What Is Relaxin-3? Definition and What Research Reports
Relaxin-3 is a two-chain, disulfide-linked peptide of the relaxin/insulin superfamily. In rodents it is expressed largely by neurons of the brainstem nucleus incertus, which project widely to forebrain regions, and its main described receptor is RXFP3. Published work is preclinical: studies have mapped relaxin-3 fibre pathways, examined RXFP3 signalling in alcohol-seeking and memory tasks, measured effects on hypothalamic gene expression in cell and animal models, and engineered analogues. This entry is definitional and educational only.
Definition
Relaxin-3 (gene symbol RLN3, historically also called INSL7) is a small peptide hormone belonging to the relaxin/insulin superfamily. Like insulin and the other relaxins, it is built as two chains — an A-chain and a B-chain — held together by disulfide bonds, a shared architecture that structural work on relaxin chimeras has used to swap chains and domains between family members and examine how the resulting molecules fold (PMID 19416154). In rodents, relaxin-3 is described primarily as a neuropeptide: it is produced by a discrete population of neurons in the brainstem nucleus incertus, which send long-range fibres to forebrain targets including the medial septum and the parahippocampal cortex, as anatomical tracing studies have reported (PMID 34239421). Its principal described receptor is the G protein-coupled receptor RXFP3 (relaxin family peptide receptor 3).
This page is for educational purposes only and is not medical advice; consult a licensed physician about any health question or any decision involving a medicine or investigational compound.
What Class of Molecule It Is, and Where It Comes From
Relaxin-3 sits in the same structural family as insulin, insulin-like growth factors, the insulin-like peptides (INSL3–6) and the other relaxins (relaxin-1, relaxin-2, relaxin-3). Family membership is defined by the two-chain, disulfide-stabilised fold rather than by shared function; relaxin-2, for example, is best known as a circulating peptide in reproductive and vascular biology, and one clinical tissue study reported relaxin expression in cerebral cavernomas from adults and children (PMID 31756710).
Relaxin-3 differs from its relatives mainly in where it is made. The bulk of published mapping work places relaxin-3-expressing cell bodies in the nucleus incertus of the rat brainstem, with axonal projections reaching septal, hippocampal and cortical territory. One developmental study traced how relaxin-3 innervation of the rat medial septum appears and matures after birth, reporting a progressive postnatal increase in fibre density rather than an adult-like pattern present at birth (PMID 37234259). Smaller amounts of relaxin-3 expression have also been described outside the brain; one study examined relaxin-3 in adipose tissue and its relationship to adipogenesis in cell models (PMID 24345292).
How the Term Is Used in Peptide Research
In the literature, "relaxin-3" is used in several distinct senses, and readers encountering the word in an abstract benefit from noting which one is meant.
| Term | What it refers to in published work |
|---|---|
| Relaxin-3 / RLN3 | The native two-chain peptide, or the gene encoding its precursor. |
| RXFP3 | The receptor most often paired with relaxin-3 in pharmacology studies, including work on alcohol-seeking behaviour in rats (PMID 28726252). |
| Nucleus incertus | The brainstem region containing most relaxin-3 neurons, reviewed in relation to explicit and implicit memory (PMID 33867946). |
| Relaxin-3 analogues | Engineered agonist or antagonist peptides; one report described building them on grafted disulfide-stabilised scaffolds (PMID 32133341). |
| Relaxin chimeras | Hybrid molecules combining chains from different relaxin-family peptides for structural analysis (PMID 19416154). |
Because the native peptide is large, two-chain and disulfide-bonded, much of the chemistry literature is concerned with making simpler, more stable surrogates. Researchers reported developing both relaxin-3 agonists and antagonists by grafting key binding elements onto disulfide-stabilised peptide scaffolds, an approach intended to reproduce receptor activity in a smaller, more synthetically tractable molecule (PMID 32133341).
