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{{protein
{{for|the [[Miles Davis]] album|Relaxin' with the Miles Davis Quintet}}
{{infobox protein
| Name = Relaxin 1
| Name = Relaxin 1
| caption =  
| caption =  
| image =  
| image = relaxin.png
| width =  
| width =  
| HGNCid = 10026
| HGNCid = 10026
| Symbol = RLN1
| Symbol = RLN1
| AltSymbols =  
| AltSymbols = H1
| EntrezGene = 6013
| EntrezGene = 6013
| OMIM = 179730
| OMIM = 179730
| RefSeq =  
| RefSeq = NM_006911
| UniProt =  
| UniProt = P04808
| PDB =  
| PDB =  
| ECnumber =  
| ECnumber =  
Line 18: Line 19:
| LocusSupplementaryData = -q12
| LocusSupplementaryData = -q12
}}
}}
{{protein
{{infobox protein
| Name = Relaxin 2
| Name = Relaxin 2
| caption =  
| caption =  
Line 25: Line 26:
| HGNCid = 10027
| HGNCid = 10027
| Symbol = RLN2
| Symbol = RLN2
| AltSymbols =  
| AltSymbols = H2, RLXH2, bA12D24.1.1, bA12D24.1.2
| EntrezGene = 6019
| EntrezGene = 6019
| OMIM = 179740
| OMIM = 179740
| RefSeq =  
| RefSeq = NM_134441
| UniProt =  
| UniProt = P04090
| PDB =  
| PDB = 6RLX
| ECnumber =  
| ECnumber =  
| Chromosome = 9
| Chromosome = 9
Line 37: Line 38:
| LocusSupplementaryData = -q12
| LocusSupplementaryData = -q12
}}
}}
{{protein
{{infobox protein
| Name = Relaxin 3
| Name = Relaxin 3
| caption =  
| caption =  
Line 44: Line 45:
| HGNCid = 17135
| HGNCid = 17135
| Symbol = RLN3
| Symbol = RLN3
| AltSymbols =  
| AltSymbols = ZINS4, RXN3, H3
| EntrezGene = 117579
| EntrezGene = 117579
| OMIM = 606855
| OMIM = 606855
| RefSeq =  
| RefSeq = NM_080864
| UniProt =  
| UniProt = Q8WXF3
| PDB =  
| PDB =  
| ECnumber =  
| ECnumber =  
Line 55: Line 56:
| Band = 13.3
| Band = 13.3
| LocusSupplementaryData =  
| LocusSupplementaryData =  
}}
}}'''Relaxin''' is a [[protein]] [[hormone]] of about 6000 Da<ref name="pmid9112071">{{cite journal | vauthors = Bani D | title = Relaxin: a pleiotropic hormone | journal = General Pharmacology | volume = 28 | issue = 1 | pages = 13–22 | date = January 1997 | pmid = 9112071 | doi = 10.1016/s0306-3623(96)00171-1 }}</ref> first described in 1926 by Frederick Hisaw.<ref name="urlIf a Gopher Can Do It ... - TIME">{{cite web | url = http://www.time.com/time/magazine/article/0,9171,796530,00.html | title = If a Gopher Can Do It … | date = 1944-04-10 | website = | publisher = Time Magazine | pages = | quote = | access-date = 2009-05-20}}</ref><ref name="pmid11231378">{{cite journal | vauthors = Becker GJ, Hewitson TD | title = Relaxin and renal fibrosis | journal = Kidney International | volume = 59 | issue = 3 | pages = 1184–5 | date = March 2001 | pmid = 11231378 | doi = 10.1046/j.1523-1755.2001.0590031184.x }}</ref>
{{SI}}
 
__NOTOC__
The relaxin-like peptide family belongs in the insulin superfamily and consists of 7 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, INSL6 remain uncharacterised.<ref name="pmid15707501">{{cite journal | vauthors = Wilkinson TN, Speed TP, Tregear GW, Bathgate RA | title = Evolution of the relaxin-like peptide family | journal = BMC Evolutionary Biology | volume = 5 | pages = 14 | date = February 2005 | pmid = 15707501 | pmc = 551602 | doi = 10.1186/1471-2148-5-14 }}</ref>
{{GS}}
 
