R3(BΔ23–27)R/I5 Chimeric Peptide, a Selective Antagonist for GPCR135 and GPCR142 over Relaxin Receptor LGR7

Kuei, Chester; Sutton, Steven W.; Bonaventure, Pascal; Pudiak, Cindy M.; Shelton, Jonathan; Zhu, Jessica; Nepomuceno, Diane; Wu, Jiejun; Chen, Jingcai; Kamme, Fredrik; Seierstad, Mark; Hack, Michael D.; Bathgate, Ross A. D.; Hossain, Mohammed Akhter; Wade, John D.; Atack, John; Lovenberg, Timothy W.; Liu, Changlu

doi:10.1074/jbc.m701416200

Cited by 143 publications

(288 citation statements)

References 40 publications

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“…RXFP3 antagonism produced no effect on food intake in rats following overnight restricted food access, suggesting no major impact of the relaxin-3/RXFP3 system on appetitive drive stimulated by the need for food in this paradigm. By comparison, in satiated rats, RXFP3 antagonism can prevent RXFP3 agonist-induced food intake (37,38), suggesting the relaxin-3/RXFP3 system may modulate the motivational or rewarding properties of food.…”

Section: Discussionmentioning

confidence: 99%

“…with 10 μg of a structurally different RXFP3 antagonist, R3(BΔ23-27)R/I5, (37) which also reduced self-administration of 10% (vol/vol) ethanol (repeated measures one-way ANOVA, effect of treatment on lever pressing for ethanol: F (2,32) = 18.73, P < 0.0001), but demonstrated no significant difference between groups in water lever responding (Fig. S1).…”

Section: Significancementioning

confidence: 99%

“…Receptor-binding affinity was assessed in competition binding assays using a single concentration of Europiumlabeled INSL5-A/H3 relaxin-B (0.5 nM), Europium-labeled H2 relaxin (1 nM), or Europium-labeled mouse INSL5 (2.5 nM) in the presence of increasing concentrations of H3 relaxin analogs in comparison with the native receptor ligands. Potency was assessed by measuring the influence on cAMP signaling using a cAMP reporter gene assay (37,38). The peptide content of batches used for i.c.v.…”

Section: Methodsmentioning

confidence: 99%

“…Because native relaxin-3 displays some pharmacological cross-reactivity with other relaxin family receptors, peptide ligands selective for RXFP3 have been developed and characterized (36)(37)(38). Central injection of a RXFP3-selective agonist increases food intake in rats, which is prevented by prior injection of a RXFP3-selective antagonist (37,38). Here, we demonstrate that the RXFP3-selective antagonists R3(B1-22)R and R3(BΔ23-27)R/I5 (37, 38) decrease alcohol intake and reinstatement behavior in rats.…”

Section: Addiction | Dependencementioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Addiction | Dependencementioning

confidence: 99%

See 2 more Smart Citations

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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“…The determinants for H3 relaxin activity on RXFP3 and RXFP4 are probably located in the B-chain alone, since synthetic S-reduced H3 relaxin B-chain is an RXFP3 and RXFP4 agonist (12,13). It has recently been demonstrated that key residues in the H3 relaxin B-chain are responsible for both binding affinity and cAMP-inhibitory activity (14). Further, a series of chimeric peptides that consist of the B-chain of H3 relaxin in combination with A-chains from other members of the relaxin family demonstrated that the A-chain from H1 relaxin, H2 relaxin, INSL3, and INSL6 does not change the pharmacological properties of the H3 relaxin B-chain significantly.…”

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 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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Localization of relaxin‐3 in brain of Macaca fascicularis: Identification of a nucleus incertus in primate

Sang

Lanciego

et al. 2009

J of Comparative Neurology

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Relaxin-3 (RLN3) is a highly conserved, ancestral member of the insulin/relaxin peptide family. RLN3 mRNA is highly expressed in rat, mouse, and human brain and molecular genetic and pharmacological studies suggest that RLN3 is the cognate ligand for the relaxin family peptide-3 receptor (RXFP3). The distribution of RLN3/RXFP3 networks has been determined in rat and mouse brain, but not in higher species. In this study we describe the distribution of RLN3 neurons in the brain of macaque (Macaca fascicularis) using in situ hybridization histochemistry and immunohistochemistry. RLN3 mRNA and high levels of RLN3-like immunoreactivity (-LI) were observed in neurons within a ventromedial region of the central gray of the pons and medulla that appears to represent the primate analog of the nucleus incertus (NI) described in lower species. Nerve fibers and terminals containing RLN3-LI were observed throughout brain regions identical to those known to receive afferents from the NI in the rat, including the septum, hippocampus, entorhinal cortex, lateral, dorsomedial and ventromedial hypothalamus, supramammillary and interpeduncular nuclei, anterodorsal, paraventricular and reuniens thalamic nuclei, lateral habenula, central gray, and dorsal raphe, solitary tract, and ambiguus nuclei. Experimental studies in the rat strongly implicate a role of this neuropeptide-receptor system in arousal, feeding, and metabolism, learning and memory, and central responses to psychological stressors. These new anatomical findings support the proposition that the RLN3 system is similarly involved in the integration and modulation of behavioral activation and arousal and responses to stress in nonhuman primates and humans.

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R3(BΔ23–27)R/I5 Chimeric Peptide, a Selective Antagonist for GPCR135 and GPCR142 over Relaxin Receptor LGR7

Cited by 143 publications

References 40 publications

Relaxin-3/RXFP3 system regulates alcohol-seeking

Relaxin-3/RXFP3 system regulates alcohol-seeking

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

Localization of relaxin‐3 in brain of Macaca fascicularis: Identification of a nucleus incertus in primate

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