Relaxin family peptide hormones

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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
Insulin-like peptide 3
Identifiers
SymbolINSL3
Other data
Locus Chr. 19
Insulin-like peptide 5
Identifiers
SymbolINSL5
Other data
Locus Chr. 1

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 (RLN and INSL) is based primarily on early findings, [1] and does not reflect the evolutionary origins or physiological differences between peptides. [2] 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. [2]

Contents

Genetics

In humans and many other tetrapods, the RLN/INSL-encoding genes exist in four distinct clusters. The largest cluster contains four loci: RLN1, RLN2, INSL4 and INSL6, situated in tandem on human chromosome 9. This cluster arose from multiple local gene duplications that took place in the ancestor of placental mammals. [3] [4] The other three RLN/INSL genes exist as single loci in two linkage groups: RLN3 (chromosome 19), INSL3 (chromosome 19, 3.8 Mb apart from RLN3) and INSL5 (chromosome 1).[ citation needed ]

Synthesis and Structure

All seven relaxin family peptide hormones are synthesized as pre-prohormones, and subsequently cleaved to form two chains stabilized by an intra-α-chain and two disulfide bonds. [5] Members of the human relaxin peptide family share a similar tertiary structure, composed of a β-chain, c-chain, and α-chain at their carboxyl-terminal. [5] [6] All members of the relaxin family peptide hormones bind to their cognate receptors via residues present in their α- and β-chains. [7]

Functions

The physiological action of RLN and its tandem duplicates (RLN1, INSL4, INSL6) and INSL3 has been quite well studied in humans and mouse models. They are primarily associated with reproductive functions, such as the relaxation of uterine musculature and of the pubic symphysis during labor (RLN1 & RLN2), [8] [6] the progression of spermatogenesis (INSL6) [7] and possibly trophoblast development (INSL4) and testicular descent and germ cell survival (INSL3).

INSL5 is produced by L-cells in the colon, plays a physiological role in food intake, and may regulate metabolism and energy balance. [7] RLN3 is thought to function in neuroendocrine regulation, and is predominantly expressed in the nucleus incertus (NI) of the hindbrain and locally affects regions of the central nervous system (CNS) including those responsible for appetite and stress regulation. [7] RLN3 has also been found to stimulate the hypothalamic-pituitary-gonadal (HPG) axis and hence affects levels of luteinizing hormone (LH) in the blood. [9]

Receptors

The receptors for the RLN/INSL peptides are collectively called “Relaxin family peptide receptors (RXFPs)”. [10] In humans there are four RXFP receptors (RXFP1-4) all of which are cell membrane-associated and coupled to G-proteins (known as G protein-coupled receptors or GPCRs). [7] There are two distinct families of RXFPs: RXFP1 and RXFP2 are evolutionarily related to the receptors of follicle-stimulating hormone (FSH) and LH, and are the cognate receptors for RLN and INSL3 respectively in humans. [10] On the other hand, RXFP3 and RXFP4 are related to somatostatin and, in humans, are the cognate receptors for RLN3 and INSL5. There is evidence that some relaxin hormones may also be able to interact with glucocorticoid-type nuclear receptors, which float freely between the cytoplasm and nucleoplasm. [11]

Receptor Genetics

Four RXFPs in humans are located in different linkage groups. Additionally there are two RXFP pseudogenes ("RXFP3-3" and "RXFP2-like") which have functional counterparts in other species. [12] [2]

Evolution

In early deuterostomes

The evolution of the gene family in primitive vertebrates is not well understood. For example, it has been shown that the gene coding for the ancestral relaxin peptide existed independently from the other genes of the insulin superfamily, i.e. INS and IGF genes, in the early chordate ancestor. [2]