==Synthesis==
In the female, it 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.<ref name="pmid2011710">{{cite journal | vauthors = MacLennan AH | title = The role of the hormone relaxin in human reproduction and pelvic girdle relaxation | journal = Scandinavian Journal of Rheumatology. Supplement | volume = 88 | issue =  | pages = 7–15 | year = 1991 | pmid = 2011710 | doi =  }}</ref>
 
== Structure ==
{{See also|Insulin/IGF/Relaxin family}}
Structurally, relaxin is a [[heterodimer]] of two peptide chains of 24 and 29 [[amino acid]]s linked by [[disulfide]] bridges, and it appears related to [[insulin]].{{Citation needed|date=October 2018}}
 
Relaxin is produced from its [[prohormone]], "prorelaxin", by splitting off one additional peptide chain reaction.{{Citation needed|date=October 2018}}
 
== Function ==


===In humans===


In females, relaxin is produced mainly by the [[corpus luteum]], in both pregnant and nonpregnant females.<ref name="pmid9112071" /> Relaxin levels rise to a peak within approximately 14 days of [[ovulation]], and then decline in the absence of pregnancy, resulting in [[menstruation]]. {{Citation needed|date=August 2013}} Relaxin may be involved in the vital process of [[Decidualization|decidualisation]], working alongside [[Steroid hormone|steroid hormones]] to allow the [[endometrium]] to prepare for [[Implantation (human embryo)|implantation]].<ref>{{cite journal | vauthors = Carp H, Torchinsky A, Fein A, Toder V | title = Hormones, cytokines and fetal anomalies in habitual abortion | journal = Gynecological Endocrinology | volume = 15 | issue = 6 | pages = 472–83 | date = December 2001 | pmid = 11826772 | doi = 10.1080/gye.15.6.472.483 }}</ref> During the [[Pregnancy|first trimester]] of pregnancy, levels rise and additional relaxin is produced by the [[decidua]]. Relaxin's peak is reached during the [[first trimester]] (14-weeks) and at delivery. Relaxin mediates the [[Hemodynamic response|hemodynamic]] changes that occur during pregnancy, such as increased [[cardiac output]], increased [[renal blood flow]], and increased [[Compliance (physiology)|arterial compliance]].{{Citation needed|date=October 2018}} It also relaxes other pelvic ligaments.<ref name="pmid21613576">{{cite journal | vauthors = Conrad KP | title = Maternal vasodilation in pregnancy: the emerging role of relaxin | journal = American Journal of Physiology. Regulatory, Integrative and Comparative Physiology | volume = 301 | issue = 2 | pages = R267-75 | date = August 2011 | pmid = 21613576 | pmc = 3154715 | doi = 10.1152/ajpregu.00156.2011 }}</ref>  It is believed to soften the [[pubic symphysis]].{{Citation needed|date=October 2018}}


In males, relaxin enhances motility of sperm in semen.<ref name="pmid2497805">{{cite journal | vauthors = Weiss G | title = Relaxin in the male | journal = Biology of Reproduction | volume = 40 | issue = 2 | pages = 197–200 | date = February 1989 | pmid = 2497805 | doi = 10.1095/biolreprod40.2.197 | url = http://www.biolreprod.org/cgi/reprint/40/2/197 | dead-url = yes | archive-url = https://web.archive.org/web/20081122033040/http://www.biolreprod.org/cgi/reprint/40/2/197 | archive-date = 2008-11-22 }}</ref>


'''Relaxin''' is a [[peptide hormone]] that was first described in 1926 by Frederick Hisaw.<ref>http://www.time.com/time/magazine/article/0,9171,796530,00.html</ref><ref>{{cite journal |author=Becker G, Hewitson T |title=Relaxin and renal fibrosis |journal=Kidney Int |volume=59 |issue=3 |pages=1184-5 |year=2001 |pmid=11231378}}</ref>
In the [[cardiovascular system]], relaxin works mainly by activating the [[nitric oxide]] pathway. Other mechanisms include activation of [[NFκB]] leading to [[vascular endothelial growth factor]] (VEGF) and [[matrix metalloproteinases]] transcription.<ref name=":0">{{cite journal | vauthors = Raleigh JM, Toldo S, Das A, Abbate A, Salloum FN | title = Relaxin' the Heart: A Novel Therapeutic Modality | journal = Journal of Cardiovascular Pharmacology and Therapeutics | volume = 21 | issue = 4 | pages = 353–62 | date = July 2016 | pmid = 26589290 | doi = 10.1177/1074248415617851 }}</ref>


