Relaxin family peptide hormones

Relaxin 1
Identifiers
Symbol	RLN1
Alt. symbols	H1
Entrez	6013
HUGO	10026
OMIM	179730
RefSeq	NM_006911
UniProt	P04808
Other data
Locus	Chr. 9 qter-q12

Relaxin 2
Identifiers
Symbol	RLN2
Alt. symbols	H2, RLXH2, bA12D24.1.1, bA12D24.1.2
Entrez	6019
HUGO	10027
OMIM	179740
PDB	6RLX
RefSeq	NM_134441
UniProt	P04090
Other data
Locus	Chr. 9 qter-q12

Relaxin 3
Identifiers
Symbol	RLN3
Alt. symbols	ZINS4, RXN3, H3
Entrez	117579
HUGO	17135
OMIM	606855
RefSeq	NM_080864
UniProt	Q8WXF3
Other data
Locus	Chr. 19 p13.3

Insulin-like peptide 3
Identifiers
Symbol	INSL3
Other data
Locus	Chr. 19

Insulin-like peptide 5
Identifiers
Symbol	INSL5
Other data
Locus	Chr. 1

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).

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 human

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 placentals and vertebrates

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

Receptors

The receptors for the RLN/INSL peptides are collectively called “Relaxin family peptide receptors (RXFPs)”. 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. 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.^[6]

Genetics of relaxin family peptide receptors

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.^[2]

Evolution of relaxin peptides and their receptors

In early vertebrates and 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,^[7] 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.^[8]

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.^[9]

See also

• Relaxin receptor
• Relaxin/insulin-like family peptide receptor 1

References

1. Sherwood, David (2004). "Relaxin's physiological roles and other diverse actions". Endocrine Reviews. 25 (2): 205–234. doi:10.1210/er.2003-0013. PMID 15082520.
2. Yegorov, Sergey; Good, Sara (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 (3): e32923. doi:10.1371/journal.pone.0032923. PMC 3310001. PMID 22470432.
3. Wilkinson, Tracy N; Speed TP; Tregear GW; Bathgate RA (2005). "Evolution of the relaxin-like peptide family". BMC Evolutionary Biology. 5 (14). doi:10.1186/1471-2148-5-14. PMC 551602. PMID 15707501.
4. Arroyo, José Ignacio; Hoffmann FG; Good S; Opazo JC. (September 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. PMID 22961112.
5. McGowan, B.M.; Stanley SA; Donovan J; Thompson EL; Patterson M; Semjonous NM; Gardiner JV; Murphy KG; Ghatei MA; Bloom SR (2008). "Relaxin-3 stimulates the hypothalamic-pituitary-gonadal axis.". American Journal of Physiology. Endocrinology and Metabolism. 295 (2): E278–286. doi:10.1152/ajpendo.00028.2008. PMC 2519759. PMID 18492777.
6. Dschietzig, Thomas; Bartsch C; Greinwald M; Baumann G; Stangl K (2006). "The pregnancy hormone relaxin binds to and activates the human glucocorticoid receptor". Annals of the New York Academy of Sciences. 1041: 256–271. doi:10.1196/annals.1282.039. PMID 15956716.
7. Olinski, Robert Piotr; 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.
8. Mita, Masatoshi (25 July 2012). "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.
9. Good, Sara; Sergey Yegorov; Joran Martijn; Jens Franck; Jan Bogerd (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.