A ghrelin receptor and oxytocin receptor heterocomplex impairs oxytocin mediated signalling
Abstract
Oxytocin mediates its behavioural effects via the centrally expressed oxytocin receptor (OTR). Oxytocin signalling has been implicated in multiple disorders involving centrally regulated pathways, including obesity, autism, schizophrenia and depression. The OTR has been described to have a complex downstream signalling pathway and an increased understanding of oxytocinergic signalling is needed for the development of novel and better treatments for centrally regulated disorders. The ghrelin receptor (GHSR), known primarily for its role in centrally regulated energy balance and food intake, has in more recent years also been shown to play a role in mood disorders, including anxiety and depression. Although there have been suggestions of crosstalk between both signalling systems, these have largely been unexplored to date. Here we show, to our knowledge for the first-time, compelling evidence for the formation of an OTR and GHSR heterocomplex, resulting in significant modulation of OTR downstream signalling. Co-localized expression of the OTR and GHSR is shown in a heterologous cellular expression system and in primary cultures of the hypothalamus and hippocampus. A physical interaction between the OTR and GHSR is confirmed using flow-cytometry based fluorescence resonance energy transfer (fcFRET). Interestingly, co-expression of the GHSR results in a significant attenuation of OTR-mediated Gαq signalling and changes in receptor trafficking within the cell. Together, these data demonstrate a potential functional relevance of an OTR/GHSR heterocomplex and its ability to alter OTR signalling, which is poised to have important implications for future therapeutic strategies, involving oxytocinergic signalling. This article is part of the Special Issue entitled 'Receptor heteromers and their allosteric receptor-receptor interactions'.
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Co-expression of the GHS-R1a and the OXTR significantly impairs oxytocin-mediated Gαq signaling.
“Notably, co-expression of the GHS-R1a and the OXTR was shown to significantly impair oxytocin-mediated Gαq signaling (Wallace Fitzsimons et al., 2019).”
From The oxytocin receptor represents a key hub in the GPCR heteroreceptor network: Potential relevance for brain and behavior (2022) · cites this paper as Wallace Fitzsimons et al., 2019
Formation of the GHS-R1a-OXTR heterocomplex leads to attenuation of oxytocin-induced calcium mobilization mediated via G alpha q signaling.
“Notably, the most significant finding was that the formation of the GHS-R1a-OXTR heterocomplex led to an attenuation of oxytocin-induced calcium mobilization mediated via G alpha q signaling.”
From The oxytocin receptor represents a key hub in the GPCR heteroreceptor network: Potential relevance for brain and behavior (2022) · cites this paper as Wallace Fitzsimons et al., 2019
The reduction of oxytocin-induced calcium mobilization by the GHS-R1a-OXTR heterocomplex was diminished upon administration of a GHS-R1a antagonist.
“This reduction was diminished upon administration of a GHS-R1a antagonist (Wallace Fitzsimons et al., 2019).”
From The oxytocin receptor represents a key hub in the GPCR heteroreceptor network: Potential relevance for brain and behavior (2022) · cites this paper as Wallace Fitzsimons et al., 2019
The novel GHS-R1a/OXTR pair was revealed using in vitro approaches and a novel flow cytometry-based fluorescence resonance energy transfer (fc-FRET) technique.
“The novel GHS-R1a/OXTR pair was revealed by the Schellekens group using in vitro approaches and a novel flow cytometry-based fluorescence resonance energy transfer (fc-FRET) technique (Wallace Fitzsimons et al., 2019).”
From The oxytocin receptor represents a key hub in the GPCR heteroreceptor network: Potential relevance for brain and behavior (2022) · cites this paper as Wallace Fitzsimons et al., 2019
Wallace Fitzsimons et al. (2019) showed increased trafficking of the OXTR/GHS-R1a pair following co-expression.
“Wallace Fitzsimons et al. (2019) showed increased trafficking of the OXTR/GHS-R1a pair following co-expression (Chruścicka et al., 2018).”
From The oxytocin receptor represents a key hub in the GPCR heteroreceptor network: Potential relevance for brain and behavior (2022) · cites this paper as Wallace Fitzsimons et al., 2019
Co-location of the GHS-R1a and OXTR protomers was observed in primary hippocampal and hypothalamic cultures of postnatal day 1 Sprague Dawley rats.
“Furthermore, co-location of the two receptor protomers was observed in primary hippocampal and hypothalamic cultures of postnatal day 1 (P1) Sprague Dawley rats.”
From The oxytocin receptor represents a key hub in the GPCR heteroreceptor network: Potential relevance for brain and behavior (2022) · cites this paper as Wallace Fitzsimons et al., 2019
GHSR, 5HT2AR and 5HT2CR dimerization with the OXTR results in attenuation of oxytocin-mediated downstream signaling.
“Both, GHSR, 5HT2AR and 5HT2CR dimerization with the OXTR have been shown to result in attenuation of oxytocin-mediated downstream signaling (Figure 2; Chruścicka et al., 2019, 2021; Wallace Fitzsimons et al., 2019; Borroto-Escuela et al., 2021).”
From The oxytocin receptor represents a key hub in the GPCR heteroreceptor network: Potential relevance for brain and behavior (2022) · cites this paper as Wallace Fitzsimons et al., 2019
In 2019, GHS-R1a-OXTR heteromerization was found for the first time.
“In 2019 the GHS-R1a-OXTR heteromerization was found for the first time (Wallace Fitzsimons et al., 2019).”
From The oxytocin receptor represents a key hub in the GPCR heteroreceptor network: Potential relevance for brain and behavior (2022) · cites this paper as Wallace Fitzsimons et al., 2019
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Detection and quantitative analysis of dynamic GPCRs interactions using flow cytometry-based FRET
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Neuroendocrine Peptides of the Gut and Their Role in the Regulation of Food Intake
Schalla, M. A., Taché, Y., & Stengel, A. (2021) · Comprehensive physiology · doi:10.1002/cphy.c200007 · Cited by 28 · see citing works
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- Authors
- Wallace Fitzsimons, S. E., Chruścicka, B., Druelle, C., Stamou, P., Nally, K., Dinan, T. G., Cryan, J. F., & Schellekens, H.
- Affiliations
- University College Cork (IE)
- Corresponding author
- Schellekens, Harriët
- Venue
- Neuropharmacology
- Publisher
- Elsevier BV
- Published
- 2019-07
- Volume
- 152
- Pages
- 90-101
- ISSN
- 0028-3908 (ISSN-L)
- OpenAlex
- W2905716623
- Cited by
- 49
- References
- 120
- Citations by year
- 2025: 4 · 2024: 7 · 2023: 1 · 2022: 9 · 2021: 18 · 2020: 4 · 2019: 6
- FWCI
- 9.50
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuropharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Science Foundation Ireland Research Centre (SFI/12/RC/2273)
- APC Microbiome Institute Ireland
- Topics
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- oxytocin receptor, growth hormone secretagogue receptor, receptor heteromers, receptor trafficking, hypothalamus, hippocampus, receptor cross-talk, depression, anxiety, mood disorders
- MeSH terms
- Humans, Oxytocin, Protein Binding, Receptors, Oxytocin, Receptor Cross-Talk, Ghrelin, Receptors, Ghrelin, HEK293 Cells
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