Relaxin-3 in GABA projection neurons of nucleus incertus suggests widespread influence on forebrain circuits via G-protein-coupled receptor-135 in the rat

Ma, Sherie; Bonaventure, Pascal; Ferraro, Tania; Shen, Peiyan; Burazin, Tanya C. D.; Bathgate, Ross A. D.; Liu, Changlu; Tregear, Geoffrey W.; Sutton, Steven W.; Gundlach, Andrew L.

doi:10.1016/j.neuroscience.2006.08.072

Cited by 185 publications

(398 citation statements)

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“…Relaxin-3 and its receptor GPCR135 are both predominantly expressed in the brain (11,14), in particular in regions dealing with sensory signals (15,16). This finding, together with recent in vivo studies that revealed that relaxin-3 is involved in stress responses (17) and in regulation of feeding (18), suggest a physiological role in neuroendocrine and sensory processing.…”

mentioning

confidence: 78%

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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confidence: 78%

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 BNST, which contains a high density of RXFP3 (19,21), has an established role in stress-induced reinstatement via a CRF-signaling pathway (41,43) and therefore was an obvious candidate region for targeted injections of R3(B1-22)R. Accordingly, intra-BNST injections of R3(B1-22)R produced a significant decrease in both alcohol selfadministration and stress (yohimbine)-induced reinstatement of alcohol-seeking. The attenuation of alcohol-seeking, rather than complete prevention, suggests other brain regions may also be involved.…”

Section: Discussionmentioning

confidence: 99%

“…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 of RXFP3 (11,15,(17)(18)(19)(20)(21)(22). This pattern of innervation, along with findings that relaxin-3 can modulate (i) food intake (23)(24)(25), (ii) responses to stress (20,26,27), (iii) arousal (28,29), and (iv) interactions with the corticotropin-releasing factor (CRF) systems (20,26), led us to hypothesize that relaxin-3 may modulate aspects of behavior related to substance use and abuse.…”

Section: Addiction | Dependencementioning

confidence: 99%

“…Although R3(B1-22)R was active in both cue-and stress-induced reinstatement paradigms of alcohol-seeking, the effect was more robust in the stress paradigm, and therefore we studied this aspect in further detail. Although there is considerable evidence that drugs of abuse interact with the mesocorticolimbic pathway, which comprises dopaminergic neurons in the ventral tegmental area and their projection targets in the nucleus accumbens (18), we considered it unlikely that the effects of RXFP3 antagonism were mediated directly via this pathway because RXFP3 expression is relatively low in these regions (19)(20)(21). In contrast, recent studies have suggested a role for the stress-responsive BNST in reinstatement of drug-and alcohol-seeking (41, 42) via a CRF-signaling mechanism (43); and in light of the dense innervation of BNST by relaxin-3 fibers (19), expression of RXFP3 in BNST (21,42), and the documented interactions between relaxin-3 and CRF systems (20,26), we targeted this nucleus for discrete microinjections of the RXFP3 antagonist.…”

Section: Rxfp3 Antagonism In the Bnst Decreases Self-administration Andmentioning

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.

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 largest population of relaxin-3 expressing neurons is located within the tegmental area known as the nucleus incertus (NI), and these neurons project broadly throughout the brain [15][16][17][18][19]. The neuroanatomy of the relaxin-3/RXFP3 system suggests a broad role as an ascending neuromodulatory network [20,21], akin to the monoamine systems including serotonin, and noradrenaline [22][23][24][25].…”

Section: Introductionmentioning

confidence: 99%

Central relaxin-3 receptor (RXFP3) activation reduces elevated, but not basal, anxiety-like behaviour in C57BL/6J mice

Zhang

Chua

Yang

et al. 2015

Behavioural Brain Research

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Relaxin-3 in GABA projection neurons of nucleus incertus suggests widespread influence on forebrain circuits via G-protein-coupled receptor-135 in the rat

Cited by 185 publications

References 70 publications

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

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

Relaxin-3/RXFP3 system regulates alcohol-seeking

Central relaxin-3 receptor (RXFP3) activation reduces elevated, but not basal, anxiety-like behaviour in C57BL/6J mice

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