RLN3/RXFP3 Signaling in the PVN Inhibits Magnocellular Neurons via M-like Current Activation and Contributes to Binge Eating Behavior

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Binge-eating disorder is the most common eating disorder. Various neuropeptides play important roles in the regulation of feeding behavior, including relaxin-3 (RLN3), which stimulates food intake in rats through the activation of the relaxin-family peptide-3 receptor (RXFP3). Here we demonstrate that a likely mechanism underlying the orexigenic action of RLN3 is RXFP3-mediated inhibition of oxytocin- and arginine-vasopressin-synthesizing paraventricular nucleus (PVN) magnocellular neurosecretory cells. Moreover, we reveal that, in male and female rats, this action depends on M-like potassium conductance. Notably, higher intra- and peri-PVN RLN3 fiber densities were observed in females, which may constitute an anatomic substrate for observed sex differences in binge-eating disorder. Finally, in a model of binge-eating in female rats, RXFP3 blockade within the PVN prevented binge-eating behavior. These data demonstrate a direct RLN3/RXFP3 action in the PVN of male and female rats, identify the associated ionic mechanisms, and reveal that hypothalamic RLN3/RXFP3 signaling regulates binge-eating behavior.

SIGNIFICANCE STATEMENT Binge-eating disorder is the most common eating disorder worldwide, affecting women twice as frequently as men. Various neuropeptides play important roles in the regulation of feeding behavior, including relaxin-3, which acts via the relaxin-family peptide-3 receptor (RXFP3). Using a model of binge-eating, we demonstrated that relaxin-3/RXFP3 signaling in the hypothalamic paraventricular nucleus (PVN) is necessary for the expression of binge-eating behavior in female rats. Moreover, we elucidated the neuronal mechanism of RLN3/RXFP3 signaling in PVN in male and female rats and characterized sex differences in the RLN3 innervation of the PVN. These findings increase our understanding of the brain circuits and neurotransmitters involved in binge-eating disorder pathology and identify RXFP3 as a therapeutic target for binge-like eating disorders.

Related collections

Most cited references 62

Record: found
Abstract: found
Article: not found

Pathways modulating neural KCNQ/M (Kv7) potassium channels.

Patrick Delmas, David A. Brown (2005)

K(+) channels play a crucial role in regulating the excitability of neurons. Many K(+) channels are, in turn, regulated by neurotransmitters. One of the first neurotransmitter-regulated channels to be identified, some 25 years ago, was the M channel. This was categorized as such because its activity was inhibited through stimulation of muscarinic acetylcholine receptors. M channels are now known to be composed of subunits of the Kv7 (KCNQ) K(+) channel family. However, until recently, the link between the receptors and the channels has remained elusive. Here, we summarize recent developments that have begun to clarify this link and discuss their implications for physiology and medicine.

0 comments Cited 185 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Vasopressin and oxytocin receptor systems in the brain: Sex differences and sex-specific regulation of social behavior.

Kelly Dumais, Alexa H. Veenema (2016)

The neuropeptides vasopressin (VP) and oxytocin (OT) and their receptors in the brain are involved in the regulation of various social behaviors and have emerged as drug targets for the treatment of social dysfunction in several sex-biased neuropsychiatric disorders. Sex differences in the VP and OT systems may therefore be implicated in sex-specific regulation of healthy as well as impaired social behaviors. We begin this review by highlighting the sex differences, or lack of sex differences, in VP and OT synthesis in the brain. We then discuss the evidence showing the presence or absence of sex differences in VP and OT receptors in rodents and humans, as well as showing new data of sexually dimorphic V1a receptor binding in the rat brain. Importantly, we find that there is lack of comprehensive analysis of sex differences in these systems in common laboratory species, and we find that, when sex differences are present, they are highly brain region- and species-specific. Interestingly, VP system parameters (VP and V1aR) are typically higher in males, while sex differences in the OT system are not always in the same direction, often showing higher OT expression in females, but higher OT receptor expression in males. Furthermore, VP and OT receptor systems show distinct and largely non-overlapping expression in the rodent brain, which may cause these receptors to have either complementary or opposing functional roles in the sex-specific regulation of social behavior. Though still in need of further research, we close by discussing how manipulations of the VP and OT systems have given important insights into the involvement of these neuropeptide systems in the sex-specific regulation of social behavior in rodents and humans.

0 comments Cited 154 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Relaxin family peptides and their receptors.

Katherine Kocan, R Bathgate, Tangi R. Summers … (2013)

There are seven relaxin family peptides that are all structurally related to insulin. Relaxin has many roles in female and male reproduction, as a neuropeptide in the central nervous system, as a vasodilator and cardiac stimulant in the cardiovascular system, and as an antifibrotic agent. Insulin-like peptide-3 (INSL3) has clearly defined specialist roles in male and female reproduction, relaxin-3 is primarily a neuropeptide involved in stress and metabolic control, and INSL5 is widely distributed particularly in the gastrointestinal tract. Although they are structurally related to insulin, the relaxin family peptides produce their physiological effects by activating a group of four G protein-coupled receptors (GPCRs), relaxin family peptide receptors 1-4 (RXFP1-4). Relaxin and INSL3 are the cognate ligands for RXFP1 and RXFP2, respectively, that are leucine-rich repeat containing GPCRs. RXFP1 activates a wide spectrum of signaling pathways to generate second messengers that include cAMP and nitric oxide, whereas RXFP2 activates a subset of these pathways. Relaxin-3 and INSL5 are the cognate ligands for RXFP3 and RXFP4 that are closely related to small peptide receptors that when activated inhibit cAMP production and activate MAP kinases. Although there are still many unanswered questions regarding the mode of action of relaxin family peptides, it is clear that they have important physiological roles that could be exploited for therapeutic benefit.