Different forms of relaxin have been described: relaxin 1, 2, and 3.
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.<ref name=":0" /> Relaxin increases the rate and force of cardiac contraction in rat models.<ref name=":1">{{cite journal | vauthors = Feijóo-Bandín S, Aragón-Herrera A, Rodríguez-Penas D, Portolés M, Roselló-Lletí E, Rivera M, González-Juanatey JR, Lago F | title = Relaxin-2 in Cardiometabolic Diseases: Mechanisms of Action and Future Perspectives | language = English | journal = Frontiers in Physiology | volume = 8 | pages = 599 | date = 2017 | pmid = 28868039 | pmc = 5563388 | doi = 10.3389/fphys.2017.00599 }}</ref> Via upregulation of VEGF, relaxin plays a key role in blood vessel formation ([[angiogenesis|angiogenesis)]] during pregnancy, tumour development or ischaemic wounds.<ref name=":1" />


==Production==
===In other animals===
In the female, it is produced by the [[corpus luteum]] of the [[ovary]], the [[breast]] and, during [[pregnancy]], also by the [[placenta]], [[chorion]], and [[decidua]].  
In animals, relaxin widens the [[pubic bone]] and facilitates [[childbirth|labor]]; it also softens the [[cervix]] (cervical ripening), and relaxes the uterine musculature.{{Citation needed|date=October 2018}} Thus, for a long time, relaxin was looked at as a pregnancy hormone. However, its significance may reach much further. Relaxin may affects [[collagen]] metabolism, inhibiting collagen synthesis and enhancing its breakdown by increasing [[matrix metalloproteinase]]s.<ref>{{cite journal | vauthors = Mookerjee I, Solly NR, Royce SG, Tregear GW, Samuel CS, Tang ML | title = Endogenous relaxin regulates collagen deposition in an animal model of allergic airway disease | journal = Endocrinology | volume = 147 | issue = 2 | pages = 754–61 | date = February 2006 | pmid = 16254028 | doi = 10.1210/en.2005-1006 }}</ref>  It also enhances [[angiogenesis]] and is a potent renal [[vasodilator]].{{Citation needed|date=October 2018}}


In the male, relaxin is produced in the [[testes]].  
In the mouse model Relaxin has been found to promote maturation of [[cardiomyocytes]].<ref name=":1" />


==Structure==
Several animal studies have found relaxin to have a cardioprotective function against [[Myocardial ischaemia|ischaemia]] and [[reperfusion injury]], by reducing cellular damage, via anti-[[Apoptosis|apoptotic]] and [[anti-inflammatory]] effects.{{Citation needed|date=October 2018}} Relaxin has been shown to reduce [[cardiac fibrosis]] in animal models by inhibiting cardiac [[fibroblasts]] secreting [[collagen]] and stimulating [[matrix metalloproteinase]].<ref name=":1" /><ref name=":0" />
Structurally, relaxin is a [[heterodimer]] of two peptide chains of 24 and 29 [[amino acid]]s that are linked by [[disulfide]] bridges and it appears related to [[insulin]].  
Relaxin is produced from its [[prohormone]], “pro-relaxin”, by splitting off one additional peptide chain.  


==Function==
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.<ref name="Arroyo_2012">{{cite journal | vauthors = Arroyo JI, Hoffmann FG, Opazo JC | title = Gene duplication and positive selection explains unusual physiological roles of the relaxin gene in the European rabbit | journal = Journal of Molecular Evolution | volume = 74 | issue = 1-2 | pages = 52–60 | date = February 2012 | pmid = 22354201 | doi = 10.1007/s00239-012-9487-2 }}</ref>
In women relaxin levels rise after ovulation as a result of its production by the corpus luteum. In the absence of pregnancy its level declines at menstruation. During the first trimester of pregnancy levels rise and additional relaxin is produced by the decidua.


