cells in the follicles will express relaxin in increasing levels depending on their size. [22] During early pregnancy, the preimplantation conceptus will express relaxin, which will promote angiogenesis in the endometrium by up-regulating VEGF. [22] [23] This will allow the endometrium to prepare for implantation. In horses alone, the embryo in the uterus will express relaxin mRNA at least 8 days after ovulation. Then as the conceptus develops expression will increase, which is likely to promote embryo development. [22]

In addition to relaxin production by the horse embryo, the maternal placenta is the main source of relaxin production, whereas in most animals the main source of relaxin is the corpus luteum. [22] Placental trophoblast cells produce relaxin, however, the size of the placenta does not determine the level of relaxin production. This is seen because different breeds of horses show different relaxin levels. [24] From 80 day of gestation onwards, relaxin levels will increase in the mare's serum with levels peaking in late gestation. [24] [25] Moreover, the pattern of relaxin expression will follow the expression of oestrogen, however, there is not yet a known link between these two hormones. [25] During labour, there is a spike in relaxin 3–4 hours before delivery, which is involved in myometrial relaxation and softening of the pelvic ligaments to aid preparation of the birth canal for the delivery of the horse foetus. [22] [24] Following birth, the levels of relaxin will gradually decrease if the placenta is also delivered, however, if the placenta is retained in the mare then the levels will remain high. [24] In addition, if the mare undergoes an abortion then the relaxin levels will decline as the placenta ceases to function. [24]

Cardiovascular function

Relaxin has been shown to relax vascular smooth muscle cells and increase nitric oxide production in rat endothelial cells, thus playing a role in regulation of cardiovascular function by dilating systemic resistance arteries. [19] Relaxin increases the rate and force of cardiac contraction in rat models and has been found to promote maturation of cardiomyocytes in mice. [20]

Several animal studies have found relaxin to have a cardioprotective function against ischaemia and reperfusion injury, by reducing cellular damage, via anti-apoptotic and anti-inflammatory effects.[ citation needed ] Relaxin has been shown to reduce cardiac fibrosis in animal models by inhibiting cardiac fibroblasts secreting collagen and stimulating matrix metalloproteinase. [20] [19]

In the European rabbit ( Oryctolagus cuniculus ), relaxin is associated with squamous differentiation and is expressed in tracheobronchial epithelial cells as opposed to being involved with reproduction. [26]

Receptors

Relaxin interacts with the relaxin receptor LGR7 (RXFP1) and LGR8 (RXFP2), which belong to the G protein-coupled receptor superfamily. [27] They contain a heptahelical transmembrane domain and a large glycosylated ectodomain, distantly related to the receptors for the glycoproteohormones, such as the LH-receptor or FSH-receptor.[ citation needed ]

Relaxin receptors have been found in the heart, smooth muscle, the connective tissue, and central and autonomous nervous system.[ citation needed ]

Disorders

Women who have been on relaxin treatment during unrelated clinical trials have experienced heavier bleeding during their menstrual cycle, suggesting that relaxin levels could play a role in abnormal uterine bleeding. [28] However, more research is needed to confirm relaxin as a direct cause.[ citation needed ]

A lower expression of relaxin has been found amongst women who have endometriosis. The research in this area is limited and more studying of relaxin's contribution could contribute greatly to the understanding of endometriosis. [28]

Specific disorders related to relaxin have not been heavily described, yet a link to scleroderma and fibromyalgia has also been suggested. [29]

Pregnancy

It is possible that relaxin in the placenta could be a contributing factor to inducing labour in humans and therefore serum relaxin levels during pregnancy have been linked to premature birth. [28]

Pharmacological targets

A recombinant form of human relaxin-2 has been developed as investigational drug RLX030 (serelaxin).[ citation needed ]

It is suggested that relaxin could be used as a therapeutic target when it comes to gynaecological disorders. [28]

Evolution

Relaxin 1 and relaxin 2 arose from the duplication of a proto-RLN gene between 44.2 and 29.6 million years ago in the last common ancestor of catarrhine primates. [30] The duplication that led to RLN1 and RLN2 is thought to have been a result of positive selection and convergent evolution at the nucleotide level between the relaxin gene in New World monkeys and the RLN1 gene in apes. [30] As a result, Old World monkeys, a group that includes the subfamilies colobines and cercopithecines, have lost the RLN1 paralog, but apes have retained both the RLN1 and the RLN2 genes. [30]

See also

Related Research Articles

<span class="mw-page-title-main">Insulin-like growth factor</span> Proteins similar to insulin that stimulate cell proliferation

The insulin-like growth factors (IGFs) are proteins with high sequence similarity to insulin. IGFs are part of a complex system that cells use to communicate with their physiologic environment. This complex system consists of two cell-surface receptors, two ligands, a family of seven high-affinity IGF-binding proteins, as well as associated IGFBP degrading enzymes, referred to collectively as proteases.