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. [2] However the exact origins of the family still remain to be elucidated. Other studies attempted to show the existence of relaxin family peptide genes in the tunicate Ciona, [13] but it has not been shown that any of these are in the same linkage group as modern relaxin genes. Multiple relaxin genes have also been identified in Amphioxus, but again syntenic relationship of these genes to modern relaxin genes is unclear and experimental work is lacking. A relaxin-like peptide, previously referred to as “Gonad Stimulating Substance” was also characterized in the echinoderm Patiria pectinifera (starfish). There is evidence that the starfish peptide is involved in reproductive processes and functions via a GPCR, which supports its relatedness to vertebrate relaxins. [14]

In vertebrates

Relaxin peptides and their receptors are an example of vigorously diversified ligand-receptor systems in vertebrates. The number of peptides and their receptors is varied among vertebrates due to lineage specific gene loss and duplications [2] For example, teleost fish have almost twice as many RXFP compared to humans, which is attributable to the Fish-Specific Whole Genome Duplication and teleost-specific gene duplication. [15]

See also

Related Research Articles

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<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">Proopiomelanocortin</span> Mammalian protein found in Homo sapiens

Pro-opiomelanocortin (POMC) is a precursor polypeptide with 241 amino acid residues. POMC is synthesized in corticotrophs of the anterior pituitary from the 267-amino-acid-long polypeptide precursor pre-pro-opiomelanocortin (pre-POMC), by the removal of a 26-amino-acid-long signal peptide sequence during translation. POMC is part of the central melanocortin system.

<span class="mw-page-title-main">Somatostatin</span> Peptide hormone that regulates the endocrine system

Somatostatin, also known as growth hormone-inhibiting hormone (GHIH) or by several other names, is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones. Somatostatin inhibits insulin and glucagon secretion.

<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">Glucose-dependent insulinotropic polypeptide</span> Mammalian protein found in Homo sapiens

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

Relaxin is a protein hormone of about 6000 Da, first described in 1926 by Frederick Hisaw.

<span class="mw-page-title-main">Kisspeptin</span> Mammalian protein

Kisspeptins are proteins encoded by the KISS1 gene in humans. Kisspeptins are ligands of the G-protein coupled receptor, GPR54. Kiss1 was originally identified as a human metastasis suppressor gene that has the ability to suppress melanoma and breast cancer metastasis. Kisspeptin-GPR54 signaling has an important role in initiating secretion of gonadotropin-releasing hormone (GnRH) at puberty, the extent of which is an area of ongoing research. Gonadotropin-releasing hormone is released from the hypothalamus to act on the anterior pituitary triggering the release of luteinizing hormone (LH), and follicle stimulating hormone (FSH). These gonadotropic hormones lead to sexual maturation and gametogenesis. Disrupting GPR54 signaling can cause hypogonadotrophic hypogonadism in rodents and humans. The Kiss1 gene is located on chromosome 1. It is transcribed in the brain, adrenal gland, and pancreas.

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

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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">INSL4</span> Protein-coding gene in the species Homo sapiens

Early placenta insulin-like peptide is a protein that in humans is encoded by the INSL4 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.

<i>Patiria pectinifera</i> Species of starfish

Patiria pectinifera, the blue bat star, is a species of starfish in the family Asterinidae. It is found in the northern Pacific Ocean along the coasts of Japan, China and Russia. It is used as a model organism in developmental biology.