Relaxin's role or necessity in human pregnancy remains under investigation, as in humans its peak is reached during the first trimester, not toward the end of pregnancy.  
In [[Horse|horses]] (''Equus caballus''), relaxin is also an important [[hormone]] involved in [[pregnancy]], however, before pregnancy occurs, relaxin is expressed by ovarian structures during the [[Estrous cycle|oestrous cycle]]<ref name=":2">{{cite journal | vauthors = Klein C | title = The role of relaxin in mare reproductive physiology: A comparative review with other species | journal = Theriogenology | volume = 86 | issue = 1 | pages = 451–6 | date = July 2016 | pmid = 27158127 | doi = 10.1016/j.theriogenology.2016.04.061 }}</ref>. Prior to [[ovulation]], relaxin will be produced by ovarian [[Stroma (tissue)|stromal]] cells, which will promote secretion of [[Gelatinase|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.<ref name=":2" /> Furthermore, granular and theca cells in the follicles will express relaxin in increasing levels depending on their size<ref name=":2" />. During early pregnancy, the preimplantation [[conceptus]] will express relaxin, which will promote [[angiogenesis]] in the endometrium by up-regulating VEGF <ref name=":2" /><ref>{{cite journal | vauthors = Klein C | title = Early pregnancy in the mare: old concepts revisited | journal = Domestic Animal Endocrinology | volume = 56 Suppl | pages = S212-7 | date = July 2016 | pmid = 27345319 | doi = 10.1016/j.domaniend.2016.03.006 }}</ref>. 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.<ref name=":2" />


In animals relaxin widens the [[pubic bone]] and facilitates [[childbirth|labor]], it also softens the [[cervix]] (cervical ripening), and relaxes the uterine musculature. Thus, for a long time, relaxin was looked at as a pregnancy hormone. However, its significance may reach much further. Relaxin affects [[collagen]] metabolism, inhibiting collagen synthesis and enhancing its breakdown by increasing [[matrix metalloproteinase]]s.<ref>{{cite journal |author=Mookerjee I, Solly N, Royce S, Tregear G, Samuel C, Tang M |title=Endogenous relaxin regulates collagen deposition in an animal model of allergic airway disease |journal=Endocrinology |volume=147 |issue=2 |pages=754-61 |year=2006 |pmid=16254028}}</ref> It also enhances [[angiogenesis]] and is a potent renal [[vasodilator]].  
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<ref name=":2" />. Placental [[Trophoblast|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<ref name=":3">{{cite journal | vauthors = Ousey JC | title = Hormone profiles and treatments in the late pregnant mare | journal = The Veterinary Clinics of North America. Equine Practice | volume = 22 | issue = 3 | pages = 727–47 | date = December 2006 | pmid = 17129800 | doi = 10.1016/j.cveq.2006.08.004 }}</ref>. From 80 day of [[gestation]] onwards, relaxin levels will increase in the mare's [[Serum (blood)|serum]] with levels peaking in late gestation<ref name=":3" /><ref name=":4">{{cite journal | vauthors = Pashen RL | title = Maternal and foetal endocrinology during late pregnancy and parturition in the mare | journal = Equine Veterinary Journal | volume = 16 | issue = 4 | pages = 233–8 | date = July 1984 | pmid = 6383806 }}</ref>. Moreover, the pattern of relaxin expression will follow the expression of [[Estrogen|oestrogen]], however, there is not yet a known link between these two hormones<ref name=":4" />. During labour, there is a spike in relaxin 3-4 hours before delivery, which is involved in [[Myometrium|myometrial]] relaxation and softening of the pelvic ligaments to aid preparation of the birth canal for the delivery of the horse foetus<ref name=":2" /><ref name=":3" />. 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<ref name=":3" />. In addition, if the mare undergoes an [[abortion]] then the relaxin levels will decline as the placenta ceases to function<ref name=":3" />.  


