Relaxin family peptide hormones

Relaxin family peptide hormones in humans are represented by 7 members: three relaxin-like (RLN) and four insulin-like (INSL) peptides. This subdivision into 2 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 [2] (e.g. RLN1, INSL4, INSL6).

See also: Insulin/IGF/Relaxin family
Relaxin 1
Identifiers
SymbolRLN1
Alt. symbolsH1
NCBI gene6013
HGNC10026
OMIM179730
RefSeqNM_006911
UniProtP04808
Other data
LocusChr. 9 qter-q12
Relaxin 2
Identifiers
SymbolRLN2
Alt. symbolsH2, RLXH2, bA12D24.1.1, bA12D24.1.2
NCBI gene6019
HGNC10027
OMIM179740
PDB6RLX
RefSeqNM_134441
UniProtP04090
Other data
LocusChr. 9 qter-q12
Relaxin 3
Identifiers
SymbolRLN3
Alt. symbolsZINS4, RXN3, H3
NCBI gene117579
HGNC17135
OMIM606855
RefSeqNM_080864
UniProtQ8WXF3
Other data
LocusChr. 19 p13.3
Insulin-like peptide 3
Identifiers
SymbolINSL3
Other data
LocusChr. 19
Insulin-like peptide 5
Identifiers
SymbolINSL5
Other data
LocusChr. 1

Genetics

In humans and many other tetrapods, the RLN/INSL-encoding genes exist in 4 distinct clusters. The largest cluster contains 4 loci: RLN1, RLN2, INSL4 and INSL6, situated in tandem on human chromosome 9 (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).

Functions

In humans

The physiological action of RLN and its tandem duplicates (RLN1, INSL4, INSL6) and INSL3 has been quite well studied in human and mouse- they are primarily associated with reproductive functions, such as the relaxation of uterine musculature and of the pubic symphysis during labor (RLN1 & RLN2), the progression of spermatogenesis (INSL6) and possibly trophoblast development (INSL4) and testicular descent and germ cell survival (INSL3), but the functions of INSL5 and RLN3 are relatively unexplored. Both RLN3 and INSL5 are thought to play important roles in neuroendocrine regulation. In the case of INSL5 this hypothesis is based on its expression (and also co-expression with its receptor) in the central nervous system (CNS), intestine and lymph nodes. At the same time, RLN3 is predominantly localized in the brain and locally affects selected regions of the CNS, such as those responsible for the sense of appetite and stress regulation. Moreover, it has been shown that RLN3 stimulates the hypothalamic-pituitary-gonadal (HPG) axis and hence affects levels of luteinizing hormone (LH) in the blood.[5]

In other vertebrates

Data available on the functions of relaxin family peptides in vertebrates other than human are very fragmented.

Receptors
Further information: Relaxin receptor

The receptors for the RLN/INSL peptides are collectively called “Relaxin family peptide receptors (RXFPs)”.[6] There are two distinct families of RXFPs, all of which are cell membrane-associated and coupled to G-proteins (known as G protein-coupled receptors or GPCRs). In humans there are 4 RXFP receptors: RXFP1 and RXFP2 are evolutionarily related to the receptors of follicle-stimulating and luteinizing hormones (FSH and LH, respectively), and are the cognate receptors for RLN and INSL3 respectively in humans.[6] On the other hand, RXFP3 and RXFP4 are related to somatostatin et al. 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 are found floating freely between the cytoplasm and nucleoplasm.[7]

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.[8][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,[9] 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 G-protein coupled receptor, which supports its relatedness to vertebrate relaxins.[10]

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 relaxin family peptide receptors compared to humans, which is attributable to the Fish-Specific Whole Genome Duplication and teleost-specific gene duplication.[11]

See also

References
  1. Sherwood OD (April 2004). "Relaxin's physiological roles and other diverse actions". Endocrine Reviews. 25 (2): 205–34. doi:10.1210/er.2003-0013. PMID 15082520.
  2. 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. 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): 73–8. doi:10.1007/s00239-012-9517-0. hdl:10533/127600. PMID 22961112. S2CID 9243065.
  5. McGowan BM, Stanley SA, Donovan J, Thompson EL, Patterson M, Semjonous NM, Gardiner JV, Murphy KG, Ghatei MA, Bloom SR (August 2008). "Relaxin-3 stimulates the hypothalamic-pituitary-gonadal axis". American Journal of Physiology. Endocrinology and Metabolism. 295 (2): E278-86. doi:10.1152/ajpendo.00028.2008. PMC 2519759. PMID 18492777.
  6. Bathgate RA, Kocan M, Scott DJ, Hossain MA, Good SV, Yegorov S, Bogerd J, Gooley PR (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. PMID 29458108. S2CID 3708498.
  7. 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: 256–71. doi:10.1196/annals.1282.039. PMID 15956716. S2CID 24814642.
  8. 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.
  9. Olinski RP, Dahlberg C, Thorndyke M, Hallböök F (November 2006). "Three insulin-relaxin-like genes in Ciona intestinalis". Peptides. 27 (11): 2535–46. doi:10.1016/j.peptides.2006.06.008. PMID 16920224. S2CID 6844537.
  10. 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: 241–5. doi:10.1016/j.ygcen.2012.07.015. PMID 22841765.
  11. 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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