<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

  1. ↑ Sherwood OD (April 2004). "Relaxin's physiological roles and other diverse actions". Endocrine Reviews. 25 (2): 205–234. doi: 10.1210/er.2003-0013 . PMID   15082520.
  2. 1 2 3 4 5 6 Yegorov S, Good S (2012). "Using paleogenomics to study the evolution of gene families: origin and duplication history of the relaxin family hormones and their receptors". PLOS ONE. 7 (3): e32923. Bibcode:2012PLoSO...732923Y. doi: 10.1371/journal.pone.0032923 . PMC   3310001 . PMID   22470432.
  3. ↑ Wilkinson TN, Speed TP, Tregear GW, Bathgate RA (February 2005). "Evolution of the relaxin-like peptide family". BMC Evolutionary Biology. 5 (14): 14. doi: 10.1186/1471-2148-5-14 . PMC   551602 . PMID   15707501.
  4. ↑ Arroyo JI, Hoffmann FG, Good S, Opazo JC (August 2012). "INSL4 pseudogenes help define the relaxin family repertoire in the common ancestor of placental mammals". Journal of Molecular Evolution. 75 (1–2): 73–78. Bibcode:2012JMolE..75...73A. doi:10.1007/s00239-012-9517-0. hdl: 10533/127600 . PMID   22961112. S2CID   9243065.
  5. 1 2 Roby KF (January 2019). "Relaxin". Reference Module in Biomedical Sciences. Elsevier. ISBN   978-0-12-801238-3.
  6. 1 2 Penn AA (January 2017). "Relaxin". In Polin RA, Abman SH, Rowitch DH, Benitz WE (eds.). Reference Module in Biomedical Sciences (Fifth ed.). Elsevier. pp. 134–144.e4. doi:10.1016/B978-0-12-801238-3.97212-X. ISBN   978-0-323-35214-7. S2CID   239355053.
  7. 1 2 3 4 5 Patil NA, Rosengren KJ, Separovic F, Wade JD, Bathgate RA, Hossain MA (May 2017). "Relaxin family peptides: structure-activity relationship studies". British Journal of Pharmacology. 174 (10): 950–961. doi:10.1111/bph.13684. PMC   5406294 . PMID   27922185.
  8. ↑ Creasy and Resnik's Maternal-Fetal Medicine: Principles and Practice (8th ed.). www.elsevier.com. Retrieved 2022-09-29.
  9. ↑ McGowan BM, Stanley SA, Donovan J, Thompson EL, Patterson M, Semjonous NM, et al. (August 2008). "Relaxin-3 stimulates the hypothalamic-pituitary-gonadal axis". American Journal of Physiology. Endocrinology and Metabolism. 295 (2): E278–E286. doi:10.1152/ajpendo.00028.2008. PMC   2519759 . PMID   18492777.
  10. 1 2 Bathgate RA, Kocan M, Scott DJ, Hossain MA, Good SV, Yegorov S, et al. (July 2018). "The relaxin receptor as a therapeutic target - perspectives from evolution and drug targeting". Pharmacology & Therapeutics. 187: 114–132. doi:10.1016/j.pharmthera.2018.02.008. hdl: 1874/377562 . PMID   29458108. S2CID   3708498.
  11. ↑ Dschietzig T, Bartsch C, Greinwald M, Baumann G, Stangl K (May 2005). "The pregnancy hormone relaxin binds to and activates the human glucocorticoid receptor". Annals of the New York Academy of Sciences. 1041 (1): 256–271. Bibcode:2005NYASA1041..256D. doi:10.1196/annals.1282.039. PMID   15956716. S2CID   24814642.
  12. ↑ Yegorov S, Bogerd J, Good SV (December 2014). "The relaxin family peptide receptors and their ligands: new developments and paradigms in the evolution from jawless fish to mammals". General and Comparative Endocrinology. 209: 93–105. doi:10.1016/j.ygcen.2014.07.014. PMID   25079565. S2CID   34136070.
  13. ↑ Olinski RP, Dahlberg C, Thorndyke M, Hallböök F (November 2006). "Three insulin-relaxin-like genes in Ciona intestinalis". Peptides. 27 (11): 2535–2546. doi:10.1016/j.peptides.2006.06.008. PMID   16920224. S2CID   6844537.
  14. ↑ Mita M (January 2013). "Relaxin-like gonad-stimulating substance in an echinoderm, the starfish: a novel relaxin system in reproduction of invertebrates". General and Comparative Endocrinology. 181: 241–245. doi:10.1016/j.ygcen.2012.07.015. PMID   22841765.
  15. ↑ Good S, Yegorov S, Martijn J, Franck J, Bogerd J (15 June 2012). "New insights into ligand-receptor pairing and coevolution of relaxin family peptides and their receptors in teleosts". International Journal of Evolutionary Biology. 2012 (310278): 310278. doi: 10.1155/2012/310278 . PMC   3449138 . PMID   23008798.
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