==Receptors==
==Receptors==
Relaxin interacts with the [[relaxin receptor]] LGR7 ({{Gene|RXFP1}}) and LGR8 ({{Gene|RXFP2}}) which belong to the [[G protein-coupled receptor|G-protein-coupled receptor superfamily]]. They contain a heptahelical [[Transmembrane helix|transmembrane domain]] and a large glycosylated ectodomain,  distantly related to the receptors for the glycoproteohormones, such as the [[LH-receptor]] or [[FSH-receptor]].  
Relaxin interacts with the [[relaxin receptor]] LGR7 ([[RXFP1]]) and LGR8 ([[RXFP2]]), which belong to the [[G protein-coupled receptor]] superfamily.<ref>{{cite journal | vauthors = Hsu SY, Nakabayashi K, Nishi S, Kumagai J, Kudo M, Sherwood OD, Hsueh AJ | title = Activation of orphan receptors by the hormone relaxin | journal = Science | volume = 295 | issue = 5555 | pages = 671–4 | date = January 2002 | pmid = 11809971 | doi = 10.1126/science.1065654 }}</ref> They contain a heptahelical [[Transmembrane helix|transmembrane domain]] and a large glycosylated ectodomain,  distantly related to the receptors for the glycoproteohormones, such as the [[LH-receptor]] or [[FSH-receptor]].


Relaxin receptors have been found in the [[heart]], [[smooth muscle]], the [[connective tissue]], and central and [[autonomous nervous system]].
Relaxin receptors have been found in the [[heart]], [[smooth muscle]], the [[connective tissue]], and central and [[autonomous nervous system]].{{Citation needed|date=October 2018}}


==Disorders==
==Disorders==
Specific disorders related to relaxin have not been described, yet it has been suggested that it could be linked to [[scleroderma]] and to [[fibromyalgia]].<ref>{{cite journal |author=Van Der Westhuizen E, Summers R, Halls M, Bathgate R, Sexton P |title=Relaxin receptors--new drug targets for multiple disease states |journal=Curr Drug Targets |volume=8 |issue=1 |pages=91-104 |year=2007 |pmid=17266534}}</ref>
Women who have been on relaxin treatment during unrelated clinical trials have experienced heavier bleeding during their menstrural cycle, suggesting that relaxin levels could play a role in [[abnormal uterine bleeding]].<ref name=":5">{{cite journal | vauthors = Marshall SA, Senadheera SN, Parry LJ, Girling JE | title = The Role of Relaxin in Normal and Abnormal Uterine Function During the Menstrual Cycle and Early Pregnancy | journal = Reproductive Sciences | volume = 24 | issue = 3 | pages = 342–354 | date = March 2017 | pmid = 27365367 | doi = 10.1177/1933719116657189 }}</ref> However, more research needs to go into this to confirm relaxin as a direct cause.{{Citation needed|date=October 2018}}


==References==
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.<ref name=":5" />
<div class="references-2column">
<references/>
</div>


==External links==
Specific disorders related to relaxin have not been heavily described, yet a link to [[scleroderma]] and [[fibromyalgia]] has also been suggested.<ref>{{cite journal | vauthors = Van Der Westhuizen ET, Summers RJ, Halls ML, Bathgate RA, Sexton PM | title = Relaxin receptors--new drug targets for multiple disease states | journal = Current Drug Targets | volume = 8 | issue = 1 | pages = 91–104 | date = January 2007 | pmid = 17266534 | doi = 10.2174/138945007779315650 }}</ref>
*[http://www.hprd.org/report?external=HprdId&accession_id=&prot_name=relaxin&gene_symbol=&function%3Alines=&ptm_type%3Alines=&localization%3Alines=&domain%3Alines=&motif%3Alines=&expression%3Alines=&prot_start=&prot_end=&mole_start=&mole_end=&disease%3Alines=&query_submit=Search Human Protein Reference Database]
* {{MeshName|Relaxin}}


=== 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 [[Preterm birth|premature birth]].<ref name=":5" />


{{hormones}}
==Pharmacological targets==
 
A recombinant form of human relaxin-2 has been developed as investigational drug RLX030 ([[serelaxin]]).{{Citation needed|date=October 2018}}
 
