Introduction
The relaxin peptide family has come a long way since its discovery by Frederick Hisaw in 1926. It was Hisaw's experimentation with serum from pregnant guinea pigs or rabbits injected into virgin guinea pigs that led to the identification of relaxin, which caused the relaxation of the animals' interpubic ligament. It wasn't until the mid-1970s to 1980s, however, when advanced protein isolation and characterization methods became available, that the primary structure of relaxin was first determined. This period also saw the emergence of recombinant DNA technology, allowing more comprehensive studies on its chemistry and physiology. As of today, the primary structure of relaxin from more than twenty species has been determined, placing it as a key member of the broader insulin peptide superfamily.
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The Evolution and Structure of Relaxin
Relaxin belongs to a superfamily of insulin peptides distinguished by a configuration of two peptide chains held together by three disulfide bonds, sharing approximately 25% sequence identity with insulin. This established the notion of a superfamily of sequences and structural features that evolved from insulin during the evolution of vertebrates. In humans, the relaxin peptide family comprises seven members: relaxin-1, -2, -3, and four other insulin-like peptides (INSL 3, 4, 5, and 6). Two different genes, RLN1 and RLN2, encode relaxin-1 and relaxin-2, respectively, in humans and other higher primates. This gene duplication likely occurred during primate evolution, with RLN2 being the orthologue of RLN1 in other mammalian species.
Fig. 1 Primary sequences of the human relaxin peptide family (Jiaying Chan L., et al. 2011).
Relaxin-3, encoded by the RLN3 gene and discovered in 2002, is considered the ancestral peptide of the relaxin family. All relaxin peptides share a common binding motif (Arg-X-X-X-Arg-X-X-Ile/Val) in the B chain, which accounts for their functional similarities. The primary sequences for each relaxin peptide family member have been either determined or predicted, revealing very low sequence homology between members. However, the six cysteine residues forming disulfide cross-links between the A- and B-chains and a single glycine residue within the B chain remain highly conserved across the relaxin family. Structural similarity is observed despite the low sequence homology, with tertiary structures resolved through X-ray crystallography or NMR spectroscopy for some members.
Physiological Roles of Relaxin Family Peptides
Relaxin-1 and Relaxin-2
Human relaxin-2 is the equivalent of relaxin-1 in non-primate species, both collectively referred to as relaxin. Known primarily as a reproductive hormone produced by the corpus luteum and/or placenta in many species, relaxin mediates varied physiological processes of pregnancy and parturition. Relaxin knockout (KO) mice and relaxin-immunoneutralized rats show prolonged and difficult pup delivery, underscoring its importance. Relaxin is involved in the remodeling and growth of the uterus, cervix, and vagina. In human pregnancy, relaxin promotes endometrial thickening and vascularization, enhancing embryo implantation, evidenced by the highest plasma levels of relaxin during the first trimester.
Relaxin is crucial for the elasticity and growth of the pubic joint cartilage and cervical ripening, facilitating childbirth. Its effects on the cervix and uterus vary between species, inhibiting uterine contractility in rats, mice, and pigs but not in sheep, cows, or humans. Additionally, relaxin is vital for the development of the mammary nipple in rodents but not in pigs, where it is essential for mammary gland development. In males, relaxin is produced in the reproductive tract and is present in seminal plasma, affecting sperm motility and potentially enhancing fertility.
Beyond reproductive roles, relaxin impacts the brain, cardiovascular system, and connective tissue homeostasis. Relaxin receptors are widely distributed in brain regions responsible for blood pressure and fluid balance, such as the circumventricular organs and the hypothalamic nuclei. Relaxin may regulate plasma osmolality, influencing water consumption and acting on the cardiovascular system by promoting vasodilation, increasing renal plasma flow, and reducing blood pressure and vascular resistance. Relaxin's anti-fibrotic properties arise from inhibiting collagen synthesis and promoting collagen degradation, making it a potential treatment for fibrotic diseases.