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Neural circuits and behaviour
A substantial share of relaxin-3 research is behavioural neuroscience in rodents. One study reported that the relaxin-3/RXFP3 system regulates alcohol-seeking behaviour in rats, implicating this signalling pathway in motivated and stress-related drug seeking (PMID 24297931). A subsequent report narrowed the anatomy, describing relaxin-3/RXFP3 signalling in the central amygdala as a modulator of alcohol seeking in rats (PMID 28726252). A separate review synthesised evidence linking the nucleus incertus and relaxin-3/RXFP3 signalling to explicit and implicit memory processes (PMID 33867946). These findings are animal and review-level, and none of them establishes an equivalent role in people.
Neuroendocrine gene expression
Relaxin-3 has also been studied as a modulator of hypothalamic gene expression. One in vitro study reported that relaxin-3 regulated corticotropin-releasing factor (CRF) gene expression in cultured rat hypothalamic 4B cells, connecting the peptide to the transcriptional machinery of the stress axis (PMID 30412752). Another study examined the effect of relaxin-3 on Kiss-1, gonadotropin-releasing hormone and gonadotropin subunit gene expression, placing the peptide within reproductive-axis signalling research as well (PMID 31607801).
Peripheral and inflammatory models
Outside the central nervous system, published work is sparser. A study of adipose tissue characterised relaxin-3 expression there and its effects on adipogenesis (PMID 24345292). A more recent laboratory report described relaxin-3 attenuating sepsis-induced myocardial injury in a model system by modulating an ACSS2/ACLY–acetyl-CoA–H3K18ac axis in macrophages (PMID 42090903). Both are mechanistic studies rather than clinical trials.
What the literature does not cover
Within this body of verified work there are no human clinical trials of relaxin-3 as an administered peptide, no established human dosing, and no approved relaxin-3 product. The chemistry literature is still at the stage of designing and characterising receptor-selective agonists and antagonists (PMID 32133341), and the anatomy literature is still mapping where the peptide's fibres go and when they develop (PMID 37234259).
Safety and Adverse Events: What Studies Report
The verified literature summarised here is preclinical — rodent behavioural work, cultured-cell experiments, anatomical tracing and peptide chemistry — and does not include human safety, tolerability or adverse-event data for relaxin-3. The behavioural studies reported effects on alcohol-seeking behaviour in rats after manipulation of relaxin-3/RXFP3 signalling (PMID 24297931, PMID 28726252), and the cell studies reported changes in hypothalamic gene expression (PMID 30412752), but these are outcome measures within experiments rather than a safety profile. No adverse-event tables, no long-term toxicology and no human exposure data appear in these sources. Any statement about how relaxin-3 behaves in people would go beyond what the cited papers support.
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- Relaxin-3 is a peptide, not a drug class. It is a naturally occurring signalling molecule studied mostly in rats and in cultured cells.
- RXFP3 is the anchor. Most pharmacology in this area is framed around the receptor rather than the peptide alone (PMID 33867946).
- Species matters. Innervation patterns, receptor distribution and behavioural readouts were characterised in rodents (PMID 34239421).
- Analogues are an active chemistry problem. The native two-chain structure is difficult to synthesise, which is why scaffold-grafting strategies were reported (PMID 32133341).
Readers with a clinical question about relaxin-family peptides should raise it with a licensed physician rather than infer anything from preclinical findings.