It is suggested that relaxin could be used as a therapeutic target when it comes to gynaecological disorders.<ref name=":5" />
 
== 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.<ref name="Arroyo_2014">{{cite journal | vauthors = Arroyo JI, Hoffmann FG, Opazo JC | title = Evolution of the relaxin/insulin-like gene family in anthropoid primates | journal = Genome Biology and Evolution | volume = 6 | issue = 3 | pages = 491–9 | date = March 2014 | pmid = 24493383 | pmc = 3971578 | doi = 10.1093/gbe/evu023 }}</ref> 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 .<ref name="Arroyo_2014" /> 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 <ref name="Arroyo_2014" />; Lawrence and Cords, 2012).
 
== See also ==
* [[Relaxin family peptide hormones]]
* [[Insulin/IGF/Relaxin family|Insulin/IGF/Relaxin' family]]
*[[Relaxin/insulin-like family peptide receptor 1|Relaxin'/insulin-like family peptide receptor 1]]
 
== References ==
{{Reflist|2}}
 
== External links ==
* {{MeshName|Relaxin'}}
* {{cite web | url = http://www.hprd.org/resultsQuery?multiplefound=&prot_name=Relaxin&external=Ref_seq&accession_id=&hprd=&gene_symbol=&chromo_locus=&function=&ptm_type=&localization=&domain=&motif=&expression=&prot_start=&prot_end=&limit=0&mole_start=&mole_end=&disease=&query_submit=Search | title = Relaxin | work = Human Protein Reference Database | publisher = Johns Hopkins University and the Institute of Bioinformatics | access-date = 2009-05-20}}
 
{{Hormones}}
{{Protein and peptide receptor modulators}}
{{Authority control}}


[[Category:Peptide hormones]]
[[Category:Peptide hormones]]
[[Category:Endocrinology]]
[[Category:Hormones of the ovary]]
{{WikiDoc Help Menu}}
[[Category:Hormones of the placenta]]
{{WikiDoc Sources}}
[[Category:Hormones of the pregnant female]]
 
[[Category:Human female endocrine system]]
[[fr:Relaxine]]
[[it:Relaxina]]
[[ja:リラキシン]]
[[pl:Relaksyna]]

Latest revision as of 07:29, 10 January 2019

For the Miles Davis album, see Relaxin' with the Miles Davis Quintet.
Relaxin 1
File:Relaxin.png
Identifiers
SymbolRLN1
Alt. symbolsH1
Entrez6013
HUGO10026
OMIM179730
RefSeqNM_006911
UniProtP04808
Other data
LocusChr. 9 qter-q12
Relaxin 2
Identifiers
SymbolRLN2
Alt. symbolsH2, RLXH2, bA12D24.1.1, bA12D24.1.2
Entrez6019
HUGO10027
OMIM179740
PDB6RLX
RefSeqNM_134441
UniProtP04090
Other data
LocusChr. 9 qter-q12
Relaxin 3
Identifiers
SymbolRLN3
Alt. symbolsZINS4, RXN3, H3
Entrez117579
HUGO17135
OMIM606855
RefSeqNM_080864
UniProtQ8WXF3
Other data
LocusChr. 19 p13.3

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

The relaxin-like peptide family belongs in the insulin superfamily and consists of 7 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, INSL6 remain uncharacterised.[4]

Synthesis

In the female, it 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.[5]

Structure

See also: Insulin/IGF/Relaxin family

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

Relaxin is produced from its prohormone, "prorelaxin", by splitting off one additional peptide chain reaction.[citation needed]

Function

In humans

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. [citation needed] Relaxin may be involved in the vital process of decidualisation, working alongside steroid hormones to allow the endometrium to prepare for implantation.[6] During the first trimester of pregnancy, levels rise and additional relaxin is produced by the decidua. Relaxin's peak is reached during the first trimester (14-weeks) and at delivery. Relaxin mediates the hemodynamic changes that occur during pregnancy, such as increased cardiac output, increased renal blood flow, and increased arterial compliance.[citation needed] It also relaxes other pelvic ligaments.[7] It is believed to soften the pubic symphysis.[citation needed]