<span class="mw-page-title-main">Progesterone</span> Sex hormone

Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the major progestogen in the body. Progesterone has a variety of important functions in the body. It is also a crucial metabolic intermediate in the production of other endogenous steroids, including the sex hormones and the corticosteroids, and plays an important role in brain function as a neurosteroid.

<span class="mw-page-title-main">Luteinizing hormone</span> Gonadotropin secreted by the adenohypophysis

Luteinizing hormone is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (GnRH) from the hypothalamus. In females, an acute rise of LH known as an LH surge, triggers ovulation and development of the corpus luteum. In males, where LH had also been called interstitial cell–stimulating hormone (ICSH), it stimulates Leydig cell production of testosterone. It acts synergistically with follicle-stimulating hormone (FSH).

<span class="mw-page-title-main">Corpus luteum</span> Temporary endocrine structure in female ovaries

The corpus luteum is a temporary endocrine structure in female ovaries involved in the production of relatively high levels of progesterone, and moderate levels of estradiol, and inhibin A. It is the remains of the ovarian follicle that has released a mature ovum during a previous ovulation.

<span class="mw-page-title-main">Gonadotropin-releasing hormone</span> Mammalian protein found in Homo sapiens

Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is a tropic peptide hormone synthesized and released from GnRH neurons within the hypothalamus. The peptide belongs to gonadotropin-releasing hormone family. It constitutes the initial step in the hypothalamic–pituitary–gonadal axis.

<span class="mw-page-title-main">Luteal phase</span> The latter part of the menstrual cycle associated with ovulation and an increase in progesterone

The menstrual cycle is on average 28 days in length. It begins with menses during the follicular phase and followed by ovulation and ending with the luteal phase. Unlike the follicular phase which can vary in length among individuals, the luteal phase is typically fixed at approximately 14 days and is characterized by changes to hormone levels, such as an increase in progesterone and estrogen levels, decrease in gonadotropins such as follicle-stimulating hormone (FSH) and luteinizing hormone (LH), changes to the endometrial lining to promote implantation of the fertilized egg, and development of the corpus luteum. In the absence of fertilization by sperm, the corpus luteum atrophies leading to a decrease in progesterone and estrogen, an increase in FSH and LH, and shedding of the endometrial lining (menses) to begin the menstrual cycle again.

<span class="mw-page-title-main">Human placental lactogen</span> Polypeptide placental hormone in humans

Human placental lactogen (hPL), also called human chorionic somatomammotropin (hCS) or human chorionic somatotropin, is a polypeptide placental hormone, the human form of placental lactogen. Its structure and function are similar to those of human growth hormone. It modifies the metabolic state of the mother during pregnancy to facilitate energy supply to the fetus. hPL has anti-insulin properties. hPL is a hormone secreted by the syncytiotrophoblast during pregnancy. Like human growth hormone, hPL is encoded by genes on chromosome 17q22-24. It was identified in 1963.

<span class="mw-page-title-main">Neurokinin B</span> Chemical compound

Neurokinin B (NKB) belongs in the family of tachykinin peptides. Neurokinin B is implicated in a variety of human functions and pathways such as the secretion of gonadotropin-releasing hormone. Additionally, NKB is associated with pregnancy in females and maturation in young adults. Reproductive function is highly dependent on levels of both neurokinin B and also the G-protein coupled receptor ligand kisspeptin. The first NKB studies done attempted to resolve why high levels of the peptide may be implicated in pre-eclampsia during pregnancy. NKB, kisspeptin, and dynorphin together are found in the arcuate nucleus (ARC) known as the KNDy subpopulation. This subpopulation is targeted by many steroid hormones and works to form a network that feeds back to GnRH pulse generator.

The relaxin receptors are a subclass of four closely related G protein-coupled receptors (GPCR) that bind relaxin peptide hormones.

<span class="mw-page-title-main">Relaxin/insulin-like family peptide receptor 3</span> Protein-coding gene in the species Homo sapiens

Relaxin/insulin-like family peptide receptor 3, also known as RXFP3, is a human G-protein coupled receptor.

<span class="mw-page-title-main">Relaxin/insulin-like family peptide receptor 1</span> Protein-coding gene in the species Homo sapiens

Relaxin/insulin-like family peptide receptor 1, also known as RXFP1, is a human G protein coupled receptor that is one of the relaxin receptors. It is a rhodopsin-like GPCR which is unusual in this class as it contains a large extracellular binding and signalling domain. Some reports suggest that RXFP1 forms homodimers, however the most recent evidence indicates that relaxin binds a non-homodimer of RXFP1.

