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

Hossain, Mohammed Akhter; Rosengren, K. Johan; Haugaard‐Jönsson, Linda M.; Zhang, Soude; Layfield, Sharon; Ferraro, Tania; Daly, Norelle L.; Tregear, Geoffrey W.; Wade, John D.; Bathgate, Ross A. D.

doi:10.1074/jbc.m801911200

Cited by 92 publications

(106 citation statements)

References 40 publications

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“…RXFP3 and RXFP4 are classic peptide receptors of the Rhodopsin family of class A GPCRs and possess small N-terminal domains that are markedly different from those described for RXFP1 and RXFP2. Additionally, the relaxin-3 B-chain alone can bind and activate RXFP3, although with lower potency than the two-chain peptide, whereas both chains are required for interaction with RXFP1 (Kuei et al, 2007;Hossain et al, 2008). Thus the mode of binding and activation differs from the relaxin/RXFP1 activation mechanism.…”

Section: B Structural Features Of Relaxin Family Peptide Receptorsmentioning

confidence: 95%

International Union of Basic and Clinical Pharmacology. XCV. Recent Advances in the Understanding of the Pharmacology and Biological Roles of Relaxin Family Peptide Receptors 1–4, the Receptors for Relaxin Family Peptides

Halls¹,

Bathgate²,

Sutton³

et al. 2015

Pharmacol Rev

117

118

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Section: B Structural Features Of Relaxin Family Peptide Receptorsmentioning

confidence: 95%

International Union of Basic and Clinical Pharmacology. XCV. Recent Advances in the Understanding of the Pharmacology and Biological Roles of Relaxin Family Peptide Receptors 1–4, the Receptors for Relaxin Family Peptides

Halls¹,

Bathgate²,

Sutton³

et al. 2015

Pharmacol Rev

117

118

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“…However, from these data it cannot be ruled out that the changes in activity are a result of the chimeras affecting the B-chain structure and that the various receptors differ in sensitivity to such changes. Indeed, we recently showed that a relaxin-3 with a truncated A-chain loses its well defined structure and also to a large extent the ability to interact with LGR7, but in contrast it retains full activity on GPCR135 (36). Thus the key question addressed in the current study was: how is the conformation of the relaxin-3 B-chain affected by the association with a new A-chain in such chimeras?…”

Section: Description Of the Structure And Comparison To Native Relaximentioning

confidence: 99%

Structure of the R3/I5 Chimeric Relaxin Peptide, a Selective GPCR135 and GPCR142 Agonist

Haugaard‐Jönsson¹,

Hossain

Daly

et al. 2008

Journal of Biological Chemistry

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The human relaxin family comprises seven peptide hormones with various biological functions mediated through interactions with G-protein-coupled receptors. Interestingly, among the hitherto characterized receptors there is no absolute selectivity toward their primary ligand. The most striking example of this is the relaxin family ancestor, relaxin-3, which is an agonist for three of the four currently known relaxin receptors: GPCR135, GPCR142, and LGR7. Relaxin-3 and its endogenous receptor GPCR135 are both expressed predominantly in the brain and have been linked to regulation of stress and feeding. However, to fully understand the role of relaxin-3 in neurological signaling, the development of selective GPCR135 agonists and antagonists for in vivo studies is crucial. Recent reports have demonstrated that such selective ligands can be achieved by making chimeric peptides comprising the relaxin-3 B-chain combined with the INSL5 A-chain. To obtain structural insights into the consequences of combining A-and B-chains from different relaxins we have determined the NMR solution structure of a human relaxin-3/INSL5 chimeric peptide. The structure reveals that the INSL5 A-chain adopts a conformation similar to the relaxin-3 A-chain, and thus has the ability to structurally support a native-like conformation of the relaxin-3 B-chain. These findings suggest that the decrease in activity at the LGR7 receptor seen for this peptide is a result of the removal of a secondary LGR7 binding site present in the relaxin-3 A-chain, rather than conformational changes in the primary B-chain receptor binding site.The human relaxin family of peptide hormones comprises seven members in humans, including relaxins 1-3 (1-3), and the insulin-like peptides INSLs 3-6 (4 -7). Relaxin-1 is the result of a gene duplication only present in higher primates and relaxin-2 is the human equivalent of "relaxin" in all other mammals. The relaxins are structurally related to insulin and, together with insulin and the insulin-like growth factors I and II, they make up the insulin/relaxin superfamily (Fig. 1). These peptides share the structural characteristics of two peptide chains, A and B, which comprise around 24 and 30 amino acids, respectively, and are cross-braced by three disulfide bonds (8). Despite being structural relatives of insulin and the insulin-like growth factors, which activate tyrosine kinase receptors, it was recently established that relaxins interact with G-protein-coupled receptors (GPCRs).3 To date four so-called relaxin family peptide receptors (RXFPs) have been characterized and identified as the endogenous receptors of relaxin, INSL3, relaxin-3, and INSL5, namely LGR7 (RXFP1) (9), LGR8 (RXFP2) (10), GPCR135 (RXFP3) (11), and GPCR142 (RXFP4) (12), respectively. Interestingly, despite these receptors interacting with similar ligands, GPCR135 and GPCR142 are of the classic peptide ligand receptor types, whereas LGR7 and LGR8 belong to an unrelated class, which is characterized by a large extracellular leucine-rich repeat containi...