In males, relaxin enhances motility of sperm in semen.[8]

In the cardiovascular system, relaxin works mainly by activating the nitric oxide pathway. Other mechanisms include activation of NFκB leading to vascular endothelial growth factor (VEGF) and matrix metalloproteinases transcription.[9]

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.[9] Relaxin increases the rate and force of cardiac contraction in rat models.[10] Via upregulation of VEGF, relaxin plays a key role in blood vessel formation (angiogenesis) during pregnancy, tumour development or ischaemic wounds.[10]

In other animals

In animals, relaxin widens the pubic bone and facilitates labor; it also softens the cervix (cervical ripening), and relaxes the uterine musculature.[citation needed] Thus, for a long time, relaxin was looked at as a pregnancy hormone. However, its significance may reach much further. Relaxin may affects collagen metabolism, inhibiting collagen synthesis and enhancing its breakdown by increasing matrix metalloproteinases.[11] It also enhances angiogenesis and is a potent renal vasodilator.[citation needed]

In the mouse model Relaxin has been found to promote maturation of cardiomyocytes.[10]

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.[10][9]

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.[12]

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[13]. 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.[13] Furthermore, granular and theca cells in the follicles will express relaxin in increasing levels depending on their size[13]. During early pregnancy, the preimplantation conceptus will express relaxin, which will promote angiogenesis in the endometrium by up-regulating VEGF [13][14]. 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.[13]

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[13]. 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[15]. From 80 day of gestation onwards, relaxin levels will increase in the mare's serum with levels peaking in late gestation[15][16]. Moreover, the pattern of relaxin expression will follow the expression of oestrogen, however, there is not yet a known link between these two hormones[16]. 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[13][15]. 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[15]. In addition, if the mare undergoes an abortion then the relaxin levels will decline as the placenta ceases to function[15].

Receptors

Relaxin interacts with the relaxin receptor LGR7 (RXFP1) and LGR8 (RXFP2), which belong to the G protein-coupled receptor superfamily.[17] 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.

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 menstrural cycle, suggesting that relaxin levels could play a role in abnormal uterine bleeding.[18] However, more research needs to go into this 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.[18]

Specific disorders related to relaxin have not been heavily described, yet a link to scleroderma and fibromyalgia has also been suggested.[19]

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.[18]

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.[18]

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.[20] 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 .[20] 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 [20]; Lawrence and Cords, 2012).

