Physiology and Molecular Biology of the Relaxin Peptide Family

Bathgate, Ross A. D.; Hsueh, Aaron J. W.; Sherwood, O. D.

doi:10.1016/b978-012515400-0/50021-x

Cited by 61 publications

(130 citation statements)

References 732 publications

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“…In most mammals other than humans and higher primates, there are only two relaxin genes that encode relaxin and relaxin-3. The RLN1 gene in these species is equivalent to the RLN2 gene in humans (encoding H2 relaxin) and higher primates and encodes the relaxin peptide that is expressed by the corpus luteum and/or placenta (2). The function of the RLN1 gene in higher primates is unknown, and an H1 relaxin peptide has not been isolated.…”

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confidence: 99%

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The A-chain of Human Relaxin Family Peptides Has Distinct Roles in the Binding and Activation of the Different Relaxin Family Peptide Receptors

Hossain

Rosengren²,

Haugaard‐Jönsson³

et al. 2008

Journal of Biological Chemistry

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The relaxin peptides are a family of hormones that share a structural fold characterized by two chains, A and B, that are cross-braced by three disulfide bonds. Relaxins signal through two different classes of G-protein-coupled receptors (GPCRs), leucine-rich repeat-containing GPCRs LGR7 and LGR8 together with GPCR135 and GPCR142, now referred to as the relaxin family peptide (RXFP) receptors 1-4, respectively. Although key binding residues have been identified in the B-chain of the relaxin peptides, the role of the A-chain in their activity is currently unknown. A recent study showed that INSL3 can be truncated at the N terminus of its A-chain by up to 9 residues without affecting the binding affinity to its receptor RXFP2 while becoming a high affinity antagonist. This suggests that the N terminus of the INSL3 A-chain contains residues essential for RXFP2 activation. In this study, we have synthesized A-chain truncated human relaxin-2 and -3 (H2 and H3) relaxin peptides, characterized their structure by both CD and NMR spectroscopy, and tested their binding and cAMP activities on RXFP1, RXFP2, and RXFP3. In stark contrast to INSL3, A-chain-truncated H2 relaxin peptides lost RXFP1 and RXFP2 binding affinity and concurrently cAMP-stimulatory activity. H3 relaxin A-chain-truncated peptides displayed similar properties on RXFP1, highlighting a similar binding mechanism for H2 and H3 relaxin. In contrast, A-chain-truncated H3 relaxin peptides showed identical activity on RXFP3, highlighting that the B-chain is the sole determinant of the H3 relaxin-RXFP3 interaction. Our results provide new insights into the action of relaxins and demonstrate that the role of the A-chain for relaxin activity is both peptide-and receptor-dependent.Relaxin was first identified more than 90 years ago and subsequently shown to be a peptide hormone having a two-chain structure similar to insulin ( Fig. 1) (1). It has since been established that relaxin is a member of the relaxin peptide family, comprising a total of seven members in the human (2). These are the H1, 3 H2, and H3 relaxin peptides that are encoded by the three relaxin genes RLN1 to -3 and the insulin-like peptides INSL3 to -6 (insulin-like peptides 3-6). Phylogenetic analyses indicate that all of these relaxin family peptides evolved from a relaxin-3 (H3 relaxin equivalent) ancestral gene prior to the emergence of fish (3). In most mammals other than humans and higher primates, there are only two relaxin genes that encode relaxin and relaxin-3. The RLN1 gene in these species is equivalent to the RLN2 gene in humans (encoding H2 relaxin) and higher primates and encodes the relaxin peptide that is expressed by the corpus luteum and/or placenta (2). The function of the RLN1 gene in higher primates is unknown, and an H1 relaxin peptide has not been isolated.In contrast to the receptors for insulin and insulin-like growth factors I and II, which are tyrosine kinases, the receptors for relaxin family peptides are members of two unrelated branches of the G-protein-coupled recepto...

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confidence: 99%

“…1) (1). It has since been established that relaxin is a member of the relaxin peptide family, comprising a total of seven members in the human (2). These are the H1, 3 H2, and H3 relaxin peptides that are encoded by the three relaxin genes RLN1 to -3 and the insulin-like peptides INSL3 to -6 (insulin-like peptides [3][4][5][6].…”

mentioning

confidence: 99%

The A-chain of Human Relaxin Family Peptides Has Distinct Roles in the Binding and Activation of the Different Relaxin Family Peptide Receptors

Hossain

Rosengren²,

Haugaard‐Jönsson³

et al. 2008

Journal of Biological Chemistry

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“…The human RLN2 gene encodes the relaxin peptide, which is best known for its important actions during pregnancy, including decidualization of stromal cells during implantation; growth and development of the uterus, mammary gland, and nipple; inhibition of myometrial contractions; mediation of pregnancyrelated cardiovascular changes; and regulation of plasma osmolality (reviewed in Ref. 4). Relaxin also regulates extracellular matrix turnover in the heart, lung, kidney and liver; promotion of wound healing; and counteraction of allergic reactions (reviewed in Ref.…”

mentioning

confidence: 99%

Prolonged RXFP1 and RXFP2 signaling can be explained by poor internalization and a lack of β-arrestin recruitment