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“…The RXFP3 antagonists R3(B1-22)R and R3(BΔ23-27)R/I5 were synthesized using solid-phase peptide synthesis and purified using reverse-phase HPLC (38,48,49). The identity and purity of the peptide was confirmed by reverse-phase HPLC and MALDI-TOF mass spectrometry.…”

Section: Methodsmentioning

confidence: 99%

Relaxin-3/RXFP3 system regulates alcohol-seeking

Ryan

Kastman

Krstew

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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114

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Relapse and hazardous drinking represent the most difficult clinical problems in treating patients with alcohol use disorders. Using a rat model of alcohol use and alcohol-seeking, we demonstrated that central administration of peptide antagonists for relaxin family peptide 3 receptor (RXFP3), the cognate receptor for the highly conserved neuropeptide, relaxin-3, decreased selfadministration of alcohol in a dose-related manner and attenuated cue-and stress-induced reinstatement following extinction. By comparison, RXFP3 antagonist treatment did not significantly attenuate self-administration or reinstatement of sucrose-seeking, suggesting a selective effect for alcohol. RXFP3 is densely expressed in the stress-responsive bed nucleus of the stria terminalis, and bilateral injections of RXFP3 antagonist into the bed nucleus of the stria terminalis significantly decreased self-administration and stress-induced reinstatement of alcohol, suggesting that this brain region may, at least in part, mediate the effects of RXFP3 antagonism. RXFP3 antagonist treatment had no effect on general ingestive behavior, activity, or procedural memory for lever pressing in the paradigms assessed. These data suggest that relaxin-3/ RXFP3 signaling regulates alcohol intake and relapse-like behavior, adding to current knowledge of the brain chemistry of rewardseeking. addiction | dependenceA lcohol abuse is a major cause of morbidity and mortality worldwide, accounting for an estimated 3.8% of all global deaths and 4.6% of the global burden of disease and injury (1). Excessive alcohol use may also lead to alcohol dependence (also termed "alcohol addiction") (2, 3), which has a lifetime prevalence of ∼12.5% (4). Economic costs due to alcohol abuse were in the order of $235 billion in the United States in 2007, or ∼2.7% of GDP (1, 5). Despite the huge impact of alcohol use disorders on society, current first-line therapeutic agents, such as naltrexone and acamprosate, are far from adequate, with high relapse rates during treatment and problems with compliance (6-8). New therapeutic agents are clearly required, particularly for the reduction of hazardous drinking and prevention of relapse (9). To this end, a major goal in addiction neuroscience is to understand the neurobiology and neurocircuitry affected by alcohol use disorders and to identify factors implicated in these conditions, which may lead to improved and more targeted therapies (7-10). Here we investigate the neuropeptide relaxin-3 for its involvement in rodent models of alcohol-seeking and consumption.Relaxin-3 is the highly conserved, ancestral neuropeptide of the relaxin/insulin superfamily, and its cognate G-protein-coupled receptor is relaxin family peptide 3 receptor (RXFP3) (11-16). Relaxin-3 is predominantly expressed in gamma-aminobutyric acid (GABA) neurons in the hindbrain nucleus incertus, which projects widely to forebrain areas, including the amygdala, bed nucleus of the stria terminalis (BNST), hippocampus, and lateral hypothalamus, which also express high levels ...

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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

Cited by 92 publications

References 40 publications

International Union of Basic and Clinical Pharmacology. XCV. Recent Advances in the Understanding of the Pharmacology and Biological Roles of Relaxin Family Peptide Receptors 1–4, the Receptors for Relaxin Family Peptides

International Union of Basic and Clinical Pharmacology. XCV. Recent Advances in the Understanding of the Pharmacology and Biological Roles of Relaxin Family Peptide Receptors 1–4, the Receptors for Relaxin Family Peptides

Structure of the R3/I5 Chimeric Relaxin Peptide, a Selective GPCR135 and GPCR142 Agonist

Relaxin-3/RXFP3 system regulates alcohol-seeking

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