See also

References

  1. ↑ 1.0 1.1 Bani D (January 1997). "Relaxin: a pleiotropic hormone". General Pharmacology. 28 (1): 13–22. doi:10.1016/s0306-3623(96)00171-1. PMID 9112071.
  2. ↑ "If a Gopher Can Do It …". Time Magazine. 1944-04-10. 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.
  4. ↑ Wilkinson TN, Speed TP, Tregear GW, Bathgate RA (February 2005). "Evolution of the relaxin-like peptide family". BMC Evolutionary Biology. 5: 14. doi:10.1186/1471-2148-5-14. PMC 551602. PMID 15707501.
  5. ↑ MacLennan AH (1991). "The role of the hormone relaxin in human reproduction and pelvic girdle relaxation". Scandinavian Journal of Rheumatology. Supplement. 88: 7–15. PMID 2011710.
  6. ↑ Carp H, Torchinsky A, Fein A, Toder V (December 2001). "Hormones, cytokines and fetal anomalies in habitual abortion". Gynecological Endocrinology. 15 (6): 472–83. doi:10.1080/gye.15.6.472.483. PMID 11826772.
  7. ↑ Conrad KP (August 2011). "Maternal vasodilation in pregnancy: the emerging role of relaxin". American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 301 (2): R267–75. doi:10.1152/ajpregu.00156.2011. PMC 3154715. PMID 21613576.
  8. ↑ Weiss G (February 1989). "Relaxin in the male". Biology of Reproduction. 40 (2): 197–200. doi:10.1095/biolreprod40.2.197. PMID 2497805. Archived from the original on 2008-11-22.
  9. ↑ 9.0 9.1 9.2 Raleigh JM, Toldo S, Das A, Abbate A, Salloum FN (July 2016). "Relaxin' the Heart: A Novel Therapeutic Modality". Journal of Cardiovascular Pharmacology and Therapeutics. 21 (4): 353–62. doi:10.1177/1074248415617851. PMID 26589290.
  10. ↑ 10.0 10.1 10.2 10.3 Feijóo-Bandín S, Aragón-Herrera A, Rodríguez-Penas D, Portolés M, Roselló-Lletí E, Rivera M, González-Juanatey JR, Lago F (2017). "Relaxin-2 in Cardiometabolic Diseases: Mechanisms of Action and Future Perspectives". Frontiers in Physiology. 8: 599. doi:10.3389/fphys.2017.00599. PMC 5563388. PMID 28868039.
  11. ↑ Mookerjee I, Solly NR, Royce SG, Tregear GW, Samuel CS, Tang ML (February 2006). "Endogenous relaxin regulates collagen deposition in an animal model of allergic airway disease". Endocrinology. 147 (2): 754–61. doi:10.1210/en.2005-1006. PMID 16254028.
  12. ↑ Arroyo JI, Hoffmann FG, Opazo JC (February 2012). "Gene duplication and positive selection explains unusual physiological roles of the relaxin gene in the European rabbit". Journal of Molecular Evolution. 74 (1–2): 52–60. doi:10.1007/s00239-012-9487-2. PMID 22354201.
  13. ↑ 13.0 13.1 13.2 13.3 13.4 13.5 13.6 Klein C (July 2016). "The role of relaxin in mare reproductive physiology: A comparative review with other species". Theriogenology. 86 (1): 451–6. doi:10.1016/j.theriogenology.2016.04.061. PMID 27158127.
  14. ↑ Klein C (July 2016). "Early pregnancy in the mare: old concepts revisited". Domestic Animal Endocrinology. 56 Suppl: S212–7. doi:10.1016/j.domaniend.2016.03.006. PMID 27345319.
  15. ↑ 15.0 15.1 15.2 15.3 15.4 Ousey JC (December 2006). "Hormone profiles and treatments in the late pregnant mare". The Veterinary Clinics of North America. Equine Practice. 22 (3): 727–47. doi:10.1016/j.cveq.2006.08.004. PMID 17129800.
  16. ↑ 16.0 16.1 Pashen RL (July 1984). "Maternal and foetal endocrinology during late pregnancy and parturition in the mare". Equine Veterinary Journal. 16 (4): 233–8. PMID 6383806.
  17. ↑ Hsu SY, Nakabayashi K, Nishi S, Kumagai J, Kudo M, Sherwood OD, Hsueh AJ (January 2002). "Activation of orphan receptors by the hormone relaxin". Science. 295 (5555): 671–4. doi:10.1126/science.1065654. PMID 11809971.
  18. ↑ 18.0 18.1 18.2 18.3 Marshall SA, Senadheera SN, Parry LJ, Girling JE (March 2017). "The Role of Relaxin in Normal and Abnormal Uterine Function During the Menstrual Cycle and Early Pregnancy". Reproductive Sciences. 24 (3): 342–354. doi:10.1177/1933719116657189. PMID 27365367.
  19. ↑ Van Der Westhuizen ET, Summers RJ, Halls ML, Bathgate RA, Sexton PM (January 2007). "Relaxin receptors--new drug targets for multiple disease states". Current Drug Targets. 8 (1): 91–104. doi:10.2174/138945007779315650. PMID 17266534.
  20. ↑ 20.0 20.1 20.2 Arroyo JI, Hoffmann FG, Opazo JC (March 2014). "Evolution of the relaxin/insulin-like gene family in anthropoid primates". Genome Biology and Evolution. 6 (3): 491–9. doi:10.1093/gbe/evu023. PMC 3971578. PMID 24493383.

External links

  • Relaxin' at the US National Library of Medicine Medical Subject Headings (MeSH)
  • "Relaxin". Human Protein Reference Database. Johns Hopkins University and the Institute of Bioinformatics. Retrieved 2009-05-20.

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