References
- Relaxin-3/RXFP3 system regulates alcohol-seeking (Proceedings of the National Academy of Sciences of the United States of America, 2013)
- Central amygdala relaxin-3/relaxin family peptide receptor 3 signalling modulates alcohol seeking in rats (British Journal of Pharmacology, 2017)
- Development of Relaxin-3 Agonists and Antagonists Based on Grafted Disulfide-Stabilized Scaffolds (Frontiers in Chemistry, 2020)
- Involvement of the Nucleus Incertus and Relaxin-3/RXFP3 Signaling System in Explicit and Implicit Memory (Frontiers in Neuroanatomy, 2021)
- Relaxin-3 Innervation From the Nucleus Incertus to the Parahippocampal Cortex of the Rat (Frontiers in Neuroanatomy, 2021)
- Postnatal development of the relaxin-3 innervation of the rat medial septum (Frontiers in Neuroscience, 2023)
- Relaxin-3 regulates corticotropin-releasing factor gene expression in cultured rat hypothalamic 4B cells (Neuroscience Letters, 2019)
- Effect of relaxin-3 on Kiss-1, gonadotropin-releasing hormone, and gonadotropin subunit gene expression (Reproductive Medicine and Biology, 2019)
- Structural properties of relaxin chimeras (Annals of the New York Academy of Sciences, 2009)
- The expression of relaxin-3 in adipose tissue and its effects on adipogenesis (Protein and Peptide Letters, 2014)
- Relaxin-3 attenuates sepsis-induced myocardial injury by modulating the ACSS2/ACLY-acetyl-CoA-H3K18ac axis in macrophages (International Immunopharmacology, 2026)
- Cerebral cavernomas in adults and children express relaxin (Journal of Neurosurgery: Pediatrics, 2020)
Frequently asked questions
What is relaxin-3 in one sentence?▾
Relaxin-3 is a two-chain, disulfide-linked peptide of the relaxin/insulin superfamily that is expressed largely by neurons of the brainstem nucleus incertus in rodents and signals at the receptor RXFP3. Structural studies of relaxin-family chimeras illustrate the shared A-chain/B-chain fold that defines this superfamily (PMID 19416154).
Which receptor does relaxin-3 act on?▾
The receptor most consistently paired with relaxin-3 in the literature is RXFP3, a G protein-coupled receptor. Rodent studies reported that relaxin-3/RXFP3 signalling regulated alcohol-seeking behaviour (PMID 24297931), and a follow-up report described central amygdala RXFP3 signalling modulating alcohol seeking in rats (PMID 28726252). Reviews have also linked this system to memory processes (PMID 33867946).
Where in the body is relaxin-3 produced?▾
In rodents, most relaxin-3-producing neurons sit in the brainstem nucleus incertus, and tracing work described their projections reaching the parahippocampal cortex (PMID 34239421). A developmental study reported that innervation of the rat medial septum increased progressively after birth (PMID 37234259). Expression has also been described in adipose tissue (PMID 24345292).
Is relaxin-3 the same thing as relaxin?▾
No. Relaxin-3 is a distinct member of the relaxin/insulin superfamily with a different expression pattern and a different principal receptor. Chimera studies swapped chains between relaxin-family peptides to study how structure maps to family identity (PMID 19416154). Separately, relaxin expression has been reported in cerebral cavernoma tissue from adults and children (PMID 31756710).
What have studies reported about relaxin-3 and hormone-related gene expression?▾
One in vitro study reported that relaxin-3 regulated corticotropin-releasing factor gene expression in cultured rat hypothalamic 4B cells (PMID 30412752). Another examined relaxin-3's effect on Kiss-1, gonadotropin-releasing hormone and gonadotropin subunit gene expression (PMID 31607801). Both were laboratory models, not human studies, and neither establishes a clinical effect.
Has relaxin-3 been studied outside the nervous system?▾
Yes, though less extensively. A study characterised relaxin-3 expression in adipose tissue and its effects on adipogenesis in cell models (PMID 24345292). A more recent mechanistic report described relaxin-3 attenuating sepsis-induced myocardial injury by modulating an ACSS2/ACLY-acetyl-CoA-H3K18ac axis in macrophages (PMID 42090903). Both remain preclinical.
What do the cited studies say about safety in humans?▾
They say nothing about it. The verified literature here consists of rodent behavioural experiments, cultured-cell studies, anatomical mapping and peptide chemistry, such as work developing relaxin-3 agonists and antagonists on grafted disulfide-stabilised scaffolds (PMID 32133341). No human trials, dosing data or adverse-event profiles appear in these sources. Clinical questions belong with a licensed physician.
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References
This page summarises published research for education — it is not medical advice, and nothing here is a recommendation to use, purchase, or dose any substance. Study parameters described are what researchers reported, not instructions. Consult a qualified clinician before any health decision.