Relaxin-3
The most recently discovered member, relaxin-3, is mainly found in the brain, specifically the ventromedial dorsal tegmental nucleus, with projections to the hypothalamus. Acting as a neurotransmitter, relaxin-3 may mediate stress responses, involving the corticotrophin releasing factor system, stress-related memory, and control of hippocampal theta rhythm. Relaxin-3 also regulates appetite, with increased mRNA transcription in stress tests and feeding modulation in satiated rats. The receptor RXFP3 is a target for developing anti-anxiety or anti-obesity drugs, and relaxin-3 demonstrates anti-fibrotic properties through high-affinity interactions with RXFP1.
INSL3
INSL3, initially identified in Leydig cells of the testis, is essential for the development of the gubernacular ligament during testicular descent. INSL3-KO mice exhibit cryptorchidism, resulting in disrupted spermatogenesis and infertility. INSL3 also influences male germ cell survival and has protective anti-apoptotic roles in ovarian follicles. In females, INSL3 is expressed in the ovarian follicle and corpus luteum, impacting follicle selection, apoptosis rates, estrous cycles, and litter sizes. Recent studies suggest INSL3 may trigger meiotic progression in oocytes, offering clinical promise for reproductive treatment.
INSL4, INSL5, and INSL6
INSL4, identified in the placenta, remains physiologically unexplored. INSL5, expressed in brain and peripheral tissues, might play roles in neuroendocrine signaling or metabolism. INSL6, primarily in the testis, seems vital for spermatogenesis, with gene-deficient mice showing impaired fertility, particularly in males. Understanding INSL6's receptor and signaling pathways remains a challenge.
Clinical Applications
Heart Failure
Heart failure, a condition with significant mortality and economic costs, is an area where relaxin shows promise. Current research suggests relaxin can induce cardiovascular adaptations such as increased plasma volume, cardiac output, and heart rate while decreasing blood pressure and vascular resistance.
Systemic Sclerosis / Scleroderma
Systemic scleroderma (SSc) is characterized by fibrosis, inflammation, and vascular damage, with no effective treatment for reversing fibrosis or halting disease progression. Relaxin's anti-fibrotic and anti-inflammatory properties make it a candidate for SSc treatment.
Pre-Eclampsia
Pre-eclampsia, a serious condition in pregnant women, poses risks due to reduced placental blood flow and increased maternal systemic vascular resistance. Relaxin's known effects include increased menstrual bleeding and vasodilation, potentially impacting platelet aggregation. Its administration in women has provided grounds for considering relaxin to improve kidney function and enhance blood flow, presenting a promising treatment for pre-eclampsia.
Orthodontic Treatment
Relaxin's impact on collagen metabolism suggests a potential role in orthodontic treatment to prevent tooth relapse by remodeling periodontal ligaments. Studies show that relaxin may reduce collagen type I and increase MMP-1 expression, increasing tooth mobility. Although relaxin does not accelerate tooth movement, its possible role in preventing relapse continues to be an area of active investigation.
Conclusion
Research into the relaxin peptide family has advanced our understanding of protein evolution, structure, and receptor interactions. These peptides have demonstrated significant therapeutic potential across various physiological systems. Ongoing research and clinical trials continue to explore their full utility, offering hope for novel treatments in cardiovascular, fibrotic, reproductive, and other diseases. The future of relaxin peptides in medicine looks promising, potentially leading to breakthroughs in human health and disease management.
References
- Jiaying Chan L., et al. The relaxin peptide family-structure, function and clinical applications. Protein and Peptide Letters. 2011, 18 (3): 220-229.
- Hisaw F. L. Experimental relaxation of the pubic ligament of the guinea pig. Proceedings of the Society for Experimental Biology and Medicine. 1926, 23 (8): 661-663.
- Sherwood O. D. Relaxin's physiological roles and other diverse actions. Endocrine Reviews. 2004, 25 (2): 205-234.
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