<span class="mw-page-title-main">Relaxin/insulin-like family peptide receptor 4</span> Protein-coding gene in the species Homo sapiens

Relaxin/insulin-like family peptide receptor 4, also known as RXFP4, is a human G-protein coupled receptor.

<span class="mw-page-title-main">Relaxin/insulin-like family peptide receptor 2</span> Protein-coding gene in the species Homo sapiens

Relaxin/insulin-like family peptide receptor 2, also known as RXFP2, is a human G-protein coupled receptor.

<span class="mw-page-title-main">INSL3</span> Protein-coding gene in the species Homo sapiens

Insulin-like 3 is a protein that in humans is encoded by the INSL3 gene.

<span class="mw-page-title-main">Insulin/IGF/Relaxin family</span> Group of proteins

The insulin/IGF/relaxin family is a group of evolutionary related proteins which possess a variety of hormonal activities. Family members in human include two subfamilies:

<span class="mw-page-title-main">Relaxin-3</span>

Relaxin-3 is a neuropeptide that was discovered in 2001, and which is highly conserved in species ranging from flies, fish, rodents and humans. Relaxin-3 is a member and ancestral gene of the relaxin family of peptides, which includes the namesake hormone relaxin which mediates peripheral actions during pregnancy and which was found to relax the pelvic ligament in guinea pigs almost a century ago. The cognate receptor for relaxin-3 is the G-protein coupled receptor RXFP3, however relaxin-3 is pharmacologically able to also cross react with RXFP1 and RXFP3.

<span class="mw-page-title-main">Relaxin family peptide hormones</span> Protein family

Relaxin family peptide hormones in humans are represented by seven members: three relaxin-like (RLN) and four insulin-like (INSL) peptides: RLN1, RLN2, RNL3, INSL3, INSL4, INSL5, INSL6. This subdivision into two classes is based primarily on early findings, and does not reflect the evolutionary origins or physiological differences between peptides. For example, it is known that the genes coding for RLN3 and INSL5 arose from one ancestral gene, and INSL3 shares origin with RLN2 and its multiple duplicates: RLN1, INSL4, INSL6.

Serelaxin is a medication which is marketed in Russia for the treatment of acute heart failure (AHF), targeting the relaxin receptor. It was also under development in other places in the world, including in the United States, Europe, and Asia, but ultimately was not marketed in these areas.

<span class="mw-page-title-main">Maternal recognition of pregnancy</span> Crucial aspect of carrying a pregnancy to full term

Maternal recognition of pregnancy is a crucial aspect of carrying a pregnancy to full term. Without maternal recognition to maintain pregnancy, the initial messengers which stop luteolysis and promote foetal implantation, growth and uterine development finish with nothing to replace them and the pregnancy is lost.

<span class="mw-page-title-main">Neohormone</span>

Neohormones are a group of recently evolved hormones primarily associated to the success of mammalian development. These hormones are specific to mammals and are not found in other vertebrates—this is because neohormones are evolved to enhance specific mammalian functions. In males, neohormones play important roles in regulating testicular descent and preparing the sperm for internal fertilisation. In females, neohormones are essential for regulating early pregnancy, mammary gland development lactation, and viviparity. Neohormones superimpose their actions on the hypothalamic-pituitary-gonadal axis and are not associated with other core bodily functions.

References

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  2. ↑ "If a Gopher Can Do It …". Time Magazine. 1944-04-10. Archived from the original on December 15, 2008. Retrieved 2009-05-20.
  3. ↑ Becker GJ, Hewitson TD (March 2001). "Relaxin and renal fibrosis". Kidney International. 59 (3): 1184–5. doi: 10.1046/j.1523-1755.2001.0590031184.x . PMID   11231378.
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  7. ↑ Haugaard-Kedström, Linda M.; Hossain, Mohammed Akhter; Daly, Norelle L.; Bathgate, Ross A. D.; Rinderknecht, Ernst; Wade, John D.; Craik, David J.; Rosengren, K. Johan (20 March 2015). "Solution Structure, Aggregation Behavior, and Flexibility of Human Relaxin-2". ACS Chemical Biology. 10 (3): 891–900. doi:10.1021/cb500918v. PMID   25547165 . Retrieved 22 January 2023.
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  18. ↑ Chen TY, Li X, Hung CH, Bahudhanapati H, Tan J, Kass DJ, Zhang Y (April 2020). "The relaxin family peptide receptor 1 (RXFP1): An emerging player in human health and disease". Molecular Genetics & Genomic Medicine. 8 (4): e1194. doi:10.1002/mgg3.1194. PMC   7196478 . PMID   32100955.
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