0 comments Cited 139 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Journal ID (nlm-ta): J Neurosci

Journal ID (iso-abbrev): J. Neurosci

Journal ID (hwp): jneuro

Journal ID (pmc): jneurosci

Journal ID (publisher-id): J. Neurosci

Title: The Journal of Neuroscience

Publisher: Society for Neuroscience

ISSN (Print): 0270-6474

ISSN (Electronic): 1529-2401

Publication date (Print): 8 July 2020

Publication date PMC-release: 8 July 2020

Volume: 40

Issue: 28

Pages: 5362-5375

Affiliations

[1] ¹Department of Neurophysiology and Chronobiology, Institute of Zoology and Biomedical Research, Faculty of Biology, Jagiellonian University, Krakow, 30-387, Poland

[2] ²Department of Physical Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, 30-387, Poland

[3] ³School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino, 62032, Italy

[4] ⁴Florey Institute of Neuroscience and Mental Health, and Florey Department of Neuroscience and Mental Health, University of Melbourne, Melbourne, 3010 Victoria, Australia

Author notes

Correspondence should be addressed to Anna Blasiak at anna.blasiak@ 123456uj.edu.pl

Author contributions: A.K., C.C., G.H., A.L.G., and A.B. designed research; A.K., A.S., P.S., A.G., E.B., and M.V.M.D.B. performed research; A.K., A.S., P.S., A.G., E.B., and M.V.M.D.B. analyzed data; A.K. and A.B. wrote the first draft of the paper; A.K., C.C., G.H., A.L.G., and A.B. edited the paper; M.A.H. and A.L.G. contributed unpublished reagents/analytic tools.

Author information

Alan Kania https://orcid.org/0000-0002-3823-6196

Agata Szlaga https://orcid.org/0000-0002-7380-7011

Patryk Sambak https://orcid.org/0000-0002-7457-2314

Anna Gugula https://orcid.org/0000-0003-0045-9025

Ewa Blasiak https://orcid.org/0000-0001-5936-064X

Maria Vittoria Micioni Di Bonaventura https://orcid.org/0000-0002-8044-1206

Andrew L. Gundlach https://orcid.org/0000-0002-6066-9692

Anna Blasiak https://orcid.org/0000-0002-4017-2988

Article

Publisher ID: JN-RM-2895-19

DOI: 10.1523/JNEUROSCI.2895-19.2020

PMC ID: 7343322

PubMed ID: 32532885

SO-VID: fcab9ab9-2c01-45a7-b682-0730fd44ba38

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License Creative Commons Attribution 4.0 International, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

History

Date received : 10 December 2019

Date revision received : 17 April 2020

Date accepted : 21 May 2020

Funding

Funded by: Ministry of Science and Higher Education Poland

Award ID: 0020/DIA/2014/43

Funded by: The National Science Centre Poland

Award ID: DEC-2012/05/D/NZ4/02984

Award ID: UMO-2016/21/B/NZ4/00204

Award ID: UMO-2017/24/T/NZ4/00225

Funded by: Institute of Zoology and Biomedical Research of the Jagiellonian University

Award ID: DS/MND/WBiNoZ/IZ/20/2016 - K/DSC/003960

Award ID: DS/MND/WBiNoZ/IZ/16/2017 - K/DSC/004650

Award ID: DS/MND/WB/IZ/9/2018 - K/DSC/005535

Funded by: http://doi.org/10.13039/501100000925Department of Health | National Health and Medical Research Council (NHMRC)

Award ID: 1122170

Award ID: 1067522

Funded by: Sir Edward ‘Weary’ Dunlop Research Fundation Mental Health Grant

Funded by: Italian Ministry of Education, University and Research

Award ID: PRIN2015KP7T2Y

Custom metadata

twij true

special-property cellular

Keywords: binge eating,m-like current,paraventricular nucleus of hypothalamus,relaxin-3,rxfp3

Data availability:

Keywords: binge eating, m-like current, paraventricular nucleus of hypothalamus, relaxin-3, rxfp3

RLN3/RXFP3 Signaling in the PVN Inhibits Magnocellular Neurons via M-like Current Activation and Contributes to Binge Eating Behavior

Read this article at

Abstract

Related collections

Neuronal Signaling

Most cited references 62

Pathways modulating neural KCNQ/M (Kv7) potassium channels.

Vasopressin and oxytocin receptor systems in the brain: Sex differences and sex-specific regulation of social behavior.

Relaxin family peptides and their receptors.

Author and article information

Journal

Affiliations

Author notes

Author information

Article

History

Funding

Categories

Custom metadata

Comments

Comment on this article

Similar content 206

Cited by 11

Most referenced authors 788