Callander¹,

Thomas²,

Bathgate³

2009

American Journal of Physiology-Cell Physiology

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laxin induces sustained physiological responses, which brings into question the deactivation processes typical of most G protein-coupled receptors (GPCR) for its receptor, relaxin family peptide receptor 1 (RXFP1). Here, we examined relaxin-dependent phosphorylation of RXFP1 and the related insulin-like peptide 3 (INSL3) receptor, RXFP2, as well as the capacity of these receptors to recruit ␤-arrestins and internalize in response to ligand stimulation. We confirmed in human embryonic kidney (HEK)-293T cells, expressing RXFP1 or RXFP2, that both receptors elicit prolonged cAMP responses up to 6 h after stimulation. Receptors immunoprecipitated from 32 P metabolically labeled cells were used to investigate the agonist-specific phosphorylation. Rapid and robust receptor phosphorylation was not observed for either RXFP1 or RXFP2, although some 32 P-incorporation was observed at 30 min; however, this was not statistically significant. In accord with this result, RXFP1 and RXFP2 demonstrated poor internalization in response to relaxin or INSL3, as compared with the angiotensin II type 1 receptor (AT1R), which undergoes rapid and robust phosphorylation and internalization in response to angiotensin II. Additionally, coexpression of GPCR kinases has no effect on the rate of internalization for either RXFP1 or RXFP2. Confocal microscopy was used to follow the trafficking of green fluorescent proteinlabeled ␤-arrestins after receptor activation. Neither RXFP1 nor RXFP2 activation results in recruitment of ␤-arrestins to the cell surface, whereas AT1R rapidly recruits both ␤-arrestins-1 and -2. The apparent lack of classical regulation for RXFP1 and RXFP2 provides the molecular basis for the prolonged signaling and physiological actions of relaxin and related peptides.G protein-coupled receptor; relaxin; insulin-like peptide 3 RELAXIN IS A MEMBER of the insulin-relaxin peptide family, which in humans includes 10 genes: INS, IGF1, IGF2, RLN1, RLN2, RLN3, INSL3, INSL4, INSL5, and INSL6. The human RLN2 gene encodes the relaxin peptide, which is best known for its important actions during pregnancy, including decidualization of stromal cells during implantation; growth and development of the uterus, mammary gland, and nipple; inhibition of myometrial contractions; mediation of pregnancyrelated cardiovascular changes; and regulation of plasma osmolality (reviewed in Ref. 4). Relaxin also regulates extracellular matrix turnover in the heart, lung, kidney and liver; promotion of wound healing; and counteraction of allergic reactions (reviewed in Ref. 4).The receptor for relaxin, relaxin family peptide 1 receptor (RXFP1), was identified in 2002 in conjunction with the receptor for insulin-like peptide 3 (INSL3), termed RXFP2 (20). RXFP1 and RXFP2 belong to the glycoprotein hormone receptor cluster of the ␦-group of G protein-coupled receptors (GPCR), which includes the classic glycoprotein hormone receptors follicle-stimulating hormone receptor (FSHR), luteinizing hormone receptor (LHR), and thyroid-stimulating hormone receptor (...

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“…Behavioral studies have demonstrated an important role of relaxin-3 in food intake regulation [56][57][58][59] . Central administration ofrelaxin-3 strongly stimulated feeding in satiated rats.…”

Section: Role Of Relaxin-3 and Rxfp3 In Food Intake Regulationmentioning

confidence: 99%

The role of relaxin-3 and its receptor RXFP3 in defense of elevated body weight in diet-induced obesity

Lenglos

Calvez

Timofeeva

2014

Receptor Clin Invest

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Incidence of overweight and obesity has dramatically increased during the past three decades. Treatment of this serious clinical problem is hindered by the fact that once obesity has developed, the elevated body weight is defended against weight-decreasing treatment strategies by mechanisms that are not yet fully understood. This review focuses on the neuronal mechanisms that contribute to the maintenance of obesity after it development in the DIO rat model. Among the neuronal factors regulating energy intake, orexigenic neuropeptide relaxin-3 and its cognate receptor RXFP3 may play an important role in the defense of elevated body weight in DIO. The levels of expression of relaxin-3 mRNA in the brainstem nucleus incertus (NI) were significantly increased in thead libitum feeding state in DIO rats compared to DR rats. However, the effects of relaxin-3 in the DIO ad libitumfed rats may be compensated by a significant decrease in the levels of expression of RXFP3 mRNA in the food intake-regulating brain regions of DIO rats including the paraventricular hypothalamic nucleus (PVN), central amygdala (CeA), NI, and nucleus of the solitary tract (NTS). Remarkably, the DIO rats showed an immediate rebound in food intake at refeeding and regained all body weight lost during starvation. This significant increase in food intake during refeeding was accompanied by an increase in the levels of expression of RXFP3 in the parvocellular PVN, CeA, NI, and NTS in the DIO rats to the levels of the DR rats. Moreover, the expression of RXFP3 in the paraventricular thalamic nucleus was significantly higher in the refed DIO rats compared to the DR counterparts. A constitutive increase in the expression of relaxin-3 accompanied by a relative increase in the expression of RXFP3 in food intake-regulating brain regions during refeeding after food deprivation may contribute to the mechanisms of defense of elevated body weight in the DIO phenotype.

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Physiology and Molecular Biology of the Relaxin Peptide Family

Cited by 61 publications

References 732 publications

The A-chain of Human Relaxin Family Peptides Has Distinct Roles in the Binding and Activation of the Different Relaxin Family Peptide Receptors

The A-chain of Human Relaxin Family Peptides Has Distinct Roles in the Binding and Activation of the Different Relaxin Family Peptide Receptors

Prolonged RXFP1 and RXFP2 signaling can be explained by poor internalization and a lack of β-arrestin recruitment

The role of relaxin-3 and its receptor RXFP3 in defense of elevated body weight in diet-induced obesity

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